Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([CH:15]1CCC(=O)C[CH2:16]1)[CH2:11][CH2:12]CC.Cl.[OH2:23]>O1CCCC1>[CH:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[F:1][CH:2]1[C:7]([F:8])([CH2:12][CH2:11][CH2:10][CH2:15][CH3:16])[CH2:6][CH2:5][CH:4]([OH:23])[CH2:3]1
Reactant: Fc1ccc(Br)cc1F
Reactant: O
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1(F)CCC(O)CC1F
Product: c1ccccc1
Temperature: 10 °C

Procedure:
Mg (12.4 g, 0.510 g atom) was added to a solution of 3,4-difluorobromobenzene (97.8 g, 0.507 mol) dissolved in dried tetrahydrofuran (100 ml), followed by reacting the mixture while keeping it at 40° C. in nitrogen current for 2 hours, and then cooling down to 10° C. to obtain a reaction fluid 1. Into this reaction fluid 1 was poured a solution of 4-pentylcyclohexanone (85.8 g, 0.510 mol) dissolved in dried tetrahydrofuran (100 ml) at such a rate that the fluid temperature might not exceed 40° C., followed by reacting the mixture while keeping it at 50° C. for 2 hours, cooling down to room temperature to obtain a reaction fluid 2. To this reaction fluid 2 were added 6N-hydrochloric acid (50 ml) and water (200 ml), followed by extracting the deposited oily substance with n-heptane (200 ml), washing the extraction fluid with water till the washing water became neutral, and distilling off n-heptane to obtain an oily substance 1 corresponding to 3,4-difluoro-(4-pentylcyclohexane-1-ol) benzene. To this oily substance 1 was added potassium hydrogen surface (20 g), followed by keeping the mixture in nitrogen current at 180° C. for 2 hours to effect dehydration reaction, cooling down to room temperature, adding water (200 ml) and n-heptane (200 ml), separating the n-heptane layer, washing it with water till the washing water became neutral, and distilling off n-heptane to obtain an oily substance 2 corresponding to 3,4-difluoro-(4-pentylcyclohexane-1-yl) benzene. This oily substance 2 was dissolved in ethyl alcohol (100 ml), followed by adding a Raney Ni (6.0 g), carrying out a catalytic reduction reaction at 25° C. under the atmospheric pressure till absorption of hydrogen ceased, filtering off the Raney Ni, distilling off ethyl alcohol from the filtrate, distilling the remaining oily substance under reduced pressure to obtain a fraction having a b.p. of 115° C./2 mm Hg, which was then recrystallized from ethyl alcohol (100 ml) to obtain the objective trans-4-pentyl-(3,4-difluorophenyl) cyclohexane (23.8 g, 0.089 mol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[N:16]1([CH:22]=[C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:16]1([CH:22]=[C:23]2[S:27][C:26](=[O:28])[N:25]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[C:24]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1NC(=O)C(=CN2CCCCC2)S1
Reactant: ClCCCCSc1cccc2nccn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1SC(=CN2CCCCC2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 241 mg (1.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 212 mg (1.0 mmol) of 5-(piperidin-1-yl)methylene-thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 3 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 330 mg (79.2%, white powder) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH3:32])[CH:34]=[CH:35]2)(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cn1ccc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-indole-5-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(Br)cc12
Yield: 64.6 %

Procedure:
To a stirred solution of 5-bromoindole-3-acetic acid (1.9 g., 7.48 mmol., 1 eq.) in dry THF (17 mL.) at 0° C. was added lithium aluminum hydride (570 mg. 14.96 mmol., 2 eq.) portionwise over 30 minutes. The reaction mixture coagulated. THF (20 mL.) was added and the cooling bath was removed. The mixture was stirred vigorously. Let stir overnight. The reaction mixture was carefully quenched with 1N aqueous HCl and then acidified with 2N aqueous HCl. The mixture was filtered through Celite™ and the Celite™ was washed with THF. The filtrate was concentrated in vacuo, dissolved in EtOAc, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. TLC analysis of the residue showed unreacted starting material. The residue was dissolved in Et2O and extracted with 0.25N aqueous NaOH. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo giving 1.16 g 5-bromo-3-hydroxyethylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:33])[C@@H:9]([NH:18][C:19]([C:21]1([CH3:32])[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1)=[O:20])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:33])[C@@H:9]([NH:18][C:19]([C:21]1([CH3:32])[O:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22]1)=[O:20])[CH2:10][C:11]([OH:13])=[O:12])=[O:5]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)C1(C)CC(c2ccccc2)=NO1)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)N[C@@H](CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)CC(c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound prepared in Example 1 (44 mg) was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (1 ml) was added at 0□. The mixture was stirred for two hours while it was slowly warmed to room temperature, and then concentrated under reduced pressure to give the title compound (Iaa) in a stoichiometric amount.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1.[H-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-chloromethylbenzoic acid as described for compound 78 using 12 mmol of sodium hydride instead of 6 mmol. After evaporating the reaction mixture, the residue was partitioned between aqueous sodium carbonate and ethyl acetate. The aqueous solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The compound was purified by chromatography (ethyl acetate) and crystallized from diethyl ether. M.p. 135°-139° C.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:21][CH2:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1.CCOC(C)=O>C1COCC1.CCCCCC>[CH3:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([CH2:21][CH2:22][CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c1-c1ccccc1C2
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc2c1-c1ccccc1C2CCC1OCCO1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of BuLi (2.5 M in hexane, 20.4 mL, 51.0 mmol) was slowly added into a cooled (-78° C.) solution of 4-methylfluorene (prepared according to Example 10; 9.0 g, 49.8 mmol) in 100 mL of THF. After 30 minutes 2-(2-bromoethyl)-1,3-dioxolane (18.9 g, 105.0 mmol) was added to the cold solution and the solution was warmed up to room temperature. The reaction mixture was stirred for weekend at room temperature. TLC (silica, 25% EtOAc in hexane) was used to monitor the reaction. The reaction was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water (×3), dried over magnesium sulfate and evaporated. Short path chromatography (5% ethyl acetate/hexane) afforded 11.2 g(82.8%) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CC(N(C)C)=O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][C:12]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[O:30])=[CH:13][CH:14]=2)=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Temperature: 100 °C

Procedure:
Into a 300 ml. pressure-vessel of stainless steel equipped with a magnetic stirrer, a thermometer, and a hydrogen inlet tube, were placed 145 ml. of dimethylacetamide, 18 grs. of N,N'-bis(4-nitrophenyl)terephthalamide prepared in Procedure (b-ii) above, and 2 grs. of Raney nickel. While stirring the contents of the vessel, the temperature was slowly raised to 100° C. Hydrogen gas of about 600 psi was introduced to the bottom of the vessel via the hydrogen inlet tube. The above hydrogen pressure and reaction temperature were maintained for about 5 to 6 hours, so that the hydrogenation reaction could be completed. The reaction product was filtered at 100° C. to separate the Raney nickel catalyst therefrom, and cooled down to 5° C. The resulting yellowish precipitate was collected by filtration and recrystallized from the dimethylacetamide solvent to afford the titled compound in the form of beautiful needle-shaped pale yellow crystals. Yield: 15.32 grs. (97.7% of theoretical value); m.p.: 300° C. (dec.). The IR spectrum showed carbonyl absorption at 1,660 cm-1, and an amide stretch at 3,300 cm-1 (asym); 3,325 cm-1 (sym). For the NMR analysis of the compound, deuterated dimethylsulfoxide solvent was used. The chemical shift of each portion in the NMR spectra was found to be as follows:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1(C)C=CC=CC=1>[C:33]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)(=[O:35])[CH3:34]
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g. 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred mixture of the indazole (4.15 g. 0.012 moles) and triethylamine (3.35 ml. 0.024 moles) in toluene (50 ml) was added acetyl chloride (0.93 ml, 0.013 moles). The reaction was stirred at ambient temperature for 2 hours and then poured into H2O. The product was extracted (CHCl3), dried (MgSO4), and concentrated to yield 4.3 g of an oil. The product was triturated with hexane and then recrystallized from CCl4 -hexane twice to yield 2.80 g of product. The product was further purified using high pressure liquid chromatography (silica gel, ethyl acetate) to yield 2.1 g (45%) of 1-acetyl-4-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[S:22]([NH2:25])(=[O:24])=[O:23])[NH2:18]>>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([NH:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][C:21]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CNc1cc(C(=O)O)ccc1OC
Reactant: Nc1ccc(S(N)(=O)=O)c(F)c1
Product: CNc1cc(C(=O)Nc2ccc(S(N)(=O)=O)c(F)c2)ccc1OC
Yield: 52 %

Procedure:
Using 3-methylamino-4-methoxybenzoic acid and 3-fluoro-4-aminosulfonylaniline as materials, compound 98 is synthesized following a similar method as in Example 28. Yield: 52%.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][CH:27]=[C:28]([CH2:30][CH3:31])[N:29]=4)=[CH:21][C:20]=3[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O[Li].O>C1COCC1.O>[CH2:30]([C:28]1[N:29]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[CH:7]4)=[C:20]([CH2:32][CH2:33][CH3:34])[CH:21]=2)[S:26][CH:27]=1)[CH3:31]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of methyl(5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)acetate (Example 53, 89 mg, 0.18 mmol) in 3.0 mL THF, was added LiOH.H2O (30 mg, 0.72 mmol) in water (1.0 mL). The mixture was stirred for 12 h at rt. The solvents were evaporated and the residue was suspended in a small volume of water. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated to give 65 mg (75%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H), 7.35 (dd, 1H), 7.10-7.05 (m, 2H), 7.08 (d, 1H), 6.90 (dd, 1H), 6.78 (s, 1H), 6.45 (d, 1H), 6.35 (d, 1H), 4.85 (s, 2H), 4.34 (t, 2H), 4.26 (t, 2H), 2.92 (q, 2H), 2.55-2.45 (m, 2H), 2.25-2.15 (m, 2H), 1.62-1.50 (m, 2H), 1.35 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[N:9]=[CH:8]1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1OB(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:7]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[N:9]=[CH:8]1
Reactant: OB(O)Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]cn2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3F)cn2)CC1
Reaction time: 72 h

Procedure:
Copper acetate (35 mg) and pyridine (0.02 ml) were added to a solution of 2 mg of the compound prepared in the above 3), i.e. tert-butyl 4-(1H-imidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate and 35 mg of 2-fluorophenylboric acid in dichloromethane and the solution was stirred for three days. The solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/2) to give 2.48 mg of the title compound as a white solid.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[NH2:18][C@@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[C:35]([N:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:41]([CH2:50][C:51](O)=[O:52])[C:40](=[O:54])[CH:39]1[CH:55]([CH3:57])[CH3:56])(=[O:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:35]([N:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:41]([CH2:50][C:51]([NH:18][C@@H:19]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:52])[C:40](=[O:54])[CH:39]1[CH:55]([CH3:57])[CH3:56])(=[O:37])[CH3:36]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C(=O)OC(C)C)C(=O)C1C(C)C
Reaction time: 8 h

Procedure:
N-Methylmorpholine (67 μl), 1-hydroxybenzotriazole (103 mg) and isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (144 mg, Reference compound No. 4-1) are added to a solution of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (160 mg, Reference compound No. 51-1) in methylene chloride (5 ml). The mixture is cooled with ice, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg) is added to the mixture, and the whole is stirred overnight. Ethyl acetate is added to the reaction mixture, the whole is washed with a 0.1 N aqueous sodium hydroxide solution, saturated brine, 0.1 N hydrochloric acid and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (259 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:19][C:20]([C:22]2[N:26]3[CH:27]=[CH:28][C:29](F)=[CH:30][C:25]3=[N:24][CH:23]=2)=[O:21])[N:12]([CH2:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=2)[N:11]=1)[CH3:9]>C1OCCOC1.CN(C)C=O>[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:19][C:20]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[CH:30][C:25]3=[N:24][CH:23]=2)=[O:21])[N:12]([CH2:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=2)[N:11]=1)[CH3:9]
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(-n5cncn5)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-1,2,4-triazole was dissolved in 4-dioxane and treated with sodium hydride (20 mg, 0.48 mmol, 60% dispersion in mineral oil) with stirring at ambient temperature for 30 minutes. N-(3-Ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) was added as a solution in N,N-dimethylformamide. The mixture was heated to 98° C. and stirred for 2 days. The mixture was quenched by the addition of water. A precipitate formed and the solid was isolated by filtration, washed with water and dried under vacuum to give N-(3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (39 mg). MS m/z 481.1 (M+1, APCI+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.NC1C=CC=CC=1.[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:43]1[S:47][N:46]=[C:45]([CH3:48])[N:44]=1)[C:40](O)=[O:41])#[N:33].C(N(CC)CC)C>ClCCl>[C:12]1([NH:8][C:40](=[O:41])[CH:39]([C:43]2[S:47][N:46]=[C:45]([CH3:48])[N:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:32]#[N:33])[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)O)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred mixture of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.63 g, 1.64 mmol) and aniline (0.14 g, 1.5 mmol) in dichloromethane (10 mL) was added over 5 min the crude solution of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid (2021052) and triethylamine. The resultant reaction mixture was then stirred at room temperature overnight before being quenched with citric acid (5 g) in water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1 hexane/ethyl acetate followed by 1:1 hexane/ethyl acetate) to afford 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (440 mg, 73% over two steps) as a yellow oil.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH2:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium hydride (60%, 6.3 g, 156.96 mmol) was added to anhydrous tetrahydrofuran (200 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl malonate (23.8 ml, 156.95 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. After cooling to 0° C., 8-bromo-1-octene (20 g, 104.64 mmol) was slowly added to the reaction mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(7-octenyl)malonate (16 g, Yield 56.56%) as a colorless oil.