Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)#[N:4].Cl.[CH3:14][C:15]([CH3:17])=[O:16]>O>[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:7][CH:6]=1)#[N:4]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(C#N)cc1
Temperature: 14 °C
Reaction time: 8 h
Yield: 49.25 %

Procedure:
Water (150 ml) and 10% NaOH aqueous solution (4.5 ml) were added under vigorous stirring to a solution of 4-cyanobenzaldehyde (7.0 g, 80.6 mmol) in acetone (40 ml) and water(25 ml). The reaction mixture was stirred at 14° C. for 8 hr, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7-8.The precipitated separated solid was collected by filtration and dried, then recrystallized from anhydrous ethanol to give 4.8 g of crystals in needles, mp: 102-103° C., yield: 49.25%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:24])[CH:21]=[CH:22][CH3:23])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Solvent: C1CCOC1
Product: CC=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.2 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1985:3482) in 5 mL of tetrahydrofuran was added dropwise a solution of 0.105 g of crotonic acid chloride in 5 mL of tetrahydrofuran. When the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 15 hours. The reaction was filtered to remove the yellow solid which was washed with tetrahydrofuran and recrystallized from 20 mL of boiling methanol to afford 0.060 g of the desired product, mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=O)[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:4]1[N:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(Cl)c1-c1ccc(Cl)cc1
Product: Clc1ccc(-c2c(Cl)cnnc2Cl)cc1
Temperature: 100 °C
Yield: 96 %

Procedure:
A suspension of 5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one, (6.8 g, 28.2 mmol) in POCl3 (14 mL) was heated at 100° C. for 1 h. After this time, the reaction mixture was cooled to RT The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound, 3,5-dichloro-4-(4-chlorophenyl)pyridazine as an off-white solid (6.9 g, 96%). LC/MS (method A): RT=3.20 min, (M+H)+=259.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])([C:24]#[N:25])[CH:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:11]2([C:24]#[N:25])[CH:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[C:15]([Cl:23])[CH:14]=2)=[C:27]([F:33])[CH:28]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 83 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (1.2 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as solid (1.1 g, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-])=O.C(O)C.[H][H]>[Ni].O>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 60 °C
Yield: 75.2 %

Procedure:
56 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were introduced into an autoclave and then hydrogen under a pressure of 65 kg/cm2 was introduced while heating. The mixture was then agitated at 60° C. and treated with a solution of 50 ml of soda lye in 450 ml of water. The solution was filtered and treated with 50 ml of hydrochloric acid. The precipitate was dried off, washed with water and dried. 36.5 g of 7-amino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 220° C.; yield: 75%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:10]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[F:11])[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Fc1ccccc1CBr
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1CN(Cc1ccccc1F)c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2-fluorobenzylbromide (416 mg; 0.265 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.063 g (18.1%); MS m/z: 350.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.73 (s, 4H); 6.71-6.72 (m, 2H); 7.08-7.11 (m, 2H); 7.17-7.19 (m, 2H); 7.20-7.28 (m, 4H); 7.32 (d, 1H, 3J=9.4 Hz); 7.92 (s, 1H); 11.94 (br s, 1H); HPLC (METHOD [A]): rt 15.61 min (100%)
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].Cl>C(OCC)(=O)C>[C:39]([NH:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:4]2[N:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A mixture of the compound obtained in Example 40 (60 mg), pyridine (600 μL) and acetic anhydride (200 μL) was stirred at 100° C. for 3 days. After cooling to room temperature, to the reaction mixture was added an aqueous 1N HCl and ethyl acetate and the mixture was stirred. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on NH-silica gel (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent; hexane/ethyl acetate=90/10 to 50/50) to give 2-acetylamino-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (38.2 mg; yield: 58%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:16]1CCO[CH:17]1[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[S:29])[NH2:28])=[CH:23][CH:22]=1>CCO>[CH2:4]([C:3]1[N:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:17]=[O:16])=[CH:22][CH:23]=2)[S:29][CH:2]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(=O)CBr
Reactant: NC(=S)c1ccc(C2OCCO2)cc1
Solvent: CCO
Product: CCCCCCCCCCCc1csc(-c2ccc(C=O)cc2)n1
Yield: 58.9 %

Procedure:
A solution of 1-bromotridecan-2-one (5.54 g, 20 mmol) and 4-(1,3-dioxolan-2-yl)benzenecarbothioamide (4.19 g, 20 mmol) in EtOH (50 mL) was refluxed overnight. After evaporation of the solvent, the residue was taken up in ether, washed with water, brine, dried over MgSO4, filtered. The solvents were evaporated under vacuum to give a yellow oil. Purification on silicagel gave the title product as a yellow solid (4.05 g, 59%). 1H NMR (CDCl3, 300 MHz) δ 10.0 (s, 1H), 8.11 (d, 2H, J=8.3 Hz), 7.93 (d, 2H, J=8.6 Hz), 6.98 (s, 1H), 2.84 (t, 2H, J=7.2 Hz), 1.78-1.72 (m, 2H), 1.50-1.20 (m, 16H), 0.87 (t, 3H, J=6.8 Hz). M+(LC/MS(ESI)): 344.3
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.CN(C=O)C.[CH:11]1([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([O:23][CH2:24][CH3:25])[C:21]=2[OH:22])[CH:17]=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:11]1([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([O:23][CH2:24][CH3:25])[C:21]=2[O:22][CH2:2][CH:3]2[CH2:5][CH2:4]2)[CH:17]=[O:18])[CH2:12][CH2:13]1
Reactant: BrCC1CC1
Reactant: CCOc1cc(C=O)cc(C2CC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)cc(C2CC2)c1OCC1CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
(Bromomethyl)cyclopropane (0.781 mL) was added to a DMF (10 mL) suspension of 3-cyclopropyl-5-ethoxy-4-hydroxybenzaldehyde (830 mg) and potassium carbonate (1.11 g), and the mixture was stirred at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.03 g).
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=O)=[CH:14][C:13]=1[N+:30]([O-:32])=[O:31]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[CH2:1])=[CH:14][C:13]=1[N+:30]([O-:32])=[O:31]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a mixture of methyltriphenylphosphonium bromide (15.6 g, 44 mmol) in tetrahydrofuran (100 mL) at 0° C. was added a solution of sodium hexamethyldisilazide (22 mL, 2.0M solution in THF, 44 mmol), and the resulting mixture was stirred for one hour at 0° C. Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (7.0 g, 22 mmol) in tetrahydrofuran (50 mL) was then added drop wise to the yellow reaction mixture and stirred at 0° C. for 30 minutes and at room temperature for four hours. The brown reaction mixture was diluted with hexanes, filtered through silica gel, and the filtrate was washed with water (100 mL), brine solution (100 mL), dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography (silica gel, eluting with 5-10% ethyl acetate-hexane) to give methyl 2-[1-(4-chloro-3-nitrophenyl)ethenyl]benzoate (0.95 g, 3 mmol, 14% yield). 1H NMR (400 MHz, CDCl3): 7.95-7.93 (dd, 1H), 7.73-7.72 (d, 1H), 7.61-7.57 (dt, 1H), 7.50-7.46 (dt, 1H), 7.46-7.43 (d, 1H), 7.39-7.34 (m, 2H), 5.77 (s, 1H), 5.37 (s, 1H), 3.63 (s, 3H); MS (EI) for C16H12ClNO4: 318 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:18]=[CH:17][O:16][CH:15]=1)=[O:13].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[C:3]([C:12]([C:14]3[CH:18]=[CH:17][O:16][CH:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12
Product: CC(C)CC(=O)Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Ex. 19 from 3-amino-6-chloro-2-(3-furoyl)indole (Example 79) and isovaleryl chloride. m.p.: 202-203° C. (recrystallized from ethyl acetate) 1H-NMR (CDCl3) δ: 10.10 (1 H, br s), 8.28 (1 H, d, J=8.8 Hz), 8.23 (1 H, br s), 8.11 (1 H, dd, J=0.7, 1.5 Hz), 7.59 (1 H, dd, J=1.5, 1.8 Hz), 7.31 (1 H, d, J=1.8 Hz), 7.10 (1 H, dd, J=1.8, 8.8 Hz), 6.89 (1 H, dd, J=0.7, 1.8 Hz), 2.39-2.22 (3 H, m), 1.06 (6 H, d, J=6.6 Hz).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH3:16])[CH:10]=2)[O:6][C:5]1=[O:17])[CH:2]=[CH2:3].[OH-:18].[K+].Cl>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:7]([OH:6])[CH2:8][C@H:4]([CH2:1][CH:2]=[CH2:3])[C:5]([OH:17])=[O:18])=[CH:10][C:11]=1[CH3:16]
Reactant: [OH-]
Reactant: C=CC[C@H]1C[C@H](c2ccc(F)c(C)c2)OC1=O
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: C=CC[C@@H](C[C@@H](O)c1ccc(F)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 150 mg (3S,5R)-3-allyl-5-(4-fluoro-3-methylphenyl)dihydrofuran-2(3H)-one in 5 mL dioxane was added 5 mL aq. 5% KOH at 25° C. The mixture was stirred for 30 min at 25° C. then hydrolyzed with 10 mL of 1M HCl. The resulting mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were then extracted with 5 mL 5% K2CO3 three times and the combined aqueous layers acidified with 1M HCl to pH3. The resulting mixture was extracted with ethyl acetate (3×30 mL), the combined organic layers washed with brine (2×20 mL) before being concentrated under reduced pressure. The crude product residue was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:2][NH:1][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:18])=[CH:4][CH:5]=1
Reactant: NCc1ccc(CO)cc1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(CO)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Using General Procedure F: To a stirred solution of 4-aminomethylbenzyl alcohol (203 mg, 1.48 mmol) in DMF (3 mL) was added picolinic acid (198 mg, 1.61 mmol), 1-hydroxybenzotriazole (213 mg, 1.58 mmol), N,N-diisopropylethylamine (0.39 mL, 2.24 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (315 mg, 1.64 mmol) and the mixture stirred overnight at room temperature. Standard work-up afforded the title compound (340 mg, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.67 (d, 2H, J=6.0 Hz), 4.69 (s, 2H), 7.36 (br s, 4H), 7.43-7.44 (m, 1H), 7.85-7.86 (m, 1H), 8.24 (d, 1H, J=9.0 Hz), 8.52 (br s, 1H), 8.52 (d, 1H, J=3.0 Hz). ES-MS m/z 243 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:39]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[O:40])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.147 mmol) in CH2Cl2 (2 mL), the solution made in Step 1 of 4-methylpiperazine-1-carbonyl chloride (62 mg, 0.163 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction was then partitioned between EtOAc (50 mL) and 10% aqueous potassium carbonate. (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated under vacuum. The residue was triturated with ether to yield 16 mg (20%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (s, 1 H), 7.78 (d 1 H), 7.58 (s, 1 H), 7.33 (m, 5 H), 7.13 (d, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.90 (m, 1 H), 3.60-3.30 (m, 8 H), 2.50-2.00 (m, 9 H); ES-MS m/z 536.3 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])[CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 97 was prepared from tri phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 2H, J=10.4 Hz), 7.34–7.21 (m, 17H), 6.90 (d, 1H, J=7.6 Hz), 6.31 (t, 1H, J=5.2 Hz), 3.43 (dd, 2H, J=6.4, 12.4 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.41 (m, 1H), 2.31 (m, 4H), 1.92 (t, 2H, J=11.6 Hz), 1.79–1.66 (m, 6H), 1.59–1.52 (m, 2H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 574.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15].Cl.[CH3:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14](=[NH:15])[O:21][CH3:20]
Reactant: CO
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Product: COC(=N)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
Following the procedure described in Example 6, 2 -(2-chloro-4-trifluoromethylphenylamino)-3-methylbutyronitrile is reacted with methanol and hydrogen chloride to give methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate, which is then reacted with 3-phenoxybenzyl alcohol, yielding the desired compound 3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:12][CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:22]=[O:23]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:13]([S:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCSc1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1ccnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 6-bromo-4-ethylsulfanyl-quinoline (1.48 g, 5.5 mmol) in THF (60 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (2.42 mL, 6.07 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned into a dark brown and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.848 mL, 11 mmol) in THF (5 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the yellow solid which was dissolved in ethyl acetate (−10 mL) at hot condition and diluted with hexanes (−20 mL). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with 10% ethyl acetate in hexanes. After drying in air, 0.614 g (51% yield) of 4-ethylsulfanyl-quinoline-6-carbaldehyde was isolated as a yellow solid: EI-HRMS m/e calcd for C12H11NOS (M+) 217.0561, found 217.0554.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cncc(-c3nc(-c4ccccn4)no3)c2)cc1
Yield: 30 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol) and Pd(PPh3)4 (57.8 mg, 0.05 mmol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 ml) was heated overnight at 105° C. Standard work up afforded 45 mg of 3-(2-pyridyl)-5-(5-phenyl-pyrid-3-yl)-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:19]=[C:16]([C:17]3[N:32]=[N:33][NH:34][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: N#Cc1cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)nc(Nc2nccs2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(-c3nn[nH]n3)cc(Nc3nccs3)n2)CC1
Temperature: 110 °C
Reaction time: 13 h

Procedure:
A mixture of 25.2 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-(thiazol-2-ylamino)isonicotinonitrile obtained in Example 104, 17.9 mg of sodium azide, 38.0 mg of triethylamine hydrochloride and 2 ml of N,N-dimethylformamide was stirred at 110° C. for 13 hours, and then the reaction solution was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=5/1) to give the title compound.