Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Temperature: 0 °C

Procedure:
To a solution containing 25 g of the naphthol compound obtained in Step (1) above, 180 ml of acetonitrile and 35 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temmperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and was poured into 800 ml of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([N:17]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=NCc1ccccc1

Procedure:
A mixture of 5.0 mL of 2-hydroxy-benzaldehyde, 6.3 mL of benzylamine and 0.05 g of p-toluenesulphonic acid was refluxed in toluene for 2 hours using a Dean-Stark trap to remove liberated water. The volatiles were removed in vacuo yielding 10.1 g of crude 2-(benzylimino-methyl)-phenol.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:9]([O:11]N1C(=O)CCC1=O)=O)[CH:2]=[CH2:3].Cl.[CH3:27][NH:28][OH:29]>ClCCl>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:8]([C:9](=[O:11])[N:28]([OH:29])[CH3:27])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: CNO
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
Starting material (8(c)) was prepared as follows. A mixture of 7(b) (2.00 g; see Example 7), N-methylhydroxylamine hydrochloride (1.06 g) triethylamine (1.72 ml) and dichloromethane (60 ml.) was stirred at 5° or 30 minutes. It was then allowed to warm to ambient temperature and stirred for a further 16 hours. The reaction mixture was then poured directly onto a flash column eluting with ethyl acetate/hexane (50:50) to give 3-(N-methyl-hydroxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(a)) as a cream solid (1.43 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(OCC)(=O)C>[C:1]([NH:5][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C. with an ice bath. 4-nitrobenzoyl chloride (18.6 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours. The reaction mixture was then filtered on a Buchner funnel, the filtrate washed three times with 5% HCl , once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through fluted filter paper, and the solvent stripped off leaving white crystalline product. The product was dried in a vacuum oven at 24 mm and 45° C. for 14 hours. This procedure produced 17.13 g of crystals of N-tert-butyl-4-nitrobenzamide (CPI1020) (77% yield), mp 162°-163° C. Proton nuclear magnetic resonance (89.55 MHz in CDCl3) showed absorptions at 8.257 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 6.097 ppm (bs, 1H; N--H); 1.500 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C)C=O.C1C=CC=CC=1>[CH3:3][S:4]([NH:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])=[O:5]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A stirred suspension of sodium hydride (57% in mineral oil) (2.33 g., 0.055 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes, with methanesulfonamide (4.75 g., 0.055 mole). This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the reaction mixture is heated at 90° C. for 20 hours. The reaction is poured into ater (200 ml.), neutralized with hydrochloric acid and extracted with ethyl acetate (2 × 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The yield of ethyl 7-(methanesulfonamido)heptanoate is 7.1 g. (51%) boiling 165°-168°/0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[S:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: c1cc(OC[C@@H]2CO2)c2ccsc2c1
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CO
Product: O[C@H](COc1cccc2sccc12)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 50.3 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.069 g, 0.301 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]thiophene (0.062 g, 0.301 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the title compound as a white amorphous solid (0.066 g, 50%). FDMS m/e 436 (M++1). C26H26FNO2S.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Br-:27].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(Cl)Cl>[Br:27][CH:17]1[CH2:16][CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:19][C:18]1=[O:20]
Reactant: O=C1CCCCC(c2ccccc2)N1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)CCCC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 5.12 g (24.6 mmol) phosphorus pentachloride and 45 ml methylene chloride. To the stirring mixture cooled to 0° C. was added dropwise over 20 minutes, a solution of 4.65 g (24.6 mmol) 7-phenyl-hexahydroazepin-2-one and 3.98 ml (49.2 mmol) pyridine in 40 ml methylene chloride. To the stirring mixture at 0° C. was then added 9.25 g (24.6 mmol) phenyltrimethylammonium bromide tribromide. The reaction was then allowed to warm to room temperature and stirred for 3 hours. It was then evaporated, taken up in tetrahydrofuran, quenched with water, evaporated, and partitioned between water and methylene chloride. The organic layer was washed with water and saturated aqueous sodium bisulfite, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/hexane as eluent to afford the product as an oil, 4.0 g (61%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.[Cu]I.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>[OH:31][C@:27]([C:24]1[N:23]=[C:22]([CH3:21])[O:26][N:25]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(I)cc1-2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)n(C)c2C2CC3C2)no1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (160 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.8 mL). The solid was collected by filtration to furnish the title compound (80 mg, 0.20 mmol, 77%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.61-1.73 (m, 2H), 2.05 (s, 3H), 2.65 (s, 3H), 2.94 (q, J=8.62 Hz, 2H), 3.47 (td, J=7.25, 3.47 Hz, 1H), 3.57-3.70 (m, 2H), 4.01 (s, 3H), 5.57 (br. s., 1H), 7.02 (d, J=7.88 Hz, 1H), 7.17 (d, J=7.88 Hz, 1H), 7.70 (br. s., 1H), 8.51 (s, 1H); M+H=404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: NNC(=Nc1ccccc1Cl)c1ccncn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccncn4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (200 mg, 0.75 mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 150 mg (0.6 mmol) of N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)pyrimidine as a solid. Yield: 30 mg.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]3[C@@H:24]4[C@H:29]([CH2:30][CH2:31][C:22]=3[CH:21]=2)[NH:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([O:19][C:18]6[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:35][CH:34]=6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc(Oc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)c2ccc3[nH]cnc3c2)cc1
Yield: 72 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-8-(4-methoxy-phenoxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; LC (method 1): tR=3.16 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:19](=O)[CH3:20])[CH:18]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9]/[N:10]=[C:19](/[C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[OH:22])\[CH3:20])=[O:8]
Reactant: NNC(=O)c1cncc(Cl)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cncc(Cl)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 35.3 %

Procedure:
5-Chloronicotinohydrazide (30 mg, 0.175 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (29.8 mg, 0.175 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (20 mg). 1H NMR (400 MHz, acetone-d6): δ 9.06 (s, 1H), 8.77 (s, 1H), 8.37 (s, 1H), 7.62 (d, 1H, J=2.8 Hz), 7.31 (dd, 1H, J=2.0 & 8.4 Hz), 6.95 (d, 1H, J=8.8 Hz), 2.58 (s, 3H). ESI-MS: 324.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:23])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:10]([F:17])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[F:7])[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
Step J (1): A mixture of 4-chloro-1H-imidazole (1.18 g, 11.5 mmol), 1,2,3-trifluoro-5-nitrobenzene (1.7 g, 9.60 mmol) and potassium carbonate (1.86 g, 13.4 mmol) in DMF (10 mL) was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and was stirred for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 4-chloro-1-(2,6-difluoro-4-nitrophenyl)-1H-imidazole (2.0 g, 80% yield). LC-MS (M+H)+=260.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.03-8.10 (m, 2 H) 7.71 (q, J=1.83 Hz, 1 H) 7.19 (q, J=1.93 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][N:29]2[C:33](=[O:34])[N:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=3)[C:38]([O:40]C)=O)[CH:31]=[N:30]2)[CH2:27][CH2:26]1.C(N)C1C=CC=CC=1>>[CH2:6]([NH:7][C:38](=[O:40])[C:37]1[CH:42]=[CH:43][N:44]=[C:35]([N:32]2[C:33](=[O:34])[N:29]([CH2:28][CH:25]3[CH2:26][CH2:27]3)[N:30]=[CH:31]2)[CH:36]=1)[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccnc(-n2cnn(CC3CC3)c2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(-n2cnn(CC3CC3)c2=O)c1
Yield: 38 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate and with methyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate to react with benzylamine, N-benzyl-2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide was obtained as a colorless solid in 38% yield: mp 137-139° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.43 (s, 1H), 7.74-7.72 (m, 1H), 7.36-7.23 (m, 5H), 6.85 (br s, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.69 (d, J=6.9 Hz, 2H), 1.29-1.16 (m, 1H), 0.59-0.53 (m, 2H), 0.40-0.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.5, 151.2, 149.3, 147.9, 144.6, 137.3, 132.2, 128.9, 128.1, 127.9, 120.7, 109.3, 50.2, 44.4, 10.2, 3.6; MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:37][CH:38](Cl)[CH3:39]>>[Cl:37][C:38]1[O:15][N:14]=[C:13]([C:12]2[CH:17]=[CH:18][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:22][C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])=[CH:20][C:19]=3[Cl:29])=[CH:10][CH:11]=2)[CH:39]=1
Reactant: ON=C(Cl)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3cc(Cl)on3)cc2)c(Cl)c1
Reaction time: 1 h

Procedure:
150 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzimidoyl chloride are placed in 1 ml of 1,1-dichloroethane at 0° C., and a solution of 76 mg of triethylamine in 1 ml of 1,1-dichloroethane is added dropwise thereto over a period of one hour. After one hour at 0° C. and 18 hours at 25° C., the reaction mixture is poured onto water and extracted with ethyl acetate. Concentration and purification over silica gel yield the title compound (compound 1.17).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]4[CH:45]=[CH:44][S:43][CH:42]=4)[CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:20]=[CH:19][N:18]=1>CC(O)C.Cl.C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[C:10]([NH:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([C:23]3[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39](=[O:46])[CH2:40][C:41]5[CH:45]=[CH:44][S:43][CH:42]=5)[CH:33]=4)=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=34)[CH:20]=[CH:19][N:18]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Reactant: Nc1cccc(CNC(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (73 mg, 0.34 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide (120 mg, 0.27 mmol) in i-PrOH (4 mL) was acidified with 3 drops of 12 N HCl and stirred at 80° C. overnight. After 16 h, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 53% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.28 (s, 1H), 9.98 (t, 1H), 9.63 (s, 1H), 8.83 (d, J=6.9 Hz, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.24 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.47-7.49 (m, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.08-7.13 (m, 2H), 6.85 (d, J=7.7 Hz, 1H), 6.51 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 3.66 (s, 2H). ES-LC/MS m/z=628 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=O)[O:2]1.ClCC1C(CC#[N:22])=CC=CC=1>>[OH:2][CH2:1][C:10]1[C:5]([CH2:4][C:3]#[N:22])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1ccccc1CCl
Reactant: O=C1Cc2ccccc2CO1
Product: N#CCc1ccccc1CO
Yield: 1.6 %

Procedure:
After completion of the reaction, the concentration of 3-isochromanone was analyzed by GC analysis and then the yield of 3-isochromanone was calculated. As a result, the yield was found to be 95% based on α-chloro-α′-cyano-o-xylene. At this time, the conversion ratio of α-chloro-α′-cyano-o-xylene was 100% and the by-product compound (α-hydroxy-α′-cyano-o-xylene) where the halogen moiety was hydrolyzed was produced in a yield of 1.6%.
Reaction SMILES: Cl.[CH:2]1([C:5]([C:7]2([CH3:10])[CH2:9][CH2:8]2)=[NH:6])[CH2:4]C1.[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].[NH4+].[CH3:17]S(C)=O>>[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].[NH3+:6][CH:5]1[C:7]2[CH2:9][CH2:8][CH2:17][C:10]=2[CH2:4][CH2:2]1
Reactant: CC1(C(=N)C2CC2)CC1
Reactant: CS(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: [NH3+]C1CCC2=C1CCC2
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 1-cyclopropyl-1-(1-methylcyclopropyl)methanimine hydrochloride (0.060 g, 0.38 mmol) in 0.60 ml of dimethyl sulfoxide was added 0.088 g (0.75 mmol) of ammonium perchlorate. The mixture was heated with stirring at 100° C. for 20 hours. The solvent was distilled out in vacuo and ether was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.36 g (Yield: 43%) of the desired compound.