Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C(N(CC)CC)C>[Cl:8][C:3]1[C:2]([N:1]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:29])[CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: CN(C)CCCNc1ccccc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1C(=Nc1cccnc1Cl)c1ccccc1

Procedure:
To a mixture of 2.82 g (0.01 mole) of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) of triethylamine and 20 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hr. The mixture was filtered to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution. The aqueous layer having a pH of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g of semi-solid product. TLC of the product showed it contained evey little starting 3-amino-2-chloropyridine. Mass Spec. analysis showed the presence of compounds with molecular weight corresponding to title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. 1HNMR spectrum in CDCl3 containing 1% TMS indicated the product was mostly title compound and some triethylamine. No 3-amino-2-chloropyridine was seen. The chemical shifts, multiplicities and assignments are given below. ##STR52##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][O:10][CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:14]([OH:15])=[CH:13][C:12]=2[CH2:11][O:10][CH3:9])[N:3]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1cccc(N)n1
Solvent: CC(=O)O
Product: COCc1cc(O)nc2nc(N)ccc12
Yield: 19.5 %

Procedure:
A mixture of 21.8 g (0.2 mol) of 2,6-diaminopyridine and 29.2 g (0.2 mol) of methyl 4-methoxyacetoacetate in 400 ml of glacial acetic acid is stirred under reflux for 3 hours. After cooling, the precipitate is suction filtered and stirred with 150 ml of cold ethanol. 8 g (20%) of the title compound is obtained; m.p.: >290° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[Mg].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+]>CCOCC>[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:1]([CH2:2][CH3:3])([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 37.5 g. of propiophenone in 200 ml. of dry ether is added dropwise to a -10° C. Grignard solution prepared from 13.6 g. of magnesium turnings and 126 g. of 3-trifluoromethyl-bromobenzene in 182 ml. of dry ether. The reaction mixture is stirred at 0° C. for 30 minutes, thereafter refluxed for 1 hour. The mixture is cooled to 0° C., and the Grignard complex is decomposed with a 10% aqueous ammonium chloride solution. The etheral phase is separated, washed until neutral, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the residual oil is subjected to fractional distillation in vacuo. This way 57.3 g. of 3-trifluoromethyl-α-ethyl-benzhydrol are obtained; b.p.: 106°-108° C./0.03 mmHg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].C1(C2C=CC=CC=2)C=CC(S([Cl:19])(=O)=O)=CC=1>>[Cl:19][C:5]1[S:1][C:2]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1cccs1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(Cl)s1

Procedure:
5.2.4 5-chlorothiophene-2-sulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 932.5 mg (94.4%) as a white solid, m.p.: 110-112° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:5]=[C:4]([C:20]([OH:22])=[O:21])[CH:3]=1.[C:23]1([C@@H](N)C)C=CC=CC=1>C(OCC)(=O)C>[CH3:23][O:21][C:20]([C:4]1[CH:3]=[C:2]([Cl:1])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([OH:19])([C:15]([F:17])([F:18])[F:16])[C:6]=2[CH:5]=1)=[O:22]
Reactant: O=C(O)c1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g) and isopropyl ether (0.250 ml) was added (S)-(−)-1-phenylethylamine (0.020 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered to give a solid (0.060 g). The solid was added as a seed crystal to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g), (S)-(−)-1-phenylethylamine (0.020 ml) and ethyl acetate (0.250 ml), which had been stirred overnight at room temperature in advance, and the mixture was further stirred at room temperature overnight. The resulting suspension was filtered, and the obtained solid was washed with ethyl acetate. The solid was dried under reduced pressure to give the title compound (0.019 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[CH:11]([NH:13][NH2:14])=[O:12]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:14][NH:13][CH:11]=[O:12])[CH3:2]
Reactant: CC(=O)c1ccncc1Cl
Reactant: NNC=O
Solvent: CCO
Product: CC(=NNC=O)c1ccncc1Cl

Procedure:
A mixture of 6.30 gm (0.0405 mole) of 4-acetyl-3-chloropyridine, 2.46 gm (0.041 mole) of formic acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer to give a solid which was collected in two crops. The product was purified by chromotography [keiselgel 60 (230-400 mesh)] and eluting with 5% methanol/methylene chloride to give 2.56 gm (32%) of white flakes which have a melting point of 175.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: NNc1ccccc1
Product: Cc1ccn(-c2cccc(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-chlorophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+ : calc. 467.094465; found 467.091517.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[O-]CC.[Na+].[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=O)[C:22](=[CH:25][C:26]=1[O:27][CH3:28])[CH:23]=O>C(O)C>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([CH:23]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:29]2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOC(=O)CC[N+](=O)[O-]
Reactant: COc1cc(C=O)c(C=O)cc1OCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 2.43 g of ethyl 3-nitropropionate in 15 ml of absolute ethanol cooled using an ice bath, is added 20 mL of 1 N sodium ethoxide in ethanol dropwise over 10 minutes keeping the temperature at 0–5° C. A slurry of 4-(2-chloroethoxy)-5-methoxyphthalaldehyde in 5 mL of ethanol is added. The ice bath is removed and the reaction allowed to warm to room temperature and stirred for 16 hours. The reaction is transferred to a beaker with 300 mL of water and neutralized with acetic acid to pH 4. The solid is collected and washed first with water, then with 40 mL of cold ethanol. The solid is dried to provide 2.48 g (70%) of ethyl 7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and ethyl 6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate (1:1 mixture) as a yellow solid, m.p. 119–29° C. dec.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (26.5 g, 142 mmol) in acetone (300 ml) at room temperature was treated with 3-bromo-propan-1-ol (14.5 ml, 156.2 mmol), potassium carbonate (50 g, 361.8 mmol) and potassium iodide (2.4 g, 14.2 mmol), and the mixture was heated at reflux for 18 h then allowed to cool to room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (27.7 g, 80%).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:23]I.[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[N:27]1.ClCCl>C(#N)C>[CH3:25][N:26]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]([I:23])[C:28]([C:34]([F:39])([F:40])[C:35]([F:37])([F:36])[F:38])=[N:27]1
Reactant: II
Reactant: Cn1nc(C(F)(F)C(F)(F)F)cc1C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC#N
Product: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)O

Procedure:
1.34 g (2.46 mmol) of ammonium cerium(IV) nitrate and then 0.75 g (2.95 mmol) of iodine are added to a solution of 1.20 g (4.91 mmol) of 1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid in 4.3 ml of acetonitrile and the reaction mixture is heated under reflux for 18 hours. After adding 20 ml of dichloromethane, washing is carried out firstly with water, with sodium disulphite solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and the solvent is distilled off at reduced pressure on a rotary evaporator. This gives 1.28 g of 4-iodo-1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid (47%) as an oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][C:8]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C1C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]([C:6]1[S:7][C:8]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:17])[F:18])=[CH:9][N:10]=1)[C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=O
Reactant: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)NCC)c1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Yield: 39 %

Procedure:
To a mixture of 2-[2-(butylamino)-1,3-thiazol-5-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol (65 mg, 0.202 mmol) obtained from step 1 in benzene (2 ml) was added ethyl isocyanate (24 μL, 0.3 mmol) under a nitrogen atmosphere The reaction mixture was refluxed for 4 h. Solvent was removed under reduced pressure to obtain an oil, which was dissolved in EtOAc. The resulting solution was washed with H2O, saturated NaHCO3 and brine, and dried over MgSO4. The solvent was evaporated to yield a crude product which was purified by preparative TLC (EtOAC:hexanes, 1:3) to afford the corresponding product as a white solid (31 mg). 1H NMR δ0.92 (t, 3H), 1.20 (t, 3H), 1.37 (m, 2H) 1.67 (m, 2H), 3.37 (q, 2H), 3.83 (t, 2H), 4.24 (brs, 1H), 7.50 (s, 1H), 8.60 (brs, 1H); ESIMS: m/z 392 (M−H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[CH:11]1)(C)(C)C.[ClH:17].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[CH:11][N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:17]
Reactant: CC(C)(C)OC(=O)NCCn1cnc(I)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCn1cnc(I)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (6.154 g; 18.253 mmol) in DCM (200 ml) was added slowly 4N HCl in dioxane (91 ml; 364 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-imidazol-1-yl)-ethylamine was obtained as a colorless solid (5.690 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.15 min.; [M+H]+=238.14 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:25](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:25])[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 2.87 g of methyl (RS)-(4-cyano-phenylamino)-(3,5-diformyl-phenyl)-acetate in 20 ml of dioxan and 1.3 ml of DMF was treated with 3.18 g of methyltriphenylphosphonium bromid and 1.84 g of potassium carbonate. The suspension was heated for 3 days to 100° C. It was left to cool to room temperature, filtered and concentrated. The crude product was isolated by extraction isoliert and purified by chromatography on silica gel. There were obtained 1.31 g of methyl (RS)-(4-cyano-phenylamino)-(3-formyl-5-vinyl-phenyl)-acetate as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[NH2:21][C:9]1[CH:8]=[C:7]([O:6][CH2:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=2)[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixture of the product from Example 218A (384.6 mg, 0.924 mmol), iron powder (317.4 mg, 5.683 mmol), and ammonium chloride (323.7 mg, 6.052 mmol) in water (3 mL) and ethanol (6 mL) was heated at 70° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and vacuum filtered, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by silica gel flash chromatography using a gradient of 7% to 10% ethyl acetate/methylene chloride as eluent to provide the title compound as a beige solid (272 mg, 0.704 mmol, 76%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.O[C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:35]([C:34]1[C:30]([O:1][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=4[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)=[N:31][N:32]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:36]
Reactant: COC(=O)c1ccccc1-c1nc(COc2ccc(CO)cc2OC)c(C)o1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of methyl 2-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.06 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (0.99 g, yield 64%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A suspension of 9.2 g (40 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 100 ml of dimethylformamide, 4.8 ml (60 mmol) of ethyl isocyanate and 5.6 ml (40 mmol) of triethylamine is stirred at 25° for 16 hrs. The dimethylformamide is evaporated under reduced pressure and the residue is treated with 200 ml of water and the pH is adjusted to 2.0 with 1 N hydrochloric acid. The solid is filtered and washed with methanol, ether and dried to give 11.8 g of 6-[4-(N-ethylcarbamoylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: Cc1ccc(Cn2cnc(NC(=O)c3cccc(F)c3)c2C(N)=O)cc1
Yield: 88 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 2.30 g (9.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 87 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 3.11 g of 4-(3-fluorobenzoylamino)-1-(4-methylbenzyl)-5-imidazole carboxamide (yield 88%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)CO.CCOC(C)=O>[CH2:18]([NH:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCCCN
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) in dry ethylene glycol (2.3 mL) was added 1-pentylamine (689 mg). The solution was stirred at reflux (120° C.) overnight. The reaction was cooled, taken up in EtOAc (30 mL) and washed with water (2×20 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a viscous brown oil (561 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32]O>C(OCC)(=O)C>[CH3:29][O:30][CH2:31][CH2:32][O:23][C:22]([C:19]1([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]1)=[O:24]
Reactant: COCCO
Reactant: O=C(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COCCOC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 60 °C

Procedure:
To a solution consisting of the product of Example 87 (0.50 g) in 2-methoxyethanol (5 mL) is added thionyl chloride (1.0 mL.) The mixture is heated to 60° C. for 18 h is and is subsequently cooled, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (0 to 50% ethyl acetate in hexanes) afforded the title compound (0.37 g); MS (APCI+) m/z 380 (MH+.)
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
Cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl]methanone (7.1 g) synthesized in the above-mentioned (4) was dissolved in tetrahydrofuran (200 mL) and methanol (20 mL), and sodium borohydride (90%, 1.6 g) was added under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were added carefully, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (6.7 g, 98%) of the title object compound as a pale-yellow oil.