Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=3)=[O:33])[C:14]1=[O:42])=[O:11])[CH2:2]2.C(=O)([O-])[O-].Br[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(OCC)(=O)C>CN(C)C=O.O>[CH:5]12[CH2:6][CH2:7][CH:1]([CH2:9][CH2:8]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:36]=3)=[O:33])[C:14]1=[O:42])=[O:11])[CH2:4]2
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1cccc(O)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydroxyphenyl)urea, pottasium carbonate and ethyl bromoacetate in dimethylformamide was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The organic solvent was evaporated to dryness, and washed with isopropyl ether and vacuumed to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(ethoxycarbonylmethoxy)phenyl]urea.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].IC.O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:16])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one (Compound 3, 2.00 g, 7.4 mmol) in acetone (100 mL) were added potassium carbonate (500 mg) and iodomethane (5.22 g, 36.8 mmol). The mixture was then heated to reflux for 2 h. After cooling to room temperature, water was added to the mixture until all solids dissolved. The resulting solution was then extracted with diethyl ether, washed with brine, dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) gained the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OCC)(=O)C>ClCCCl>[C:47]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(=O)c1ccccc1)OCc1cncs1
Reaction time: 2 h
Yield: 48.2 %

Procedure:
The product from Example 26D (50 mg, 0.088 mmol) in 1,2-dichloroethane (2 mL) was treated with triethylamine (14 μl, 0.097 mmol) and benzoyl chloride (10.3 μl, 0.088 mmol) at ambient temperature. After stirring for two hours, the mixture was treated with ethyl acetate (8 mL), wash with aqueous 10% NaHCO3 (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (28.4 mg, 48%). 1H NMR (CDCl3) δ 8.78 (d, 2H), 7.83 (s, 2H), 7.40-6.75 (m, 15H), 5.24 (s, 4H), 4.27 (brs, 2H), 3.88 (brs, 2H), 3.28 (m, 3H), 2.91 (br s, 1H), 2.78 (br s, 1H), 2.45 (br s, 2H); MS (ESI+) m/z 670 (M+H)+.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)=O.[CH2:23](N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[F:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:23][C:6]3[N:7]=[C:8]([C:12]4[S:13][C:14]5[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=5[C:16](=[O:18])[N:17]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CN3CCN(c4ccc(F)cc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 1-(4-fluorophenyl)piperazine (0.17 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.19 g, 50%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:18]=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21]([CH:23]=1)[NH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[NH2:22][C:21]1[CH:23]=[C:17]([CH:18]=[CH:19][C:20]=1[N+:24]([O-:26])=[O:25])[O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N)c2)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 68.4 %

Procedure:
To a solution of tert-butyl (3-hydroxyphenyl)carbamate (6.89 g, 32.9 mmol) and 5-fluoro-2-nitroaniline (5.09 g, 32.6 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (11.2 g, 80.9 mmol), and the mixture was vigorously stirred at 100° C. for 14 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (125 ml) and hexane (125 mL), washed with water (150 mL×2) and saturated brine (100 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→30/70) to give the title compound (7.7 g, 69%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:11][C:12]1C=C[C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.C([O:24]C(=O)C)C>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][O:24]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Yield: 97 %

Procedure:
6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methyl benzene sulfonic acid (12 mg, 0.07 mmol), and 3,4-dehydro-2H-pyran (0.9 mL, 9.7 mmol) were added into ethylacetate solvent and stirred. The reactant was stirred at 90° C. for approximately 1 hour until the solid is dissolved completely. After concentrating the solvent, the residuals were refined by means of column chromatography, so that 749 mg of the target compound, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 97%), was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]2[N:17]=[CH:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.CCCCCC.CON(C)[C:38](=[O:40])[CH3:39]>C1COCC1.CC(O)=O>[C:7]1([C:5]2[N:6]=[C:2]([CH2:1][C:38]([CH3:39])=[O:40])[S:3][C:4]=2[C:13]2[N:17]=[CH:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (32.6 g, 100 mmol) in THF (1.8 L), was dropwise added 1.6M solution of n-butyllithium in hexane (150 mL, 240 mmol) at −78° C. over 1 h, and the mixture was stirred for 1 h at the same temperature. To the reaction mixture was dropwise added a solution of N-methoxy-N-methylacetamide (10.3 g, 100 mmol) in THF (600 mL) at −78° C. over 3 h. After addition, the mixture was stirred for 30 min at the same temperature. The reaction mixture was neutralized by the addition of AcOH (13.8 mL), and the mixture was allowed to warm to rt. The solvent was evaporated under reduced pressure and then, to the residue, were added EtOAc (400 mL) and saturated aqueous ammonium chloride (300 mL). The aqueous layer was extracted with EtOAc, the combined organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and then insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane=5/95→80/20) to give the title compound (28.4 g, 74%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[C:18]1([S:24]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.31 g, and anhydrous pyridine (50 mL). Add, by dropwise addition, phenylsulfonyl chloride (2.35 g, 13.33 mmol). Stir for 48 hours at room temperature. Pour into 1N hydrochloric acid (500 mL), extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound (3.15 g, 63%); mp 245°-7° C.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:15]([NH2:26])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH2:8]CC.[CH3:28][C:29](=O)[CH2:30][C:31](=O)[CH3:32]>Cl>[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:17][N:16]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:28])=[N:26][C:15]=12)[CH3:8]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn2c(C)cc(C)nc12

Procedure:
A solution of 35.5 g (0.089 mole) of 3-amino-5-(4-chlorophenyl)-1H-pyrazole-4-acetic acid butyl ester ethanedioate, 8.9 g (0.089 mole) of pentane-2,4-dione, and 10 ml of concentrated hydrochloric acid was stirred at room temperature for 17 hours under a nitrogen atmosphere.
Reaction SMILES: ClC[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)[OH:22]>>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=1)([OH:4])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)CCc1ccc(C(=O)CCl)cc1
Reactant: O=[N+]([O-])O
Product: COC(=O)CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
36.26 Grams of methyl 3-(4-chloroacetylphenyl)propionate was dissolved in 300 ml of concentrated sulfuric acid, then 20.9 g of fuming nitric acid (d=1.52) was added dropwise thereto under an ice-cooled condition with stirring. The reaction mixture was further stirred at a room temperature for 3 hours, then was poured into ice-water, and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography, then crystallized by adding ether. The crystals formed were collected by filtration, recrystallized from methanol to obtain 26.7 g of methyl 3-(4-carboxy-2-nitrophenyl)propionate in the form of light yellowish prism-like crystals.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7](S(=O)(=O)NC)[CH:6]=1)=[O:4].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27]>C(O)(=O)C.O>[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Reactant: CN1CCCC1CN
Solvent: CC(=O)O
Solvent: O
Product: CN1CCCC1CNC(=O)c1cccc2c1OCCO2
Yield: 112 %

Procedure:
169 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1,250 ml of water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 100 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 189°-190° C.; yield: 83.6%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CC(N(C)C)=O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:18](=[O:19])[CH2:17][Cl:16])[S:13][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 10 g of ethyl α-methoxyimino-α-(2-aminothiazol-4-yl)acetate in 100 ml of dimethylacetamide is dropwise added 5.91 g of chloroacetyl chloride under ice-cooling. After the stirring for 1 hour at room temperature, the reaction mixture is poured into ice-water and the resultant solution is extracted with ethyl acetate. The organic layer is washed and dried, followed by the distillation of solvent to give 12.66 g of ethyl α-methoxyimino-α-[2-(chloroacetamido)thiazol-4-yl]acetate as a crystal.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CCO.CC(O)=O>CCOC(C)=O.[Pd]>[NH2:15][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([F:1])[F:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCC(F)F)ccc1N
Reaction time: 24 h

Procedure:
21 g of methyl 5-(2,2-difluoroethoxy)-2-nitrobenzoate obtained in stage 3.1 and 1 g of Pd/C (10%) in a mixture of 300 ml of AcOEt, 50 ml of EtOH and 5 ml of AcOH are stirred at AT under a hydrogen atmosphere for 24 h 00.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:1][CH3:2])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCI
Reactant: CCc1cc(OCc2ccccc2)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
Ethyl iodide (0.268 mL) was added to a suspension of 4-benzyloxy-2-ethylbenzoic acid (0.572 g) and potassium carbonate (0.617 g) in N,N-dimethylformamide (5.6 mL) at room temperature with stirring. The mixture was stirred at 50° C. for 1.5 hrs and at room temperature for 13 hrs, and then water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium chloride and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.635 g).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:49])[C@@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:49])[C@@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:20]1[OH:21]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Solvent: CCCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OCc2ccccc2)[C@H]1O
Yield: 65.5 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-D-phenylalanylamino)-β-D-ribofuranuronic acid (199 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-D-phenylalanylamino)-β-D-ribofuranuronic acid (360 mg) prepared in Example 6 with n-butylamine (3 ml) according to a similar manner to that of Example 23, mp. 196°-202° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:31]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc2ccccc2c1

Procedure:
172.8 g (1.2 mol) 2-naphthol (98%) is added to a solution of 48 g (1.2 mol) sodium hydroxide (99%) in 1 l ethanol in a 4 l three-neck flask with stirrer, cooler and thermometer, after it has dissolved 417 g (1.25 mol) n-octadecylbromide are added and the reaction mixture is heated for 14 hours under reflux. After addition of a further 1 l ethanol the hot solution is aspirated over a Seitz filter to remove inorganic material and the weak pink coloured filtrate is brought to crystallization by placing it in an ice bath for 30 minutes. After aspiration of the almost colourless crystals, the filter cake is washed in portions with ca 700 ml ethanol and after drying over diphosphorus pentoxide 371.9 g (93.7% of the theoretical yield) 2-octadecyloxynaphthalene are obtained as colourless crystals, mp 64°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C[C:29]([C:32](C2N(C)C(CC(OC)=O)=CC=2)=[O:33])=CC=1.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:32](=[O:33])[CH3:29])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) [prepared by the method described in Example 5, but substituting zomepirac methyl ester for tolmetin methyl ester in Step (a)] and acetic anhydride (0.375 ml, 3.96 mmol) in THF was stirred at 60° C. for 4 h. The solvents were removed under reduced pressure and the residue was crystallized from hexane-chloroform to give N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-acetamide (295 mg, 88%) as a solid, mp 194-195° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[NH:36]1CCOCC1.C[C:43]1(C)[C:69]2[C:64](=[C:65](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH:66]=[CH:67][CH:68]=2)O[C:45]2[C:46](P(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:47][CH:48]=[CH:49][C:44]1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([NH:30][C:28]([NH:27][C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:36]=[C:43]([C:69]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:7][N:6]=2)([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(N=C(c2ccccc2)c2ccccc2)cn1
Temperature: 100 °C
Yield: 70.1 %

Procedure:
1-(1-(5-Bromopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea (122 mg, 0.22 mmol), morpholine (1.3 eq), Pd2(dba)3 (70 mg), Xantphos (95 mg) and Na—O-t-Bu (84 mg) were stirred in toluene (0.7 mL) at room temperature. The reaction mixture was purged with N2 several times and then was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and CH2Cl2 was added. The resulting solution was filtered through Celite and concentrated to dryness. The residue was purified by chromatography (silica gel, hexanes/EtOAc) to give 1-cyclopentyl-3-(1-(5-(diphenylmethyleneamino)pyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea as white solids (101 mg, yield: 70.1%). LC-MS ESI 651.45 (M+H) (10-90% MeOH in H2O with 0.1% TFA in a 4-min run, retention time=4.47min).