Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=2[N:3]=1.[CH3:31][O-:32].[Na+]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:10]3[C:9]4[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=4[N:3]=[C:2]3[O:32][CH3:31])=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: C[O-]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 8-chloro-7-[4-(4-chlorobenzoyl)-benzyl]-1,3-dimethylxanthine (866 mg) in DMF (40 ml) was added sodium methoxide (10 ml, 28% in methanol) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as colorless powder (470 mg, 54%). 1H-NMR (CDCl3) δ: 3.40(3H,s), 3.54(3H,s), 4.17(3H,s), 5.36(2H,s), 7.38-7.78(8H,m).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15 min., a solution of benzaldehyde (48 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4 and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]=[C:11]([OH:22])[C:10]([OH:23])=[N:9]2>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13]([N:12]=[C:11]([OH:22])[C:10]([OH:23])=[N:9]2)=[C:14]([N+:1]([O-:4])=[O:2])[C:15]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To an ice-cooled mixture of 50 ml 100% nitric acid and 100 ml glacial acetic acid was added gradually 10 g 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline. Stirring was continued at 0° C. for 90 min. The reaction mixture was poured into 500 ml ice-water to give 10 g (86%) 7-chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline as yellow crystals, m.p.>300° C. NMR (DMSO-d6): 12.2 (1H, broad s), 11.7 (1H, broad m), 9.3 (1H, broad s), 7.33 (1H,S), 4.0 (2H,q), 1.2 (3H,t).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:5]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:4][N:3]=1.FC(F)(F)C(O)=O.C([SH:40])C>ClCCl>[CH3:1][C:2]1[NH:3][C:4](=[S:40])[N:5]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCS
Reactant: CCOC(=O)C1=C(c2cccc([N+](=O)[O-])c2)N(S(=O)(=O)c2ccccc2)CN=C1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=S)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 0.95 g (0.0016 mole) of 1, 6-dihydro-2-[(4-methoxyphenyl)methyl]thio]-4-methyl -6-(3-nitrophenyl)-1-(phenylsulfonyl)-5pyrimidinecarboxylic acid, ethyl ester, 0.6 ml (0.0066 mole) of trifluoroacetic acid and 0.24 g (0.0037 mole) of ethanethiol in 20 ml of dichloromethane was stirred at room temperature overnight. The solvent was evaporated and the residue (solid) was treated with isopropyl ether to give 0.68 g of the title compound as a colorless solid, melting point 162°-164° C. Analysis Calc'd. for C20H19N3O6S2 : C, 52.04; H, 4.14; N, 9.10; S, 13.89. Found: C, 51.77; H, 4.09; N, 8.96; S, 13.71.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:10]=[N:11][C:7]=2[CH:6]=1)=[N+]=[N-]>CO.[Pd]>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:9]1[C:8]2[CH:18]=[CH:19][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=2[N:11]=[CH:10]1
Reactant: [N-]=[N+]=NCc1ccc2c(c1)ncn2C1CCCCO1
Agent: [Pd]
Solvent: CO
Product: NCc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 26 (1.0 g, 3.9 mmol) in MeOH (20 mL) was added 20% Pd—C (200 mg), and the mixture was stirred vigorously under H2 (1 atm.) atmosphere at RT for 18 h. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo to afford 740 mg (82%) (1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (28) as yellow oil, which was used into the next step without further purification: MS (ESI) m/z=232.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][Br:9]
Reactant: Nc1ccc(OCCBr)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A portion (2.3 g, 9.18 mmol) of the 1-(4-amino-2-chlorophenoxy)-2-bromoethane produced in (6) above was dissolved in pyridine (10 ml) and the resulting solution was cooled to 0° C., followed by dripping of methanesulfonyl chloride (1.43 ml, 0.018 mol) and stirring at room temperature for 2 h. Thereafter, the solvent was evaporated and the residue was diluted with an aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The extract was dried with sodium sulfate and the solvent was evaporated, with the residue being thereafter purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (6.6%) to yield the end compound 1-(2-chloro-4-methanesulfonamidophenoxy)-2-bromoethane (2.78 g) as a pale yellow solid mass.
Reaction SMILES: C(O[C:9]([N:11](C)[CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)=[O:14])=O)C1C=CC=CC=1>[Pd]>[CH3:9][NH:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)=[O:14]
Reactant: CN(CC(=O)NC1CN(C(=O)OC(C)(C)C)C1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CNCC(=O)NC1CN(C(=O)OC(C)(C)C)C1

Procedure:
To a flask containing tert-butyl 3-(2-(((benzyloxy)carbonyl)(methyl)amino)acetamido)azetidine-1-carboxylate (3.10 g, 8.21 mmol, prepared in the previous step) and a stirbar, was added 10% Pd/C (136 g, 0.127 mmol). The flask was evacuated and back filled with argon. Methanol (100 mL) was carefully added via syringe and the flask was evacuated with stirring. It was then back filled with hydrogen and stirred 2 days under a hydrogen balloon. After evacuation with stirring and back filling with argon, the catalyst was removed by filtration over Celite 521 and concentrated in vacuo to afford the product.
Reaction SMILES: NC[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.N1CCC([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)CC1>>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:11]3[N:10]=[C:9]([N:6]4[CH2:7][CH2:8][CH:3]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:4][CH2:5]4)[C:14]([F:15])=[CH:13][N:12]=3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)OCc5ccccc5)CC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using benzyl piperidin-4-ylcarbamate. MS 548.4 (M+H); UV 215.8, 258.8, 279.8 nm.
Reaction SMILES: [I:1]I.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][N:6]=1.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:8]1[C:9]([OH:11])=[CH:10][C:5]([C:4]([F:3])([F:12])[F:13])=[N:6][CH:7]=1
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cc(C(F)(F)F)ncc1I
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
Iodine (8.16 g, 32.1 mmol) was added in five portions to a solution of 2-(trifluoromethyl)pyridin-4-ol (5 g, 30.65 mmol) and K2CO3 (4.66 g, 33.7 mmol) in methanol (34 mL) at 0° C. and the resulting mixture was stirred at room temperature for 20 h. The solution was washed with saturated aqueous sodium sulfite then acetic acid (10 mL) was added and the solution was extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give 5-iodo-2-(trifluoromethyl)pyridin-4-ol (5.1 g, 57%). Retention time (min)=1.761, method [1], MS(ESI) 290.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:41](=[CH:42][C:43]=1[OH:44])[C:8]1[N:9]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[C:7]=1[CH2:6]2.[H-].[Na+].C1(N[S:54]([C:57]([F:60])([F:59])[F:58])(=[O:56])=[O:55])C=CC=CC=1>C1COCC1>[F:58][C:57]([F:60])([F:59])[S:54]([O:44][C:43]1[CH:42]=[C:41]2[C:5]([CH2:6][C:7]3[C:11]([C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[N:10][N:9]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]=32)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:56])=[O:55]
Reactant: COc1cc2c(cc1O)-c1c(c(-c3ccc(-c4ccc(OCOCC[Si](C)(C)C)cc4)cc3)nn1COCC[Si](C)(C)C)C2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)-c1c(c(-c3ccc(-c4ccc(OCOCC[Si](C)(C)C)cc4)cc3)nn1COCC[Si](C)(C)C)C2
Yield: 115.6 %

Procedure:
To the solution of Example 267H (1.29 g, 2.04 mmol) in THF (10 mL) at room temperature was added 95% NaH (51.6 mg, 2.04 mmol). The mixture was stirred for half an hour, and N-phenyltrifluoromethane sulphonamide (0.88 g, 2.45 mmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was purified by flash chromatography to give the desired product (1.80 g, 100%). MS (APCI) m/z 763 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>C(O)C>[CH2:2]([O:3][C:4]([CH:6]1[CH2:12][C:11]2[C:19]3[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=3)[NH:21][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 97.6 %

Procedure:
4-Cyclohexanonecarboxylic acid ethyl ester (77 g, 450 mmol) and 4-fluorophenylhydrazine hydrochloride (72 g, 443 mmol) were refluxed in 1.25 L of anhydrous ethanol overnight. The resulting yellow solution was cooled, crystals filtered, the filtrate evaporated, the residue partitioned between ethyl acetate and water, organic layer dried over sodium sulfate, evaporated, crystallized from ethyl acetate/heptane to give 113 g (98%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)CCc3ccccc32)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C2C=Cc3ccccc32)c1
Yield: 80.5 %

Procedure:
To a mixture of 23 g (0.095 mol) of 1-(3-methoxyphenyl)-indan-1-ol and 100 mg of p-toluene sulfonic acid monohydrate was added 1 L of toluene and the solvent was distilled in vacuo (40 mm) until an oil residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.0 g (80.1%) of 1-(3-methoxyphenyl)-indene as a pale yellow oil.
Reaction SMILES: C[Al](C)C.[NH3:5].O1CCOCC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][N:24]=1)[C:16]([O-])=[O:17]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][N:24]=1)[C:16]([NH2:5])=[O:17]
Reactant: N
Reactant: O=C([O-])c1ccc(Nc2nccc(-c3ccccc3)n2)c(Cl)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Nc2nccc(-c3ccccc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum (0.8 mL, 2.0 mmol, 2.5M in hexanes) was slowly added to a solution of ammonia in dioxane (4 mL, 0.5 mmol) under argon at room temperature. After stirring for 15 min at room temperature, 3-chloro-4-(4-phenylpyrimidin-2-ylamino)benzoate (0.67 g, 2.0 mmol) in CH2Cl2 was added slowly. The mixture was stirred at room temperature until the ester had been consumed as judged by analytical HPLC analysis. The reaction was quenched with 1 N HCl and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organics were dried (MgSO4) and concentrated to afford (3-chloro-4-(4 phenylpyrimidin-2-ylamino)benzamide. MS (ESI) 325 (M+H).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=O.[NH3:30]>O1CCCC1.CO>[NH2:30][C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])=[O:3]
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) (5.6 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and 2 M ammonia in methanol solution (2 mL). After stirring for 16 h at room temperature, the solvent was evaporated under vacuum and the residue was coevaporated with toluene (5 mL twice) under vacuum. Purification by reverse phase preparative HPLC provided the title compound (3.4 mg). HPLC/MS [M+H]+, 397; HPLC/MS [M+H-NH3]+, 380.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[N:39][CH:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS 335255-65-7] (302 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (420 mg, 80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[NH:9][C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26].O>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:10]1[NH:9][C:8]2[CH:22]=[CH:23][C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: NN
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Solvent: O
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Yield: 15 %

Procedure:
2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (20 mg, 0.057 mmol) and hydrazine hydrate 0.2 ml was heated to reflux until reaction completion, then put cool water, diluted with ethyl acetate. The organic phase was separated, washed with brine and water, dried over anhydrous MgSO4. The resultant crude was filtered and concentrated under reduced pressure to afford 2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid hydrazide as a solid (3 mg, 15% yield).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10]>CCOC(C)=O>[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]=[C:4]=[O:3])([O-:11])=[O:10]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ccccc1[N+](=O)[O-]

Procedure:
Method a (from 2-nitroanilines): To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:50])[C@H:25]([CH2:48][OH:49])[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>N1C=CC=CC=1.O>[C:27]([NH:26][C@H:25]([C:24]([OH:23])=[O:50])[CH2:48][O:49][P:6]([OH:8])([OH:7])=[O:5])(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CO)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous pyridine (3 ml) was added to dry N-arachidonoyl-L-serine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 20 h, the mixture was cooled to 0° C., water (0.5 ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-arachidonoyl-L-serine methyl ester was eluted from column with chloroform-methanol (30-40:70-60, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (70-60:30-40, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired product was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TLC plates with molybdate spray were combined and evaporated to dryness to give 82 mg (35%) of (6): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1,3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 3.9-4.0 br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:16][CH:13]1[CH2:15][CH2:14]1)=[O:8]
Reactant: NC1CC1
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Solvent: c1ccccc1
Product: O=C(/C=C/c1cccc(Cl)c1)NC1CC1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 3-chlorocinnamoyl chloride (6 g) in dry tolune (100 ml) was added with stirring to a solution of cyclopropylamine (6 g) in dry benzene (50 ml). The reaction mixture was allowed to stand at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was thoroughly triturated with water containing a small amount of sodium carbonate, washed with water and filtered. Recrystallization of the resulting crude product from ethanol-water (1:10) gave trans 3-chloro-N-cyclopropylcinnamamide (5 g), m.p. 112°-113° C. Elemented analysis, nmr and ir data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([NH2:14])[CH3:13]>C(O)C>[CH2:12]([NH:14][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCN
Solvent: CCO
Product: CCNCc1ccc([N+](=O)[O-])cc1

Procedure:
6.0 g of 4-nitrobenzyl bromide are dissolved in 25 ml of ethanol, combined with 25 ml of 10% ethanolic ethylamine solution and refluxed for 2 hours. Then the solution is concentrated by rotary evaporation, the residue is taken up with methylene chloride and washed with dilute sodium hydroxide solution. Finally the organic phase is evaporated down.