Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][C:13]([C:15]([O:17]C)=[O:16])=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:11][C:10]=2[C:27]([O:29]C)=[O:28])=[CH:4][CH:3]=1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+].Cl>O.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:11][C:10]=2[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)CC(C(=O)OC)=C(Nc2ccc(F)cc2)C1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Nc2ccc(F)cc2)c(C(=O)O)cc1Nc1ccc(F)cc1
Yield: 97.1 %

Procedure:
Dimethyl 2,5-bis{(4-fluorophenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate (6.21 gm, 15 mmol), the sodium salt of 3-nitrobenzenesulphonic acid (3.6 gm; 16 mmol), ethanol (90 ml) and 1.0M sodium hydroxide (50 μl) were heated to reflux overnight under a nitrogen atmosphere. The bright yellow solution was allowed to cool and water (120 ml) was added. The mixture was acidified with conc. hydrochloric acid when a red solid precipitated out. This material was filtered off, washed with water and dried under vacuum over phosphorous pentoxide to give 5.6 gm (97%) of 2,5-bis{(4-fluorophenyl)amino}terephthalic acid λmax(ab) 295 nm, 380 nm. (0.1M sodium hydroxide)
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.[Pd]>[NH:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:12]=2[N:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2[nH]cnc12

Procedure:
4-Nitro-1H-benzimidazole was hydrogenated (48 psi) with 1 g 10% Pd/C in HOAc (100 mL) for 3 h. The crude mixture was filtered through a pad of Celite, washing with MeOH, and concentrated. The residue was taken up in 2 M aq HCl and applied to a Phenomenex Strata-X-C ion exchange column (5 g). The column was washed with H20 and MeOH, The washings contained additional material and were applied to another Strata X-C ion exchange column (5 g). The columns were washed with H20 and MeOH. Each of the columns containing product were washed separately with 10% concentrated NH4OH in MeOH and the product collected in fractions. The collected fractions were concentrated to give 1H-Benzimidazol-4-amine as a deep red solid. 1H NMR (500 MHz, d6-DMSO) δ 12.10 (bs, 1H), 7.98 (s, 1H), 6.87 (t, J=7.81 Hz, 1H), 6.72 (d, J=7.82 Hz, 1H), 6.34 (d, J=7.57 Hz, 1H), 5.16 (bs, 2H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:19](=[O:29])[NH:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C1C=CC=CC=1>CCO.C1(C)C=CC=CC=1.[Pd]>[C:25]([O:24][C:22]([CH2:21][NH:20][C:19]([C@H:12]([NH2:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:29])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](N)c1ccccc1
Reaction time: 5.5 h
Yield: 98.7 %

Procedure:
(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 4; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) and toluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation was performed at atmospheric pressure for 5.5 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and the solvents were evaporated to give the title compound (8.4 g, 99%). NMR (600 MHz, CDCl3): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31–7.42 (m, 5H), 7.51 (brs, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:12])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2ccc3c(c2)CCC3)cc1

Procedure:
A solution of 4.8 g of 1-(2,3-dihydro-1H-inden-5-yl)ethanone 5; 30 mmoles), 4.5 g of p-dimethylaminobenzaldehyde (30 mmoles), and 1.32 g of sodium hydroxide in 40 ml of methanol was stirred under nitrogen at room temperature for 48 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 3-[4-(dimethylamino)phenyl]-1-(2,3-dihydro-1H-inden-5-yl)-2-propen-1-one was collected by filtration and washed with cold methanol. Yield: 4.2 g (48%); m.p. 106° to 108°. λmax (EtOH): 416 nm (ε=34,700); 272 nm (15,400). Calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.19, 82.12; H, 7.21, 7.24; N, 4.70, 4.67.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14](S(C)(=O)=O)[N:15]=1>C1COCC1.O>[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(OC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of cyclopentanol (0.287 g, 3.33 mmol) in THF (5 mL) was added sodium hydride (0.016 g, 0.67 mmol) and the mixture stirred at rt under a nitrogen atmosphere for 30 min. Then, the mixture was added treated with a solution of 4-chloro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.155 g, 0.67 mmol) dropwise in THF (2 mL) and the resulting mixture stirred at rt for 2 h. After this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0:080 g, 52%). MW=238.71. 1H NMR (CD3OD, 300 MHz) δ 5.64-5.40 (m, 1H), 2.90 (t, J=7.6 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.21-2.08 (m, 2H), 1.90-1.71 (m, 4H), 1.71-1.59 (m, 2H), 1.38-1.18 (m, 2H); APCI MS m/z 239 [M+H]+.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH3:12][S:13]([O:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])[C@H:19]([CH2:35][O:36][CH2:37][C:38](=O)[NH:39][CH3:40])[CH2:18]1)(=[O:15])=[O:14].Cl.[N+:43]([C:46]1[CH:56]=[CH:55][C:49]([CH2:50][O:51][C:52](Cl)=[O:53])=[CH:48][CH:47]=1)([O-:45])=[O:44].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.CO>[CH3:12][S:13]([O:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])[C@H:19]([CH2:35][O:36][CH2:37][CH2:38][N:39]([CH3:40])[C:52]([O:51][CH2:50][C:49]2[CH:48]=[CH:47][C:46]([N+:43]([O-:45])=[O:44])=[CH:56][CH:55]=2)=[O:53])[CH2:18]1)(=[O:14])=[O:15]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a suspension of sodium borohydride (1.87 g) in tetrahydrofuran (75 ml) was added boron trifluoride etherate (18.7 ml) in a nitrogen stream with stirring at 0°-10° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-2-(methylcarbamoyl)methyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (7.35 g) in tetrahydrofuran (7.5 ml) at 0°-10° C. The mixture was stirred at the same temperature for 3 hours and at ambient temperature overnight. Methanol (5 ml) was added to the reaction mixture at 0°-10° C. After 2 hours, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. A solution of the residue in a mixture of concentrated hydrochloric acid (7 ml) and methanol (70 ml) was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (75 ml), washed with water (75 ml×2) and brine (75 ml) in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was dissolved in a mixture of water (30 ml) and tetrahydrofuran (30 ml), and to this mixture was added a solution of 4-nitrobenzyloxycarbonyl chloride (3.55 g) in tetrahydrofuran (7 ml) under ice-cooling with stirring, keeping the pH between 8.5-9.5 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours. The tetrahydrofuran was removed under reduced pressure from the reaction mixture and ethyl acetate (50 ml) was added thereto. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-4-methanesulfonyloxy-2-[2-{N-methyl-N-(4-nitrobenzyloxycarbonyl)amino}ethyloxymethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.33 g).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:22]([CH2:24][NH2:25])[OH:23].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[NH:25][CH2:24][CH2:22][OH:23]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c3c(NCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
To a solution of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (396 mg, 1.0 mmol) in DMF (4.0 mL) and ethanolamine (Aldrich, 0.6 mL, 610 mg, 10.0 mmol) was added NaH (Aldrich, 95%, 270 mg, 10.0 mmol) in portions at 0° C. After stirring at the same temperature for 10 minutes, the reaction mixture was heated to 130° C. for 2 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 20% ethyl acetate in hexanes) to afford 6-fluoro-5-(2-hydroxy-ethylamino)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 25.0 mg, 8.0%).
Reaction SMILES: [O:1]=[C:2](N1CCOC1=O)[CH2:3][CH2:4][CH:5]=O.[NH2:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1>>[OH:21][CH2:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:13]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: O=CCCC(=O)N1CCOC1=O
Reactant: N[C@H]1CC[C@@H](CO)CC1
Product: O=C1CCCN1[C@H]1CC[C@@H](CO)CC1

Procedure:
Using the method of Example 167, 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (Dominique Urban, Troels Skrydstrup, and Jean-Marie Beau, J. Org. Chem., 1998, 63(8), 2507-2516) (4.2 g, 24.54 mmol) and (cis-4-amino-cyclohexyl)-methanol (Thomas P. Johnston, etc. J. Med. Chem., 1977, 20(2), 279-290) (3.17 g, 24.54 mmol) yield 4.87 g (100%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[CH3:19]I.O>CN(C)C=O>[CH3:19][N:6]([C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:3](=[O:5])[CH3:4]
Reactant: CI
Reactant: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(N(C)C(C)=O)nc1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20.6 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (180 mg) in N,N-dimethylformamide (2 ml) at 0° C. under nitrogen and the mixture was stirred for 1 hour. Methyl iodide (116 mg) was added to the mixture under the same condition and the mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-[6-(N-methyl-N-acetylamino)pyridin-3-yl]acrylate (115 mg) as a powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:24][NH:25]C=O>>[CH2:19]([O:18][C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])[CH2:6]2)=[CH:11][C:10]=1[C:14]([NH:25][CH3:24])=[O:15])[CH3:20]
Reactant: CNC=O
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)OC)cc2C1
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NC)cc2C1

Procedure:
Using procedure 41, methyl 2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxylate (77, 0.32 g, 1 mmol) was treated with N-methylformamide (0.58 mL, 10 mmol). Chromatographic purification yielded pure product 83 as a oil which was converted into the HCl salt and crystallized from EtOAc/MeOH to give a white solid (m.p. 156-159° C.).
Reaction SMILES: BrCCBr.C=C.C[Si](C)(C)Cl.I[C:13]1[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=1[CH3:19].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:40][O:41][C:42](=[O:64])[C@H:43]([CH2:55][C:56]1[CH:61]=[CH:60][C:59](I)=[C:58]([CH3:63])[CH:57]=1)[NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].[Cl-].[NH4+]>C1COCC1.CC(N(C)C)=O.[Zn].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]>[CH3:40][O:41][C:42](=[O:64])[C@H:43]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[C:58]([CH3:63])[CH:57]=1)[NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1C
Reactant: COC(=O)[C@H](Cc1ccc(I)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
To a suspension of zinc dust (15 mmol, 0.98 g) in THF (1.5 mL) was added 1,2-dibromoethane (1 mmol, 0.13 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased. Then, the suspension was cooled to room temperature and trimethylchlorosilane (0.5 mmol, 70 uL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (2.5 mmol, 700 mg) in DMA (2 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which, had been quenched with saturated ammonium chloride, indicated the absence of starting material. Then, the reaction mixture was diluted with THF (3 mL) and the excess zinc dust was allowed to settle. The above prepared solution containing the zinc compound (2.5 mmol) was added to a solution of Pd(dba)2 (0.05 mmol, 27 mg), trifurylphosphine (TFP) (0.2 mmol, 50 mg) and N-(benzyloxycarbonyl)-4-iodo-3-methyl-L-phenylalanine methyl ester (0.5 mmol, 227 mg) in THF (2 mL) at room temperature and the light yellow mixture was stirred for 15 h at 45° C. Then, the reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 71 mg (30% yield) of N-(benzyloxycarbonyl)-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as an yellow oil. ES-HRMS m/e calcd for C26H29N3O6 (M+Na) 502.2173, found 502.2174.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(OC(C)C)(C)C.[F:12][C:13]([F:40])([S:36](F)(=[O:38])=[O:37])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].Cl>O>[CH2:1]([NH:4][S:36]([C:13]([F:12])([F:40])[C:14]([F:34])([F:35])[C:15]([F:32])([F:33])[C:16]([F:30])([F:31])[C:17]([F:28])([F:29])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])(=[O:38])=[O:37])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(C)OC(C)C
Product: C=CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Allyl amine (45.0 milliliters, 3.0 molar equivalent) and isopropyl ether (200.0 milliliters) were charged into a 3-neck 500-milliliter round bottom flask equipped with a Claisen joint adapter, dropping funnel and overhead mechanical stirrer at room temperature under a nitrogen blanket. The Claisen joint adapter was attached to a Thermowatch® thermometer adapter and water cooled condenser (to the nitrogen inlet). The mixture was warmed to 25° C. with stirring. Perfluoro-1-octanesulfonyl fluoride (100.0 grams, 1.0 molar equivalent, Aldrich Chemical Co.) was added by the dropping funnel over 1.5 hours. The reaction mixture was maintained at about 25° C. by immersing the reaction flask in a room temperature water bath. After the addition was completed, the reaction mixture was heated for 2 hours at 30° C., followed by 2 hours at 40° C. Upon cooling to 30° C. using a water bath, 120 milliliters of a 9% aqueous hydrochloric acid solution was added over 15 minutes while maintaining the temperature at 25° C. After separation of the layers in a separatory funnel, the organic layer was washed with an aqueous 4.5% hydrochloric acid 4.0% ferrous sulfate solution. The organic phase was isolated and evaporated in vacuo, further dried under vacuum (0.1 millimeters Hg) in a water bath at 70° C. for 0.5 hours to give a red pasty solid. The crude reaction product was subjected to high vacuum distillation to give a slightly yellow solid (boiling point 98° C.) (0.1 millimeters Hg)(85.62 grams, 80% purified yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:22][CH:23]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is prepared from 3-methoxybenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 105-107° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.57 (t, J=4.8 Hz, 4H), 2.88 (t, J=5.7 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.85 (s, 3H), 4.31 (t, J=5.4 Hz, 2H), 7.02 (d, J=8.1 Hz, 1H), 7.17 (dd, J=2.4 and 8.4 Hz, 1H), 7.42-7.68 (m, 5H), 7.85-7.89 (m, 1H), 8.19-8.22 (m, 1H), 10.24 (s, 1H); MS 407 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[O:4].[OH-].[K+]>CO.O>[CH3:1][N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:4]
Reactant: CCOC(=O)COc1ccccc1C(=O)N(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C(=O)c1ccccc1OCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Thus obtained ethyl 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetate (18.23 g.) was added to 10% solution of potassium hydroxide in methanol (2 parts) and water (1 part), and the solution was stirred at room temperature for an hour and allowed to stand overnight. After concentrating the solution under reduced pressure, ethyl acetate was added to the concentrate. After shaking sufficiently, the aqueous solution was separated, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to give crystals (13.21 g.) of 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetic acid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])[CH2:3][CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br.O>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(N(CC2CC2)C(N)=O)cc1
Reactant: O=Cc1ccccc1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=O)N2CC1CC1
Yield: 79.8 %

Procedure:
To a suspension of 28.6 g (0.13 mole) of N-cyclopropylmethyl-N-(p-methoxyphenyl) urea in 140 g of toluene were added 13.8 g (0.13 mole) of benzaldehyde and 0.55 g (0.0033 mole) of a 48% hydrobromic acid. The resulting mixture was heated under relux for 10 hours with stirring using a water separator. Thereafter the solvent was removed under reduced pressure and the residue was suspended in a mixture of 80 ml of methanol and 40 g of a 2% hydrochloric acid. The mixture was cooled with ice with stirring. The precipitated crystals were collected by filtration, washed with a mixture of methanol-2% hydrochloric acid (2:1) and then with water, and dried to give 32.0 g (80%) of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 133° C.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[S:28][C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([CH2:38][C:39]([OH:41])=O)=[CH:37][C:31]=3[N:30]=2)=[CH:26][CH:25]=1.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][C:50]2=[O:55])=[CH:45][CH:44]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:23][C:24]1[S:28][C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([CH2:38][C:39]([NH:42][C:43]4[CH:44]=[CH:45][C:46]([N:49]5[CH2:54][CH2:53][O:52][CH2:51][C:50]5=[O:55])=[CH:47][CH:48]=4)=[O:41])=[CH:37][C:31]=3[N:30]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.3 139 mg (0.445 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate (TBTU) are added to a solution of 100 mg (0.342 mmol) of [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetic acid and 65.7 mg (0.342 mmol) of 4-(4-aminophenyl)morpholin-3-one in 2 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogencarbonate solution is added to the reaction mixture, and the resultant precipitate is filtered off, washed with water and dried, giving 2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide as a brownish solid; ESI 467.