Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11](Cl)[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8].O>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([O:3][CH2:2][CH3:1])[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8]
Reactant: COC(=O)c1cc(Cl)c2c(cc(OC)c3ncccc32)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2cc(OC)c3ncccc3c12

Procedure:
2 g of sodium ethylate are added to a solution of 6.2 g of 1-chloro-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester in 100 ml of anhydrous N,N-dimethylformamide and the mixture is heated, whilst stirring and with the exclusion of water, for 10 hours at 100°. The solution is then evaporated to dryness in vacuo, the residue is divided between three times 200 ml of chloroform and 200 ml of water, the organic phases are dried over sodium sulphate and evaporated to dryness in vacuo. By fractionated crystallisation from ethanol, the 1-ethoxy-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester having a melting point of 188°-190° is obtained from the residue.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:10])[CH3:9])[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].O>C(OCC)(=O)C>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([NH:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:9])[CH3:10])[OH:4])=[O:46]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN)C(C)C)cc12
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CNC(=O)C(C)(C)C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.035 g of tert-butyl {1-(2-amino-1-hydroxyethyl)-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 0.60 ml of ethyl acetate is admixed successively with 0.60 ml of 2M sodium carbonate solution and 0.012 ml of pivaloyl chloride and stirred at room temperature over a further 1 hour. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Yield: 63.9 %

Procedure:
A solution of methyl 2-(4-fluorophenyl)amino-4-hydroxy-6-nitroquinazoline-8-carboxylate (1.89 g) and lithium hydroxide monohydrate (5.182 g) in tetrahydrofuran (500 mL) and water (350 mL) was stirred at room temperature for 24 h. The reaction was acidified to pH 2 with 2 N hydrochloric acid, then was concentrated to ca. 400 mL. The yellow precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a tan solid (1.16 g). 1H NMR (300 MHz, DMSO-d6 (w/TFA (50 uL)): 8.90 (d, J=2.6 Hz, 1H), 8.84 (d, J=2.6 Hz, 1H), 7.59 (dd, J=8.1, 4.9 Hz, 2H), 7.31 (t, J=8.8 Hz, 2H). HPLC (Method F): 5.97 min. MS (APCI+): m/z 345.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[N:12]1[C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[N:14][C:13]1=[O:32]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[N:12]1[C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][N:14]([CH3:1])[C:13]1=[O:32]
Reactant: C[Mg]Br
Reactant: COc1cc(-c2ccc(F)cc2Cl)c2cnc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(F)cc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)N(C)C2
Temperature: 0 °C

Procedure:
A solution of methylmagnesium bromide (3.0M ethyl ether, 0.5 mL) was added dropwise to 1-(2,6-dichlorophenyl)-5-(2-chloro-4-fluorophenyl)-7-(methoxy)-2(1H)-quinazolinone (230 mg, 0.511 mmol) (INTERMEDIATE 56) in THF (10 mL) at −78C. After 20 min the solution was warmed to 0° C. After 40 min at 0° C. the solution was partitioned between NaHCO3 and EtOAc. The phases were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated. The crude was absorbed on SiO2 and purified by silica gel chromatography using 2% acetone in DCM as the eluent to give 1-(2,6-dichlorophenyl)-3-methyl-5-(2-chloro-4-fluorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): diastereomeric atropisomers δ 1.29 (m, 3H), 3.69 (s, 3H), 4.31 (m, 0.5H), 4.41 (m, 0.5H), 5.32 (m, 0.5H), 5.35 (m, 0.5H), 5.76 (m, 1H), 6.37 (d, 0.5H, J=2.5 Hz), 6.44 (d, 0.5H, J=2.2 Hz), 7.08-7.14 (m, 1H), 7.28-7.40 (m, 3H), 7.50-7.56 (m, 2H). MS(ES) 465 (M+H); LC 1: 3.63 min. and MS(ES) 465 (M+H); LC 1: 3.71 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:10]([Cl:25])=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(#N)C>[Cl:25][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])=[C:18]([NH:19][CH2:20][C:21]([OH:23])([CH3:22])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: COCCC(=O)Cl
Solvent: CC#N
Product: COCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
3-Methoxypropionyl chloride (5.5 g, 0.045 mole) was slowly added with stirring to a solution of 1[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (10 g, 0.038 mole) in acetonitrile (140 mL). After the addition was completed, the reaction mixture was heated at reflux for 30 minutes then allowed to stir at room temperature overnight. The reaction mixture was filtered to provide 12.4 g of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)=[N:5]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-isoxazole (257 mg, 0.83 mmol) and 1-bromo-3-(bromomethyl)benzene (206 mg, 0.83 mmol) in DMF (20 mL), was added K2CO3 (286 mg, 2.07 mmol). The mixture was stirred at RT for 16 h, then diluted with H2O (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel chromatography (Petroleum ether:EtOAc=1:1) to give the title compound as a white solid (230 mg, 58%). MS (ES+) C20H14BrF3N4O2 requires: 478. found: 479 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Yield: 77 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [[3-(3,4-dichlorophenyl)phenyl]sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 77% yield (17.2 mg). MS (ESI+) calcd mass for C19H13Cl2N5O2S 445.016701, found 445.016851.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1

Procedure:
A solution of 7'-bromo-3', 4'-dihydrospiro[1,3-dioxolane-2,2'(1H)-naphthalene](3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml), 50 mmol) (Aidrich), triphenyephosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.2 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether: hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3', 4'-dihydro-7'[2-(trimethylsilyl)-ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3) 1.93 (t, J=7 Hz, 2 CH2), 2.95 (t, J=7 Hz, 2H, CH2) 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [C:1]1([C:7]2([C:10](Cl)=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12>>[NH2:13][C:14]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:10]([C:7]3([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:9][CH2:8]3)=[O:11])=[CH:24][CH:25]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3ccccc3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-Phenyl-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 371 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].II.[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24](CC(Cl)=O)[CH2:23][CH2:22]1)[CH2:19][CH3:20]>O1CCCC1.O>[F:14][C:4]1[CH:3]=[C:2]([C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)c(F)c2)CC1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (38.1 gram) in tetrahydrofuran (60 ml) was added over 20 minutes to magnesium turnings (4 gram) suspended in tetrahydrofuran (20 ml), reaction being initiated by adding a crystal of iodine and warming as usual. This Grignard reagent was now added to a solution of trans-4-propylcyclohexylacetyl chloride (40 gram) and cuprous chloride (0.4 gram) in tetrahydrofuran (200 ml) with stirring at -60° C. over 90 minutes. After allowing to warm to room temperature over two hours, the mixture was decomposed with water and the product extracted with petroleum ether (bpt. 60°-80°). The crude material was recrystallized twice from ethanol at 5° C. to give the product (20.6 gram, 40% theory), m.p. 96.5°-97.3° C., which was found to be 99.6 pure by glc.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15])[N:10]=2)[CH2:3]1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C)C=O>[Si:20]([O:18][CH2:17][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:19])[CH:14]([CH3:16])[CH3:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (750 mg, 2.60 mmol) (obtained as described in Reference Example 36(3)) in dimethylformamide (38 ml) were added t-butyldimethylsilyl chloride (470 mg, 3.12 mmol) and imidazole (212 mg, 3.12 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:3) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (700 mg, yield 67%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[N:17]([CH3:18])[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Reactant: C1COCCN1
Product: CN1CC(CCN2CCOCC2)N(C)c2nc3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 3.0 g (0.0103 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one was added 20 mL of morpholine. The mixture was stirred at 60° C. for 4 hr. The morpholine was removed at 60° C. and approximately 1 mm Hg. The residue was partitioned between 100 mL of CH2Cl2 and 100 mL of 1N NaOH. The basic layer was reextracted with 50 mL of CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to afford 2.1 g (59%) of white analytically pure crystals, mp 149°-151.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH3:38][O:39][C:40](=[O:45])[C@H:41]([CH2:43][OH:44])[NH2:42]>>[CH3:38][O:39][C:40](=[O:45])[CH:41]([NH:42][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:43][OH:44]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Product: COC(=O)C(CO)NC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with L-serine methyl ester hydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)N1CCC(CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (200 mg), 4-methoxyphenylboronic acid (83.6 mg) and tetrakis(triphenylphosphine)palladium(0) (21.2 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and aqueous 2M sodium carbonate (0.75 ml) was stirred for 2 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified with silica gel column chromatography (eluent; 0.5-3% methanol in chloroform) to give N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (130 mg) as an amorphous powder.
Reaction SMILES: NC1N=C(C)C2C(=O)CC(C3C=C([F:20])C=CC=3C3C=CC=CC=3)CC=2N=1.[NH2:27][C:28]1[N:37]=[C:36]([CH3:38])[C:35]2[C:34](=[N:39][OH:40])[CH2:33][CH:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:31][C:30]=2[N:29]=1>>[NH2:27][C:28]1[N:37]=[C:36]([CH3:38])[C:35]2[C:34](=[N:39][OH:40])[CH2:33][CH:32]([C:41]3[CH:46]=[CH:45][C:44]([F:20])=[CH:43][C:42]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:31][C:30]=2[N:29]=1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1cc(F)ccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (16 mg, 0.046 mmol) from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
2-Bromomethylnaphthalene (5.00 g, 22.6 mmol) was dissolved in N,N'-dimethylformamide (100 ml) and potassium carbonate (9.4 g, 68 mmol) and 3-bromophenol (3.91 g, 22.6 mmol) were added. The mixture was stirred vigorously for 16 h at room temperature and then poured into water (700 ml). The precipitate was filtered off, washed with water and dried in vacuo at 50° C. for 16 h to give 6.17 g (87%) of 2-(3-bromophenoxymethyl)naphthalene as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc4ccccc4c3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 53.7 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2-bromo-2′-acetonaphthone (970 mg, 3.89 mmol) was added. After heating the reaction mixture at 80-85° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole (318 mg, 54%) as a pale yellow solid: mp 204-206° C. Anal Calc'd. for C26H19N2SO2Cl: C, 68.04, H, 4.17, N, 6.10, S, 6.99. Found: C, 67.65, H, 4.19, N, 5.96, S, 7.10.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)C>[N+:13]([C:4]1[CH:3]=[C:2]([O:1][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred and refluxed mixture of 25 parts of ethyl 4-hydroxy-2-nitrobenzoate, 11 parts of potassium carbonate and 200 parts of 2-propanone were added dropwise 21 parts of (bromomethyl)benzene. Upon completion, stirring was continued overnight at reflux temperature. After cooling, the whole was filtered and the filtrate was evaporated, yielding 25 parts (69%) of ethyl 2-nitro-4-(phenylmethoxy)benzoate as a residue (3).