Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:11]([C:24]([OH:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]1([C:33]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:34]=[C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:35]([O:25][C:24](=[O:26])[C@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)OC(C(=O)c2ccccc2)c2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a mixture of cis4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline (21.87 g), benzoin (12.25 g), and 4-dimethylaminopyridine (7.04 g) in CH2Cl2 (200 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (10.52 mL) at 5° C., and the mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated, and the residue was dissolved in EtOAc (250 mL), washed with 1N HCl (150 mL), water, saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 5:2 elution) to give cis4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline 2-oxo-1,2-diphenylethyl ester (21.62 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH2:9]1)=O)(C)(C)C.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:14][N:13]([CH3:15])[C:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)=[O:16].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C1CNC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 324.3 mg (1.42 mmol) 3-dimethylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 7.5 mL DCM was added 2.5 mL TFA and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a TFA salt, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15](O)=O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O1CCCC1.C[Si]([Cl:30])(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[CH2:15][Cl:30])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(-c2ccc(CCl)c(=O)[nH]2)c1

Procedure:
A stirred suspension of 2.6 g. of 6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 130 ml. of tetrahydrofuran is treated with 1.24 ml. of triethylamine. After a few minutes, the resulting solution is treated with 1.12 ml. of trimethylsilyl chloride and stirred 1 hour at room temperature. The solution is then treated with 1.28 ml. of thionyl chloride and stirred for 2 hours at room temperature. The resulting solution is diluted with 200 ml. of hexane and the precipitate of 6-[3-aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride is collected by filtration, washed with hexane and dried. The acid chloride is used as such without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]([O:24]C)=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4].O[Li].O.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3nc(C)ccc3c2=O)cn1
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccc(C(=O)O)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To 3-(6-methoxycarbonyl-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 100) (0.2 g) in THF (10 mL) was added LiOH.H2O (0.06 g) and H2O (2 mL), and the mixture stirred at RT for 1 h. The product was taken up in EtOAc, washed with H2O and HCl (2M, 2 mL), filtered, and worked up with EtOAc and H2O. The organic layer was dried over MgSO4, and concentrated to a yellow oil. The oil was taken up in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a yellow solid to provide 3-(6-carboxy-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (0.11 g). M+H=430.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[S:19]1[CH:23]=[C:22]([C:24]2[NH:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[N:21]=[CH:20]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[C:1]1([C:7]2([C:10]([NH:33][C:31]3[CH:30]=[CH:29][C:27]4[NH:28][C:24]([C:22]5[N:21]=[CH:20][S:19][CH:23]=5)=[N:25][C:26]=4[CH:32]=3)=[O:12])[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]c(-c3cscn3)nc2c1)C1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-phenylcyclopropane-1-carboxylic acid (2.0 g, 12.3 mmol) in dichloromethane (40 mL) was treated at ambient temperature with oxalyl chloride (1.06 mL, 12.3 mmol) and three drops of DMF. A drying tube was placed on the flask and the reaction bubbled (HCl, CO, and CO2) for three hours. 2-Thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-6, 2.67 g, 12.3 mmol) and diisopropyl ethyl amine (3.22 mL, 18.5 mmol) were dissolved in 30 mL of dry N,N-dimethylformamide and cooled to 0° C. The acid chloride solution was concentrated, re-dissolved in 10 mL of dichloromethane, and cannulated into the stirring amine solution over a five minute period. The reaction was allowed to warm slowly to ambient temperature after the addition was complete. The reaction was complete after half an hour by TLC analysis and was partitioned between ethyl acetate and dilute sodium bicarbonate solution. The aqueous was extracted (3×10 mL) with ethyl acetate and the layers were separated. The organic layer was washed twice with water, once with brine, separated, dried (MgSO4), filtered, and concentrated in vacuo. The resulting yellow oil was filtered thru a plug of silica gel eluted with ethyl acetate. The filtrate was concentrated in vacuo and the residue was triturated in ethyl acetate/hexanes mixtures to afford the pure 1-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide as a white solid (3-10); 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.49 (d, 1H), 7.36 (m, 6H), 1.48 (dd, 2H, J=4.4, 2.4 Hz), 1.15 (dd, 2H, J=4.4, 2.4 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][CH:17]=[O:18])([O-:3])=[O:2].C(=O)(O)[OH:20].[NH2:23][NH:24][C:25]([NH2:27])=[NH:26]>C1COCC1>[C:17]([O-:18])(=[O:20])[CH3:16].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][CH:17]=[N:23][NH:24][C:25]([NH2:27])=[NH2+:26])([O-:3])=[O:2]
Reactant: O=CC=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Reactant: N=C(N)NN
Reactant: O=C(O)O
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: NC(=[NH2+])NN=CC=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Yield: 55 %

Procedure:
2 g (8.3 mmol) 4a and 1.1 eqv. of aminoguanidine bicarbonate was mixed in THF and refluxed for 30 min. The solvent was evaporated and the residue was diluted with acetonitrile and the product crystallised. Purification by recrystallisation from acetonitrile yielded 1.35 g (55%) of the final product 5a (m.p. 192-194° C.).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([OH:13])[CH:12]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:13][CH2:17][CH2:18][Cl:19])[CH:12]=1
Reactant: ClCCBr
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OCCCl
Temperature: 70 °C
Reaction time: 5 h
Yield: 103.4 %

Procedure:
To 1.2 L of N,N-dimethylformamide solution containing 159 g (0.79 mol) of 5-bromo-2-methoxyphenol (see WO 01019785) were added 340 g (2.37 mol) of 1-bromo-2-chloroethane and 120 g (0.868 mol) of potassium carbonate, and the mixture was stirred at 70° C. for 5 hours. Then, 220 g (1.53 mol) of 1-bromo-2-chloroethane and 80 g (0.58 mol) of potassium carbonate were additionally added thereto twice by dividing them to two portions during the reaction, and the mixture was further stirred for 7 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The organic layer after separation was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 217 g of the title compound as a dark brownish solid substantially quantitatively.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:31][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[C:9]1[O:10][CH2:11][C:12]([CH3:14])([CH3:15])[N:13]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCc1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C2=NC(C)(C)CO2)c(F)c1
Temperature: -70 °C
Reaction time: 8 h
Yield: 94529.8 %

Procedure:
The 4-ethylphenyloxazoline (2.03 g, 10 mmol) was dried in a vacuum oven at 60° C. for 2-3 hours, dissolved in 50 mL of dry THF, and charged to a 300 mL round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stir bar. The mixture was cooled under nitrogen to −70° C. in a dry ice/acetone bath. Butyl lithium in hexane (7.5 mL, 0.012 mmol) was added in two portions and warmed to −25° C. over 2 hours. The mixture was cooled again to −65° C. and N-fluorobenzenesulfonimide (3.79 g, 0.012 mmol) was added in three portions. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched with 100 mL of saturated NH4Cl, and transferred to a separatory funnel with ethyl ether washes. 25% NaOH was added slowly and mixed until an aqueous phase with pH=10 was achieved. The aqueous phase was extracted with ether and the ether was washed with a small volume of water. The ether extracts were dried over MgSO4 and evaporated to give 2.51 g of 2-(2-fluoro-4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a brown oil. In a second experiment, a rate of 70% fluorination was achieved (highest) with a reactant ratio of 1:1.5:1.5 oxazoline:BuLi:N-fluorobenzenesulfonimide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.0 (d, 2H), 7.78 (t, 1H), 4.1 (s, 2H), 2.7 (q, 2H), 1.39 (s, 6H), 1.2 (t, 3H).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=O)(C)(C)C.Br[CH2:39][CH:40]([S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:44])=[O:43])O.C(=O)([O-])[O-:52].[Na+].[Na+]>COCCOC.O>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][C:15]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[S:42]([CH2:40][CH2:39][OH:52])(=[O:44])=[O:43])=[CH:16][C:11]=3[N:10]=2)=[CH:29][CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccccc1)C(O)CBr
Reactant: CC(C)(C)OC(=O)n1c(COc2ccc(C(F)(F)F)cc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(CCO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Yield: 59.2 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(4-trifluoromethyl-phenoxymethyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (0.046 g, 0.0887 mmol), 2-bromophenylsulfonylethanol (0.036 g, 0.133 mmol), sodium carbonate (0.056 g, 0.532 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.006 g, 0.00887 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, EtOAc) to afford the title compound as a light brown solid (0.025 g, 59%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.17 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.76-7.61 (m, 6H), 7.46 (dd, 1H, J=7.6 Hz, J=1.2 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.26 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 3.63 (t, 2H, J=6.6 Hz), 2.91 (t, 2H, J=12.8 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23F3N3O4S: 518.5 (M+MeCN+H), Found 518.2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOP([O:23][C:24]([CH3:26])=[O:25])(OCC)=O.[H-].[Na+].O1CC[CH2:31][CH2:30]1>>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=[CH:26][C:24]([O:23][CH2:30][CH3:31])=[O:25])=[CH:11][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOP(=O)(OCC)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1ccc(C(=O)OC(C)(C)C)s1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.7 g (8 mmol) of the product obtained in step c) were dissolved in 5 ml of dry tetrahydrofuran. The solution was added dropwise to a mixture of 2.24 g (10 mmol) of diethyl phosphonoacetate and 440 mg sodium hydride (55% in paraffin oil) in 30 ml of dry tetrahydrofuran. The resulting mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, the mixture was poured onto water/ethyl acetate. The organic phase was separated, washed with 10% aqueous citric acid and dried with anhydrous magnesium sulfate. After filtration, the solvents were removed to give 2.6 g of raw product. This material was purified by column chromatography (silica gel; ethyl acetate/n-heptane (1/5; v/v)). The fractions containing the title compound were combined and evaporated to give 1.2 g of a clear light yellow oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=[N:8][OH:9].[OH-].[K+].C(OCCO)C>[Cu](Cl)Cl.CCCCCC>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=NO)c2sccc2Br)c1
Agent: Cl[Cu]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCCO
Product: COc1cccc(-c2noc3ccsc23)c1
Yield: 67.6 %

Procedure:
Reflux a mixture of (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone oxime (10 g, 0.032 mol), KOH (3.6 g, 0.064 mol dissolved in 10 mL water) and 2-ethoxyethanol (40 mL) under nitrogen for one hour at 105–110° C. Add copper chloride (0.16 g, 0.0016 mol) whereupon the reaction mixture becomes dark brown in color. Heat the reacton for an additional four hours. TLC shows that the reaction is complete. Add water and extract the organics into ether. Wash the ether phase with water, dry (MgSO4), filter and concentrate to yield an oil. Purify the oil by column (alumina) chromatography, and elute with 15% ether in hexane to obtain white crystals. Recrystallize the crystals from ether:hexane to yield the title compound (5 g, 68% Yield), m.p. 51–52° C.
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][N+:16]([O-:5])=[CH:15][C:14]=1[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(Cc1cnccc1Cl)C(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: CN(Cc1c[n+]([O-])ccc1Cl)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Phthalic anhydride (566 mg, 3.82 mmol) was dissolved in acetonitrile (10 mL) and treated with urea-hydrogen peroxide complex (360 mg, 3.82 mmol) and the suspension was stirred for 15 min. A portion of the Boc-derivative from stage (i) (890 mg, 3.48 mmol) was added and the suspension was stirred at room temperature for 20 h. The residue was partitioned between potassium carbonate solution (100 mL) and DCM (200 mL). The organic layer was separated and the aqueous layer was re-extracted with DCM (3×50 mL). The combined organic fractions were washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (90:10:1)] afforded the title compound (680 mg, 72%); δH (CDCl3, 300 MHz) 1.42 (9H, s), 2.91 (3H, s), 4.44 (2H, s), 7.23 (1H, d), 8.00 (1H, d), 8.08 (1H, s); MS m/z (TS+) 273 (MH+).
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.Cl.[Br:30]N1C(=[O:36])CCC1=O>CO>[C:26]([OH:27])(=[O:36])/[CH:9]=[CH:1]\[C:2]([OH:4])=[O:3].[Br:30][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:13]2[C:12]3[CH:25]=[C:26]([O:27][CH3:28])[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: O=C(O)C(=O)O
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)C(Oc1ccc(Br)cc1)CNCC2
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A solution of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (6.5 g, 22 mmole) in 300 ml methanol was acidified to pH 1 with ethereal hydrogen chloride. After this solution was cooled with an ice bath, N-bromosuccinimide (4.2 g, 24 mmole) was added. The reaction mixture slowly warmed to ambient temperature, was evaporated, stirred with water, basified with saturated sodium carbonate and was extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride and were dried (anhydrous MgSO4), filtered and evaporated to 8 g of an oil. This oil was converted to the maleate salt (8 g, 74%, m.p. 95°-100° C.) by the addition of ethereal maleic acid of which 4 g was recrystallized twice from isopropanol-ether to give 2.4 g (45%) of 1-(4-bromophenoxy)-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine maleate, d 145°-146° C.
Reaction SMILES: Cl.Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=O)=O>C(O)(=O)C.O>[SH:3][C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CC(C)=O)cc1S
Yield: 93.6 %

Procedure:
While ice-cooling a suspension of 84 g of stannous chloride-2H2O in 320 ml of glacial acetic acid with stirring until a transparent solution was obtained, hydrochloric acid gas was introduced into the solution and then 14.3 g of 3-chlorosulfonyl-4-methoxyphenylacetone was added to the solution at 25°-30° C. After further stirring the mixture at room temperature for 30 minutes, the reaction mixture obtained was poured into 320 ml of concentrated hydrochloric acid and after diluting the mixture with 640 ml of water, the product was extracted with 400 ml of chloroform. The chloroform layer formed was washed with water and then chloroform was distilled off to provide 10 g of oily 3-mercapto-4-methoxyphenylacetone.
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])SC.[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:21][NH2:22]>C(O)C>[C:21]([NH:8][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:6][CH3:3])#[N:22]
Reactant: NCCSCc1ncccc1Br
Reactant: CSC(=NC#N)SC
Reactant: CN
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1ncccc1Br
Reaction time: 8 h

Procedure:
Sequential reaction of dimethylcyanodithioimidocarbonate with 2-((2-aminoethyl)thiomethyl)-3-bromopyridine) and excess methylamine at room temperature in ethanol, the methylamine being added after initial standing overnight and the solution then allowed to stand for a further four hours, followed by chromatographic purification on a column of silica gel with elution by ethyl acetate and final recrystallisation from ethyl acetate-petroleum ether gave N-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-N"-methylguanidine m.p. 114°-116°.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Indole-4-carbaldehyde (580 mg) was dissolved in 8 ml of dimethylformamide, then 176 mg of sodium hydride (content 60%) was added to the resulting solution with ice-cooling, followed by stirring for one hour, addition of 777 mg of benzenesulfonyl chloride and stirring for one hour. To the reaction solution, there were added 50 ml of ethyl acetate and 50 ml of a saturated sodium hydrogen carbonate aqueous solution followed by stirring for 30 minutes. After separation of phases, the aqueous phase was further extracted with 50 ml of ethyl acetate. The combined organic phase was washed with 50 ml of saturated common salt solution, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to give a crude product. The crude product was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=9/1) to give 842 mg of 1-benzenesulfonylindole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 74%.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N(CCCC)CCCC)CCC>C(OCCOCC)C>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([O:32][CH3:33])[C:24]=3[O:23][CH3:22])[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)c(OC)c1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: CCOCCOCC
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Yield: 91.2 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 1.4 g (0.005 mole), 1.1 g (0.005 mole) of 2,3,4-trimethoxybenzyl chloride, and 0.93 g (0.005 mole) of tributylamine were dissolved in 10 ml of ethylene glycol diethyl ether, and the resulting solution was heated at the refluxing temperature for 2.5 hours. The reaction liquid was left to cool, and filtered, and concentration of the filtrate under reduced pressure produced 2.1 g of oily 1-(3,3-diphenylpropyl)-4-(2,3,4-trimethoxybenzyl)piperazine (91.2% yield).