Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:11])=[O:9])[C:4](=[O:22])O1.[CH2:24]=O.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:24][N:26]([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])=[CH:20][CH:19]=1
Reactant: C=O
Reactant: NCCN1CCOCC1
Reactant: CN(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CN(CCCc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 33 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methyl-acetamide (0.245 g, 0.76 mmol) with the paraformaldehyde —N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.103 g (33% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.92 (2H, m, CH2), 2.47 (4H, broad, 2×NCH2), 2.54 (2H, broad t, NCH2), 2.63 (2H, t, J=7.5 Hz, CH2), 3.04 (3H, s, NCH3), 3.42 (2H, broad t, NCH2), 3.58 (2H, broad, NCH2), 3.66 (4H, broad, 2×OCH2), 4.12 (2H, broad s, NCH2), 6.97 (2H, m, aromatics), 7.14 (2H, m, aromatics). HRMS (FAB+) calculated for C21H29FN3O4: [M+H]+: 406.214210. found: 406.214016.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])=[CH:22][CH:21]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Fc1ccc(S)cc1
Product: Cc1ccc(Sc2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
The product from Example 6a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol following the procedure from Example 5H for 18 h giving 1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane providing a solid (3.39 g, 74%). 1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene was reduced with SnCl2 following the procedure from Example 5I giving 2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22].O>CN(C=O)C>[CH3:22][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:16](=[O:18])[CH3:17]
Reactant: CI
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3cccc(Cl)c3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 3-chlorophenyl isocyanate to give the title compound as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: [C:1]([NH:3][C:4]([NH:29][CH3:30])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC2C=CC=CC=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]>[Pd]>[C:1]([NH:3][C:4]([NH:29][CH3:30])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]
Reactant: CNC(=NCCSCc1ncccc1OCCCCOCc1ccccc1)NC#N
Agent: [Pd]
Product: CNC(=NCCSCc1ncccc1OCCCCO)NC#N

Procedure:
N-Cyano-N'-methyl-N"-[2-((3-(4-benzyloxybutoxy)-2-pyridyl)methylthio)ethyl]guanidine which may be hydrogenolysed using palladium on charcoal catalyst to give N-cyano-N'-methyl-N"-[2((3-(4-hydroxybutoxy)-2-pyridyl)methylthio)ethyl]guanidine
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Hg](C#N)[C:16]#[N:17].N1C=CC=CC=1.Cl>CN(C)C=O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: N#C[Hg]C#N
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(I)cc2)cc1
Temperature: 200 °C
Yield: 86.8 %

Procedure:
A mixture of 15 g (33.2.10-3 mol) of 4,4'-diiodo-1,1'-biphenyl, 3.13 g (34.9.10-3 mol) of mercuric cyanide and 2.75 g (34.9.10-3 mol) of pyridine is heated at 200° C. for 15 minutes and 6 ml of dimethylformamide are then added to the mixture. After cooling, the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid. The expected product is extracted with ethyl acetate. The organic phase obtained is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and evaporated under vacuum. 3.28 g (yield: 33%) of a yellow solid are obtained after purification by flash chromatography using a chloroform/toluene mixture (1/1 v/v) as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[NH2:6].[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[C:3]([CH:4]=1)[CH2:2][NH:1][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 3-(aminomethyl)-4-(ethylsulfonyl)aniline (1.1 g, 5.1 mmol) in DMF (5 mL) and TEA (2.75 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.4 g, 5.7 mmol) in DCM (15 mL). The solution was stirred for 18 h before quenching with water (25 mL). The reaction mixture was extracted with DCM (2×30 mL), washed with brine and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 28A (1.0 g, 59%) as an oil. MS (ESI) m/z 349.2 (M+H)+.
Reaction SMILES: C(O)C.[C:4](=[S:6])=S.[NH2:7][C:8]1[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=1[NH2:14].[OH-].[Na+]>O>[SH:6][C:4]1[NH:7][C:8]2[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: S=C=S
Reactant: COc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(S)[nH]c2c1

Procedure:
70 ml of ethanol and 15 ml of carbon disulfide were added to 2.6 g of 3,4-diaminoanisole and then a solution of 1.5 g of sodium hydroxide in 5 ml of water was added thereto. After heating with a water bath for 3.5 hours, the mixture was cooled with ice, filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was dissolved in ethanol. The solution was filtrated to remove the insoluble matter and then the solvent in the filtrate was distilled off under reduced pressure. The residue was recrystallized from water-containing methanol to obtain 2.0 g of the titled compound (13).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 16 mg (0.022 mmol) of [(t-Bu)2P(Cl)PdCl2]2, 1.0 (8.8 mmol) of chlorobenzene, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.72 g (53% yield) of biphenyl.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2Cl>CN(C=O)C>[CH2:3]([O:10][C:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([Br:11])[CH:13]=2)[N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nccc(OCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 60% NaH in mineral oil (1.75 equiv.) in DMF (0.5 M) was added benzyl alcohol (2.5 equiv.) dropwise. After stirring for 30 minutes, 6-bromo-4-chloroquinoline (1.0 equiv.) was added and the solution was heated in a microwave at 100° C. for 30 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed further with H2O (3×) and NaCl(sat.), dried over MgSO4, concentrated and triturated with hexanes to yield 4-(benzyloxy)-6-bromoquinoline (73%). LC/MS=314.0/315.9 (M+H), LC=2.89 min.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>N1C=CC=CC=1>[F:12][CH:13]([F:16])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Reaction time: 72 h

Procedure:
Combine p-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in pyridine (15 mL) at room temperature and treat dropwise with 2,2-difluoroethanol (5.0 g, 60.9 mmol) via syringe. Stir the reaction mixture under nitrogen for 72 hours, partition between water (20 mL) and dichloromethane (20 mL). Separate the aqueous phase and extract with additional dichloromethane (2×40 mL). Combine the organic extracts and wash sequentially with 1 N hydrochloric acid (2×50 mL), sodium bicarbonate (2×50 mL), and brine (2×50 mL). Dry the organic layer over sodium sulfate and concentrate in vacuo to give the title compound as a yellowish oil: 1H NMR (300 MHz, CDCl3): 7.82 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=9.0 Hz), 5.92 (tt, 1H, J=55.0, 0.4 Hz), 4.19 (td, 2H, J=12.6, 4.0 Hz), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[F:7][C:8]([F:28])([F:27])[C:9]([F:26])([F:25])[C:10]([F:24])([F:23])[C:11]([F:22])([F:21])[C:12]([F:20])([F:19])[C:13]([F:18])([F:17])[CH2:14][CH2:15][I:16]>C1(C)C=CC=CC=1>[I-:16].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:15][CH2:14][C:13]([F:17])([F:18])[C:12]([F:19])([F:20])[C:11]([F:21])([F:22])[C:10]([F:23])([F:24])[C:9]([F:26])([F:25])[C:8]([F:28])([F:27])[F:7])[CH:3]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: C[n+]1ccn(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Product: [I-]
Temperature: 110 °C
Reaction time: 24 h
Yield: 103.5 %

Procedure:
1-Methylimidazole (4.32 g, 0.52 mol) was partially dissolved in reagent-grade toluene (50 ml) in a large round-bottomed flask and stirred vigorously. 1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluoro-8-iodooctane (26 g, 0.053 mol) was added, and the mixture was heated under reflux at 110 degrees C. for 24 hours. The solvent was removed under vacuum giving 1-methyl-3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)imidazolium iodide (30.5 g) as a waxy solid. Potassium 1,1,2,2-tetrafluoroethanesulfonate (TFES-K, 12 g) was added to reagent grade acetone (100 ml) in a separate round-bottomed flask, and this solution was carefully added to the 1-methyl-3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)imidazolium iodide which had been dissolved in acetone (50 ml). The reaction mixture was heated under reflux for approximately 16 hours. The reaction mixture was then filtered using a large frit glass funnel to remove the white KI precipitate formed, and the filtrate was placed on a rotary evaporator for 4 hours to remove the acetone. The oily liquid was then filtered a second time to yield the product, as shown by proton NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)[N:7]=1)[CH3:10]
Reactant: CCOc1ccnc(Cl)n1
Reactant: OC1CCNC1
Product: CCOc1ccnc(N2CCC(O)C2)n1

Procedure:
The title compound was prepared as described in Example 555, Step 2 using 2-chloro-4-ethoxypyrimidine (2.4 g, 15 mol) and pyrrolidin-3-ol (1.6 g, 18 mmol) as the starting materials.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1)(C([O-])=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[S:23]([O-:26])([O-:25])=[O:24].[Na+:27].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:23]([O-:26])(=[O:25])=[O:24])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[Na+:27]
Reactant: CCOC(=O)C(Cc1ccc(CCl)cc1)(NC(C)=O)C(=O)[O-]
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccc(CS(=O)(=O)[O-])cc1)C(=O)O
Temperature: 120 °C
Yield: 39 %

Procedure:
1.1 g of ethyl 2-acetamido-2-(4-chloromethylbenzyl)malonate are added to a solution of 3.31 g of sodium sulfite in 20 cm3 of distilled water, and 8 cm3 of a 10% aqueous solution of caustic soda, and the reaction mixture is heated for 3 hours to a temperature of about 120° C. After cooling to a temperature of about 20° C., the reaction mixture is taken to pH=1 by means of a 1N aqueous solution of hydrochloric acid, and the mixture is again heated to 120° C. for 1 hour. The reaction mixture is cooled to a temperature of about 20° C., and taken up in 150 cm3 of ethanol; the inorganic salts are separated off by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 30° C. The residue obtained is passed through a 2.5 cm diameter chromatography column packed with 100 g of silica gel, eluting with a mixture of dichloromethane, methanol, water and acetic acid (respectively 70-30-6-3 by volume). 424 mg of monosodium N-acetyl-4-sulfonatomethylphenylalanine are thus obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@@:12]23[CH2:27][CH2:26][C:25](=O)[CH2:24][C@H:13]2[CH2:14][O:15][C:16]2[C:21]3=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:32][O:33][NH2:34].CCN(CC)CC>CCO>[CH3:32][O:33][N:34]=[C:25]1[CH2:24][CH:13]2[CH2:14][O:15][C:16]3[C:21]([C:12]2([S:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:8][CH:7]=2)(=[O:10])=[O:11])[CH2:27][CH2:26]1)=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23]
Reactant: CON
Reactant: O=C1CC[C@@]2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C1CCC2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OCC2C1
Reaction time: 8 h

Procedure:
To a solution of trans-10a-(4-trifluoromethyl-benzenesulfonyl)-1,4-difluoro-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one (40 mg, 0.10 mmol) in EtOH (2 mL) was added O-methyl hydroxylamine hydrochloride (20 mg, 0.23 mmol), and NEt3 (20 uL, 0.14 mmol). The reaction mixture was stirred overnight and then PS-dimethylaminoethyl resin was added, the stirring was continued for 2 h and then the resin removed by filtration. The solvent was removed under a stream of N2 and the residue purified by preparative TLC eluting with 25% ethyl acetate in hexanes (22 mg, 47%).
Reaction SMILES: [CH:1]([C:3]1[C:4]2[N:25]=[C:22]([C:23]=1[CH3:24])[CH:21]=[C:20]1[NH:26][C:17]([C:18]([CH3:29])=[C:19]1[CH:27]=[CH2:28])=[CH:16][C:15]1=[N:30][C:12]([C:13]([CH2:32][CH2:33][CH2:34][Br:35])=[C:14]1[CH3:31])=[CH:11][C:9]1[NH:10][C:6](=[C:7]([CH3:40])[C:8]=1[CH2:36][CH2:37][CH2:38]Br)[CH:5]=2)=[CH2:2].[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Br-:35].[Br-:35].[CH:1]([C:3]1[C:4]2[N:25]=[C:22]([C:23]=1[CH3:24])[CH:21]=[C:20]1[NH:26][C:17]([C:18]([CH3:29])=[C:19]1[CH:27]=[CH2:28])=[CH:16][C:15]1=[N:30][C:12]([C:13]([CH2:32][CH2:33][CH2:34][N+:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:14]1[CH3:31])=[CH:11][C:9]1[NH:10][C:6](=[C:7]([CH3:40])[C:8]=1[CH2:36][CH2:37][CH2:38][N+:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:5]=2)=[CH2:2]
Reactant: C=CC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCCBr)C(CCCBr)=C4C)c(C)c3C=C
Reactant: c1ccncc1
Product: C=CC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCC[n+]1ccccc1)C(CCC[n+]1ccccc1)=C4C)c(C)c3C=C
Product: [Br-]

Procedure:
To 100 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipitated crystals are recovered by filtration, washed with 3 ml of pyridine and dried, whereby 116 mg (yield 94.5 of brownish black desired compound is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([CH2:27][CH2:28]CN)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[C:38](#[N:40])C>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][N:40]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH3:38])=[CH:31][CH:32]=1
Reactant: COc1ccc(CCCN)cc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CCN(C)CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)cc1

Procedure:
A mixture of 11-chloroacetyl-5,11-dihydro-6H-pyrido- [2,3-b][1,4]benzodiazepine-6-one (288 mg) (German patent 1,936,670), N-(4-methoxyphenethyl)methylamine (182 mg) and sodium hydrogen carbonate (92 mg) in acetonitrile (25 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between 2M aqueous sodium hydrogen carbonate solution and dichloromethane and the organic layer washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ethyl acetate to give the title compound as a colourless solid, 216 mg (52%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:8][CH:9]=1
Reactant: COCCN
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCNCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a dark-yellow solution of 6-bromopyridine-3-carbaldehyde 7 (30 g, 161 mmol) in DCM (300 ml) and 2-methoxyethylamine 8 (1.05 eq, 14.72 ml, 169 mmol) in a 1 L round-bottom flask was added acetic acid (1 eq, 9.23 mL, 161 mmol). After 15 min, sodium triacetoxyborohydride (1.05 eq, 35.9 g, 169 mmol) was added over 10 min and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was then quenched with 10% HCl (200 mL). The two layers were separated and the organic layer was extracted with 10% HCl (2×100 mL). The aqueous layers were combined, basified to pH=9 with 4M NaOH (450 mL), extracted with EA (3×150 mL) and combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered and evaporated to afford 9 as brown oil that could be used crude for next step (31.1 g, 127 mmol, 79% yield). MS (m/z): 245.1 (M+1)
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16].C(OCC)C.S(Cl)([Cl:37])=O>>[N:1]#[N:2].[ClH:37].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([NH:18][C@H:19]([C:27]([Cl:37])=[O:29])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16]
Reactant: COc1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COc1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cccc12
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.00 g of N2 -(5-methoxy-1-naphthalenesulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(5-methoxy-1-naphthalenesulfonyl)-L-arginyl chloride hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10].[Br:16][C:17]1[CH:24]=[C:21]([CH:22]=O)[C:20]([OH:25])=[CH:19][CH:18]=1>CC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][C:8]([C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:22][C:21]=2[CH:24]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C(CBr)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1cc2cc(Br)ccc2o1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as described in J. Med. Chem. 30, 1497 (1987)) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2×50 mL) and the filtrate was evaporated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5-bromobenzo[b]furan-2-yl)-(thiophen-2-yl)methanone. Yield: 8.0 g (77%). M.p. 84-86° C. RF (SiO2, hexane/ethyl acetate 3:1) 0.70.