Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]1[S:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]1=[O:29].[CH3:30][C:31]([C:34]1[CH:38]=[CH:37][NH:36][N:35]=1)([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:30][C:31]([C:34]1[CH:38]=[CH:37][N:36]([CH:14]2[S:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]2=[O:29])[N:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1C(O)SCN1c1cccc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccn(C2SCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tetrahydrofuran (15 mL) at about −10° C. stirred under a nitrogen atmosphere were added diethyl azodicarboxylate (0.66 mL, 4.18 mmol), 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-thiazolidinone (1 g, 3.8mmol), 3-(1,1-dimethylethyl)-1H-pyrazole (0.48 g, 3.8 mmol) and triphenylphosphine (1.2 g, 4.41 mmol). After the addition, the reaction mixture was allowed to warm up to room temperature, and stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue taken into a small amount of methylene chloride and then filtered. The filtrate was loaded on silica gel in a medium pressure liquid chromatography column and eluted with a solution of 20% ethyl acetate and 80% hexanes followed by a solution of 33% ethyl acetate and 67% hexanes to give 0.26 g of a crude product. The crude product was further purified by medium pressure liquid chromatography (silica gel, 9% ethyl acetate/91% hexanes) to afford the title compound, a compound of this invention, as a viscous oil (130 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>ClCCl>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N(C)C)cc1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of N,N-dimethylbenzene-1,4-diamine (1.0 eq) in dichloromethane, triethylamine (2.2 eq) was added at 0° C. and stirred for 15 min. To the above mixture was then added a solution of acetic anhydride (1.0 eq) in dichloromethane at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-[4-(dimethylamino)phenyl]acetamide. (Yield=69%)
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
The DMSO (436 mL, 61.4 mmol) was dissolved in 100 mL of DCM and treated with oxalyl chloride (4.02 μL, 46.6 mmol) at −78° C. The solution stirred for 30 minutes at −78° C. before the 2-(4-chlorophenyl)-2-methyl-propan-1-ol (5.67 g, 30.7 mmol) was added dropwise as a solution in 10 mL of DCM. After addition was complete, the solution was stirred for two hours at −78° C., and then treated with triethyl amine (25.7 mL, 184 mmol). The solution was allowed to warm to ambient temperature and stir for three hours. The solution was quenched with the addition of water and partitioned with more DCM. The aqueous was extracted with DCM, and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica, hexanes/ethyl acetate gradients) to afford 2-(4-chlorophenyl)-2-methylpropionaldehyde as a yellow oil (5.60 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 9.48 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 1H), 1.45 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:32]>CCO.[Pd]>[ClH:32].[C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 99 %

Procedure:
Nα-BOC-Nε-CBZ-L-lysine tert-butyl ester (22) (34.51 g, 79.15 mmol) was dissolved in a mixture of 300 ml absolute EtOH and 1 N HCl (88 ml). Prior to the introduction of H2 gas, 10% Pd—C (2.95 g) was added. After 7 hours, additional catalyst (1.0 g) was added. After 5 hours, the black suspension was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated and the residue dried under high vacuum to give the Nα-BOC-L-lysine tert-butyl ester as its hydrochloride salt (23) (26.59 g, 99%). 1H NMR (CD3OD) δ3.95 (dd, 1H, J=8.8, 5.0 Hz), 2.93 (t, 2H, J=7.7 Hz), 1.84-1.60 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CD3OD) δ173.5, 158.2, 82.7, 80.5, 79.5, 55.5, 40.6, 32.1, 28.7, 28.3, 23.9. HRMS m/z calcd. for C15H31N2O4 303.2284, found 303.2272. [α]26D−10.1° (c=1.00, CH3OH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.[Pd](Cl)Cl.O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCC
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2sccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g), triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen, was added bis(triphenylphosphine)palladium (11) chloride (1.65 g) followed by copper (1) iodide (0.233 g) with stirring, at room temperature. The reaction mixture was covered with foil and stirred at reflux, under nitrogen, over the weekend. Additional bis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper (I) iodide were added, and the reaction mixture was stirred at reflux for three days, cooled, filtered through a bed of celite and the filter cake was washed with ether. The residue was flash chromatographed (silica, 1% ethyl acetate-heptane). The appropriate fractions were collected and evaporated to give 56.3 g (89%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (66.6D) (available from Alfa Aesar, Avocado, Lancaster) (50.0 g, 231 mmol) in MeOH (300 mL) was added a cold solution of sulfuric acid (2.50 mL, 47 mmol). The mixture was heated to 80° C. and monitored by TLC. After 16.5 hours, the solvent was removed and the reaction mixture was diluted with EtOAc. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield 66.6E as a white solid (yield 100%) that was used without purification.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>CCCCCC.O.O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[C:20]([OH:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[C:17]([F:16])([F:27])[F:28])[C:12]#[N:13])=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture comprising 5.8 g of 63% sodium hydride, 25 ml of tetrahydrofuran and 10 ml of liquid paraffin, was heated, and a mixture comprising 13.5 g of 4-tert-butylbenzyl cyanide and 15.0 g of 2-trifluoromethylbenzoyl chloride, was dropwise added thereto over a period of 2 hours at a temperature of from 65 to 70° C. After completion of the dropwise addition, the reaction was carried out for 2 hours at the same temperature. The reaction mixture was left to cool to room temperature, and 250 ml of water was poured into the solution. Then, 80 ml of n-hexane was poured, followed by stirring and washing for 10 minutes, and the mixture was left to stand still for 30 minutes, whereupon the aqueous layer was separated and obtained. To the aqueous layer, 8.3 g of concentrated hydrochloric acid was gradually dropwise added with stirring, followed by further stirring for 30 minutes. Precipitated crystals were collected by filtration and washed with 100 ml of water, and then dried at 55° C. for 24 hours to obtain 23.8 g of the desired product. The NMR spectrum data of this product were the same as in Reference Preparation Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[CH:6]=1.N[C:19]1([C:31]#[N:32])[CH:24]=[CH:23][C:22](C2C=CC=CC=2)=[CH:21][CH2:20]1.COC1C(CC(OC)=O)CC(OC)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:22]3[CH:23]=[CH:24][C:19]([C:31]#[N:32])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=1
Reactant: N#CC1(N)C=CC(c2ccccc2)=CC1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: COC(=O)CC1CC(OC)OC1OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 60 %

Procedure:
According to the procedure described in Example 14(a) for the preparation of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)acetate were condensed in 6 hours at 80° C. to give a crude product. Successive flash column chromatography with EtOAc/CH2Cl2/hex gave in 60% yield 2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid. 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.8 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.10-7.09 (m, 2H), 6.33 (t, 1H, J=2.2 Hz), 3.73 (s, 3H), 3.58 (s, 2H). Anal. Calculated for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86; H, 5.14; N, 8.90.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C1NCC2=C1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CC3=C(CNC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
0.4 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 0.6 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 40 ml of acetonitrile and the suspension was refluxed in 100° C. oil bath for 7 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with methanol. 0.3 g of the titled compound was obtained (yield 57%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7])(=[O:4])=[O:3].C(OCC)C>[Pd].O.C(O)C>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CS(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 84.6 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(methylsulphonylaminocarbonyl)-3-nitrobenzene (4 g, 16 mmol), 10% palladium on carbon (0.5 g, 12.5% (w/w)) in water (5 ml) and ethanol (100 ml), the title compound (2.9 g, 83%) was afforded as a tan powder after trituration with diethyl ether. mp 153°-155° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.3 (3H, s), 6.79 (1H, d, J=7.7 Hz), 7.05 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=1.9 Hz), 7.13 (1H, dd, J=7.7 and 7.7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].Cl.[OH2:18]>C(C(C)=O)C.O.O.O.O.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Reactant: O
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CCC(C)=O
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 50 °C

Procedure:
5.5 g (0.025 mol) of 8-nitro-1,4-naphthoquinone-1-oxime and 21 g (0.11 mol) of iron (II) chloride tetrahydrate are heated to reflux temperature in 100 ml of methyl ethyl ketone. 25 g of hydrogen chloride gas are then introduced over a period of 20 minutes during which the sump temperature is kept at 87° to 90°C. The reaction mixture is stirred for another hour at this temperature, after which it is poured into 1000 ml of water heated to approximately 50°C, followed by stirring for 30 minutes at that temperature. The reaction product precipitated is then filtered off under suction. Recrystallization from toluene following the addition of 2 g of active carbon gives 4 g (78 percent of the theoretical yield) of 5-nitro-1,4-naphthoquinone melting at 164°C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>O=S(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: C[O+](C)C
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: OCc1cc(Cl)ccn1
Yield: 43.3 %

Procedure:
A solution of 4-chloropyridine N-oxide (5 g, 38.6 mmol) and trimethyloxonium tetrafluoroborate (5.94 g, 40.1 mmol) in CH2Cl2 (115 mL) was stirred for two hours at ambient temperature. The solvent was evaporated and the residue taken up in MeOH (115 mL) and heated to near boiling. Ammonium persulfate (1.76 g, 7.72 mmol) dissolved in H2O (7.7 mL) was added and the mixture was heated to reflux for 30 min. A second portion of ammonium persulfate (0.88 g) in H2O (3.9 mL) was added and the mixture was refluxed for another 30 min. The solvent was evaporated and the residue was partitioned between CH2Cl2 and aqueous Na2CO3 (10% w/v). The organic layer was washed with H2O, dried over MgSO4, and evaporated leaving 2.4 g (43%) of the title compound. 1H NMR (CDCl3) δ 8.20 (d, 1H, J=5.0 Hz, H-6); 7.31 (s, 1H, H-3); 7.04 (d, 1H, J=5.0 Hz, H-5); 5.46 (s, 1H, OH); 4.61 (s, 2H, CH2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1.C(Cl)Cl>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([N:43]([CH:44]([CH3:46])[CH3:45])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:39][CH:38]=1
Reactant: CC(C)Nc1ccc(Cl)nc1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (30 mg, 0.06 mmol) and (6-chloro-pyridin-3-yl)-isopropyl-amine (Preparation 2(A)) (10.1 mg, 0.06 mmol) in benzene (2 mL) was added PCl3 (2.0 M in CH2Cl2, 0.1 mL, 0.198 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature and was diluted with CH2Cl2. The organic solution was washed consecutively with aqueous NaHCO3 (1×), water (1×), 1N HCl (1×), and water (1×). The organic solution was dried (MgSO4) and the volatiles were concentrated in vacuo. The residue was purified by medium pressure chromatography eluting with 10% EtOH in CH2Cl2 to yield 5 mg of N-(6-chloro-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.17 (s, 1H), 7.76-7.29 (m, 11H), 7.06 (m, 3H), 6.83 (d, 1H), 5.04-4.87 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.82 (m, 3H), 3.72 (m, 1H), 0.06 (s, 6H); MS 616.6 (M+1), 614.5 (M−1).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25](Cl)[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C(C(C(O)=O)O)O>O1CCCC1.O>[CH3:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25]([O:3][CH2:2][CH2:1][OH:4])[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 50 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
Ethylene glycol (315.29 g, 107 eq) was mixed in tetrahydrofuran (175 ml, 7 vol) and sodium hydroxide (19.01 g, 10 eq) was added. The mixture was heated to 50° C. for 30 minutes or until the solution became clear. To the clear solution was added 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide (25 g, 1 eq) at 50° C. and stirred at 65° C. for 12 hours. The tetrahydrofuran was distilled out under vacuum at 210-220 mbar pressure at 35° C. The resulting solution was cooled to 10° C., a solution of tartaric acid (35.65 g, 5 eq) in water (100 ml, 4 vol) was added and stirred for 1.5 hours at the same temperature. The resultant solid was filtered, washed with a mixture of isopropyl alcohol (100 ml, 4 vol), ethanol (50 ml, 2 vol) and water (200 ml, 8 vol), and dried under vacuum at 60° C. to obtain the product as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.C1C(=O)N([Br:24])C(=O)C1.O>FC(F)(F)C(O)=O>[Br:24][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]+, 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).
Reaction SMILES: [OH2:1].[C:2]([O-:5])(=O)[CH3:3]>>[O:1]=[CH:3][C@@H:2]([C@H:3]([C@@H:2]([C@@H:3]([CH2:2][OH:5])[OH:1])[OH:5])[OH:1])[OH:5]
Reactant: O
Reactant: CC(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.08 h

Procedure:
The end 15 of the electrode is placed into a solution of water soluble DCC (25 mg/ml) in acetate buffer, pH 4.5 for 1 hour. It is then rinsed, in buffer only, for 5 minutes and thereafter placed in a solution of glucose oxidase (10 mg/ml) in acetate buffer, ph 5.5, for 11/2 hours before again rinsing in buffer. The tip of the electrode 15, with the layers of dimethyl ferrocene and immobilised enzyme is then dipped into a solution of cellulose acetate dissolved in acetone and formamide and put into ice water for several minutes, to give a protected and stable electrode.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:10][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:9][C:6]1[S:5][C:4]([C:1]([OH:3])([CH3:10])[CH3:2])=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Br)s1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetyl-5-bromothiophene in THF (2.5 mL/mmol) at −30° C. was added 1.4M methylmagnesium bromide in 3:1 toluene-THF (1.5 eq) and the resulting mixture was warmed to −10° C. and stirred for 1.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water. The organic fraction was dried and evaporated, and the crude material was chromatographed on silica gel eluting with a 1:4 mixture of ether and hexane to afford the 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene compound.