Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:22]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[O:23])=[N:11][C:12]([S:15][C:16]3[N:20]([CH3:21])[CH:19]=[N:18][N:17]=3)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.Br.Br[CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:30][C:27]1[N:26]=[C:25]([NH:24][C:22]([C:10]2[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:7][CH:6]=3)=[CH:14][CH:13]=[C:12]([S:15][C:16]3[N:20]([CH3:21])[CH:19]=[N:18][N:17]=3)[N:11]=2)=[O:23])[S:29][N:28]=1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(O)cc2)n1
Reactant: BrCCCN1CCCC1
Agent: Br
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCCN3CCCC3)cc2)n1
Yield: 16.9 %

Procedure:
Using 19 mg of 3-[(4-hydroxyphenyl)thio]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Reference Example (step 3) and 13 mg of 1-(3-bromopropyl)pyrrolidine hydrobromide obtained in the step 1, 4 mg of the entitled compound was obtained as a pale yellow solid in the same method as in Example 2 or in accordance with the method or by combining it with an ordinary method.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22]>CO.C(O)(=O)C>[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C)cn1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1C)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-5-methylpyridine (1.00 g, 7.40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV234 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water: Yield: 1.54 g (73% of theory).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[S:28][C:29]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=4)=[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:45]1[CH:60]=[CH:59][C:48]([C:49]([O:51]CC2C=CC=CC=2)=[O:50])=[CH:47][CH:46]=1>CO.CCOC(C)=O.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[S:28][C:29]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=4)=[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:45]1[CH:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[CH:59][CH:60]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)O)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 88 %

Procedure:
A mixture of 6 (50 mg, 0.061 mmol) and 10% Pd—C (20 mg) in MeOH (8 mL) and EtOAc (3 mL) was stirred under 1 atm H2 atmosphere until no 6 was detected by TLC. The resulting solution was filtered and concentrated in vacuo to give 7 as a yellow amorphous solid (39 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.77-7.65 (m, 7H), 7.59 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 2H), 7.11 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 4.34 (brt, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 3.52 (brt, 2H), 1.72-1.65 (m, 2H), 1.51-1.47 (m, 2H), and 1.24 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.63, 171.67, 170.53, 168.73, 157.13, 149.52, 143.65, 141.52, 137.98, 137.73, 137.34, 134.34, 134.25, 131.97, 131.89, 131.84, 130.82, 130.56, 130.40, 129.55, 129.37, 123.54, 121.93, 121.17, 120.89, 116.52, 116.44, 112.83, 104.34, 61.59, 43.97, 37.38, 34.90, 27.46, 25.84, and 14.40.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]1N(C2C=CC=CC=2)CCN1C1C=CC=CC=1.Cl.[OH2:29]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:29]
Reactant: O
Reactant: CN(C)c1ccc(C2N(c3ccccc3)CCN2c2ccccc2)c(O)c1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C=O)c(O)c1

Procedure:
The reaction product (XV) obtained in accordance with Example 16 is suspended in warm ethanol. A clear solution is formed, following the addition of 5 ml of 5% aqueous hydrochloric acid. 10 ml of water are added and the aqueous solution is extracted by repeated shaking with 10 ml batches of chloroform. After the chloroform has been distilled off in vacuo from the combined chloroform extracts, 2-hydroxy-4-dimethylaminobenzaldehyde (XVI) is obtained in the form of pale yellow needles, melting at 77° to 78° C.
Reaction SMILES: [CH:1]([N:4]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:5](=[O:24])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:3])[CH3:2].[C:33]1([NH:39][N:40]=[C:41]([C:45](Cl)=[O:46])[C:42](Cl)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:1]([N:4]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:5](=[O:24])[CH2:6][N:7]1[C:42](=[O:43])[C:41](=[N:40][NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:45](=[O:46])[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]1=2)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Reactant: COc1ccc(CNc2ccccc2NCC(=O)N(c2ccc(OC)cc2)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-isopropyl-2-[2-(4-methoxybenzylamino)-phenylamino]-N-(4-methoxy phenyl)-acetamide (3.25 g, 7.51 mmol) in THF (50 mL) cooled in an ice bath (<5° C.) was added 2-(phenyl-hydrazono) propandioyl dichloride (1.84 g, 7.51 mmol) in THF (50 mL) dropwise over 20 minutes. After complete addition, the solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the resultant oil was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution (100 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (4.55 g, 7.51 mmol) as a yellow oil: 1H NMR (300 MHz, CDCl3): d 11.46 (s, 0.5H), 10.69 (s, 0.5H), 7.56-6.95 (m, 15H), 6.77-6.66 (m, 2H), 5.34 (m, 1H), 5.05 (m, 1H), 4.79 (m, 1H), 4.34-4.08 (m, 2H), 3.86 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.11 (m, 6H); TLC (EtOAc/Hexanes(2:3)): Rf =0.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cccc(Br)c1
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
Product: COc1ccc(-c2cccc(N)c2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-methoxyphenyl boronic acid (0.105 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum. And the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.063 g in 68% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([Cl:21])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([Cl:21])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)c(Cl)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(Cl)cc2c(c1Cl)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.7 %

Procedure:
The ester from Step 2 (8.39 g 23.6 mmol) was dissolved in THF (30 mL) and ethanol (20 mL), treated with 2.5 N sodium hydroxide (20 mL, 50 mmol), and stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered, and recrystallized from ethanol/water to yield a yellow solid (6.0 g, 78%): mp 229.9–230.9° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.58 (s, 1H), 6.00 (q, 1H, J=6.8 Hz), 2.50 (s, 3H). FABLRMS m/z 325 (M−H). FABHRMS m/z 324.9636 (M−H, Calc'd 324.9646). Anal. Calc'd for C12H7Cl2F3O3: C, 44.07; H, 2.16; Cl, 21.68. Found: C, 44.06; H, 2.21; Cl, 21.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH3:20][CH:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:24]3[CH2:23][CH2:22][CH:21]([CH3:25])[CH3:20])[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: CC(C)CCN
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCC(C)C
Reaction time: 10 h
Yield: 56.3 %

Procedure:
4.6 g (0.01755 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.04 ml (0.01755 mol) of 3-methyl-butylamine were added thereto and the mixture was boiled for 24 hours on a water separator. After concentration the residue was hydro-genated with 1.8 g of Raney-nickel in 200 ml of ethanol at 120° and 140 bar for 10 hours. The material obtained was chromatographed over silica gel with cyclohexane/ethyl acetate 3:1. The product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 2.84 g (56%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 81°-82° and 0.79 g (16%) of oily material from the mother liquors.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C[O:13][C:14]([C:16]1[CH:21]=[N:20][C:19](Br)=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:17]=1)=[O:15]>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]2[N:17]=[C:16]([C:14]([OH:15])=[O:13])[CH:21]=[N:20][C:19]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl-methanol (2.2 g, 30.6 mmol, 10.0 eq) was dissolved in dry tetrahydrofuran (10 ml, 20 vol) and potassium tert-butoxide (3.4 g, 30.6 mmol, 10.0 eq) added portion-wise. After stirring for 15 minutes at room temperature 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (0.95 g, 3.06 mmol, 1.0 eq) was added drop-wise as a tetrahydrofuran (10 ml) solution. The reaction mixture was stirred overnight at room temperature or until deemed complete by HPLC-MS analysis. The solution was concentrated in vacuo and the residue re-dissolved in ethyl acetate (20 ml). The resulting solution was washed with water (5 ml) and the aqueous phase extracted with ethyl acetate (10 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to afford 6-(4-fluoro-phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxylic acid. Yield=0.89 g (75%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][CH2:4][C:3]1=[O:14].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([SH:38])[CH3:37]>ClCCl>[CH2:36]([S:38][C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][N:5]=1)[CH3:37]
Reactant: CCS
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCSC1=NCC(=O)N(C)c2ccccc21
Temperature: -51 °C
Reaction time: 0.03 h

Procedure:
A solution of 1.0 mmol of 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Tett. Lett. 1994, 50(30), 9051) in 8 mL dry dichloromethane (Aldrich Sure Seal), in an oven-dried round bottom flask under nitrogen cover, is treated with 1.1 equivalents of anhydrous pyridine (Mallinkrodt). The reaction is cooled to −51° C. in a dry ice/acetone bath and treated, dropwise via syringe over three minutes, with 1.1 equivalents of trifluoromethanesulfonic anhydride (Aldrich; sealed ampules). The reaction mixture is allowed to stir twenty minutes while maintaining a reaction temperature between −47 and −35° C. The temperature is brought to 0° C. over 1-2 minutes and then maintained at that temperature for one hour. Ethanethiol (3.4 equivalents) is introduced via syringe and the mixture allowed to stir overnight, still immersed in an ice water-filled Dewar. The temperature had risen to 16° C. by morning. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The aqueous portion is further extracted three times with methylene chloride and the combined extracts dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification is effected by flash chromatography (silica gel; gradient elution using methylene chloride/ethyl acetate in 100/1, 95/5, 90/10 and 85/15. The title compound is obtained as a colorless oil which crystallizes on standing.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[N+:12]([O-:23])[C:13]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][CH2:20]4)=[CH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:25].C(Cl)Cl>>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[N+:12]([O-:23])[C:13]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][CH2:20]4)=[CH:16][C:14]=3[N+:15]=2[O-:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCC3
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 2.8 mL, ca. 56 mmol) was added dropwise to a stirred solution of TFM (7.9 mL, 56 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 76 (1.76 g, 5.6 mmol) and TFA (2.2 mL, 28 mmol) in DCM (40 mL) at 0° C. and the solution was stirred at 20° C. for 6 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 76 (173 mg, 10%); and (ii) 1,4-dioxide 77 (868 mg, 47%) as a yellow solid: mp (MeOH/DCM) 109-110° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.27 (s, 1H, H-5), 3.44 (br t, J=4.4 Hz, 4H, 2×CH2O), 3.24 (br t, J=7.3 Hz, 2H, CH2), 3.13-3.19 (m, 4H, H-6, H-8), 2.50 (t, J=6.5 Hz, 2H, CH2N), 2.38 (br t, J=4.3 Hz, 4H, 2×CH2N), 2.27 (p, J=7.5 Hz, 2H, H-7), 2.06-2.12 (m, 2H, CH2); 13C NMR δ 155.2, 155.1, 150.5, 139.0, 133.7, 115.8, 113.8, 67.0 (2), 58.0, 53.5 (2), 33.3, 32.8, 28.5, 25.5, 21.8. Anal. calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.0; H, 6.8; N, 17.2%.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCCOc2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 53 mg, 0.2 mmol), 1-(2-bromo-ethoxy)-benzene (48.3 mg, 0.22 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in acetone (0.8 ml) is refluxed for 3 h. The suspension is cooled to rt and filtered through a short pad of silica-gel. The volatiles are removed in vacuo and the residue is dried under high vacuum affording the title compound as a colourless oil. This material was used in the next step without further purification: tR=2.55 min (LC-2), MS (pos.): m/z 385.2 [M+H]+; 1H NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBu), 3.96 (m, 2H, SCH2), 4.48 (t, 2H, OCH2), 4.90 (s, 2H, CH2CO2), 6.90 (d, 2Harom), 7.24-7.38 (m, 5Harom), 7.86 (m, 1Harom).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccccc1

Procedure:
A sulfuric acid stream (11), a nitric acid stream (12), a fresh benzene stream (13) and a recycle benzene stream (21) are fed into a reactor (1). The benzene is used in 5 to 10% excess, based on nitric acid. The amount of recycle benzene obtained depends on this excess and the quality of the starting benzene. Once all the nitric acid has reacted with the benzene to give nitrobenzene under adiabatic reaction conditions, the reaction product (14), now at a temperature of approx. 130° C., is fed into a phase separation apparatus (2), in which the reaction product (14) separates into an organic phase ((15)=crude nitrobenzene, comprising benzene and low boilers in addition to nitrobenzene) and an aqueous phase ((16)=waste acid, still comprising small proportions of nitrobenzene and benzene in addition to sulfuric acid). The aqueous phase (16), comprising mainly sulfuric acid, is subjected to a flash evaporation of water in the evaporator (3) by sudden pressure reduction, and is thereby concentrated. The concentrated sulfuric acid (17) is stored in the sulfuric acid tank (4) until it is re-used. After separation in the phase separation apparatus, the crude nitrobenzene (15) is cooled to approx. 50° C. in the crude nitrobenzene cooler (5) and fed into the wash (6). The resulting stream of purified crude nitrobenzene (18), substantially freed of nitrophenols and salts, is heated again and, in a distillation column (7), freed of water, benzene and other low boilers, which are separated off (19) overhead, to give dried pure nitrobenzene (20), which is stored in a tank (8). The condensed head product (19) of the distillation column (7) is fed into a phase separation apparatus (9), in which the head product separates into an organic phase ((21), comprising benzene and low boilers) and an aqueous phase (22). The organic phase (21) is temporarily stored in a buffer tank (10) and from there, as already described above, is returned into the inlet of the reactor (1) for reaction. Nitrobenzene prepared in this way typically has a purity of approx. 99.96% (GC), a residual benzene content of 0.0028% (GC), a 1,3-dinitrobenzene content of 0.0273% (GC) and a nitrophenole content of <5 ppm (HPLC). Furthermore, the nitrobenzene has a water content of 0.0079% (Karl-Fischer).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)CO
Agent: [Na]
Product: CC(C)COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isobutanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 3 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CCNc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)cc1
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing 4-(2-aminoethyl)benzenesulfonamide (0.161 g) and N-ethyldiisopropylamine (0.5 ml) was stirred for 16 hours. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 4:6 as eluant) to give the title compound (310 mg).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 1 h

Procedure:
Triethylamine (122 μL, 0.874 mmol, 5.00 equiv) and 2-chloroethanesulfonyl chloride (29 mg, 0.175 mmol, 1.00 equiv) were added sequentially to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 45 mg, 0.175 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated to provide 4-(2,5-difluorophenyl)-2-phenyl-1-(vinylsulfonyl)-2,5-dihydro-1H-pyrrole (8-1) as a brown oil. LRMS m/z (M+H) 348.0 found, 348.1 required.