Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.CS([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)(=O)=O.[CH2:27]([NH:31][CH3:32])[CH2:28][CH2:29][CH3:30]>O>[CH2:27]([N:31]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)[CH3:32])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCNC
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(C)c1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To 3 ml of N,N-dimethylformamide were dissolved 0.50 g (1.6 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate, followed by the addition of 0.28 g (3.2 mmol) of N-butyl-N-methylamine and stirring at room temperature for 30 minutes. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate ether:hexane=1:7) to obtain 0.41 g (yield: 80%) of 4,4-difluoro-3-methyl-3-butenyl 2-(N-butyl-N-methylamino)-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([Mg]Br)=[CH2:12].[NH4+].[Cl-].[CH2:17]1COC[CH2:18]1>>[CH:17]([P:7](=[O:8])([CH:11]=[CH2:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:18]
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of phenylphosphonic dichloride (29 mL, 200 mmol) dissolved in anhydrous THF (600 mL) was cooled to −78° C. and mechanically stirred under an atmosphere of dry nitrogen. Vinylmagnesium bromide (1M in THF, 500 mL) was slowly added so that the temperature of the reaction mixture never exceeded −70° C. The addition took 2 hours. After an additional 1 hour of stirring at −78° C., the cold reaction mixture was poured directly into cold, saturated NH4Cl (1 L). The mixture was extracted twice with CH2Cl2 and the combined organic phase was washed with 1 M NaOH, brine, and then dried over Mg2SO4. Filtration and solvent evaporation provided divinyl-phenyl-phosphine oxide (26.8 g, 75%) as a viscous yellow oil that solidified upon standing. 1H NMR (400 MHz, DMSO-d6); δ 7.8-7.4 (m, 5H), 6.7 (m, 2H), 6.4-6.1 (m, 4H). 31P NMR (DMSO-d6); δ 17.0 (s).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([OH:30])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.CI.Cl.[NH:37]([C:39]1[N:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[NH2:38].[CH3:45][O:46]C(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.BrCCOC.N(C1N=CC=CN=1)N>>[C:24]([OH:26])(=[O:46])[CH3:25].[O:2]=[C:3]1[N:37]([C:39]2[N:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[N:38]=[C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:18])=[NH:15])=[CH:10][CH:9]=2)[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:45])[CH:21]=2)[NH:4]1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)cc(OC)c1
Reactant: NNc1cccnn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)c(OC)c(OC)c1
Agent: COCCBr
Agent: Cl
Agent: NNc1ncccn1
Solvent: CI
Product: CC(=O)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3cccnn3)c(=O)[nH]2)cc(OC)c1OC

Procedure:
The same procedure was carried out as in Example (6a), except that {2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, methyl iodide and 3-hydrazinopyridazine hydrochloride were used instead of respectively the {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, 1-bromo-2-methoxyethane and 2-hydrazinopyrimidine, to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](Cl)=[O:15].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O.CN1CCCC1=O.O>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:14]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[C:20]4[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=4)[CH:6]=3)[CH:1]=2)=[O:15])=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C(=O)c2ccc3cc(C(=O)c4ccc(OC)cc4)ccc3c2)cc1
Temperature: 25 °C

Procedure:
A stirred reactor comprising a 750 ml sulfonation flask, thermometer, condenser and nitrogen inlet is charged with 25.3 g (0.1 mol) of naphthalene-2,6-dicarbonyl dichloride and 32.4 g (0.2 mol) of anisole in 200 ml of nitrobenzene and, with stirring, 26.6 g (0.2 mol) of aluminium chloride are added over 15 minutes at 12°-18° C. The reaction mixture is thereafter allowed to react for 90 minutes at 40° C., then cooled to room temperature and thoroughly mixed with 1.5 liters of water containing HCl. The resultant suspension is diluted with 1.2 liters of N-methylpyrrolidone, and the mixture is heated to 130° C. The clear solution so obtained is cooled and the crystallised product is isolated by filtration. The filter residue is vacuum dried at 130° C., giving 25.9 g (65.4% of theory) of the desired product, which melts at 251° C.
Reaction SMILES: C([O:3][C:4](=[O:52])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[C:16]2=[NH:51])[CH:6]=1)C.O[Li].O>C1COCC1.CO.O>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH2:37][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:17]4[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:4]([OH:52])=[O:3])[C:16]4=[NH:51])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)=[CH:45][CH:46]=1
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(N4CCN(Cc5ccccc5-c5ccc(Cl)cc5)CC4)cc3)c3ccccc32)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
To a solution of 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (140 mg, 0.20 mmol) in THF (1.2 ml), MeOH (1.2 ml) and H2O (0.6 ml) at 0° C. was added LiOH.H2O (16 mg, 0.39 mmol). The reaction was warmed to rt where it was maintained for 20 h. After this time, the mixture was concentrated under reduced pressure and then partitioned between saturated NaHCO3 and dichloromethane to adjust the pH to ˜8. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by preparative HPLC provided 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid (15 mg, 11%). HPLC-MS 686 [M+1]+, 344.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH2:36][C@@H:37]([OH:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC[C@@H](O)c1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4carbonyl chloride, and (1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14](I)=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:20])[CH:11]=2)[CH:6]=1.C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:20])[CH:11]=2)[CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1C#C[Si](C)(C)C
Temperature: 150 °C
Yield: 74.5 %

Procedure:
To a solution of (4-acetoxy-6-fluoro-3-iodo-naphthalen-2-yl)acetic acid methyl ester (300 mg, 0.75 mmol) and triethylamine (3 mL) in N,N-dimethylformamide (3 mL), was added bis(triphenylphosphine)dichloropalladium(II) (53 mg, 0.075 mmol), copper iodide (42 mg, 0.229 mmol) and trimethylsilanylacetylene (108 mg, 1.12 mmol) under an argon atmosphere. After being heated at 150° C. for 6 minutes with microwave irradiation, the resulting mixture was cooled, diluted with ethyl acetate (20 mL), and washed with brine (15 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (elution with 10% ethyl acetate in petroleum ether) to afford (4-acetoxy-6-fluoro-3-trimethylsilanylethynyl-naphthalen-2-yl)-acetic acid methyl ester (208 mg, 75%) as a light yellow solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]\[CH2:4][S:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1.[CH3:21][C:22]1[C:23]([CH2:31]Cl)=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]>CN(C)C=O.C(Cl)Cl>[CH3:21][C:22]1[C:23]([CH2:31][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2c(SC/C=C(\C)CCC=C(C)C)nc3ccccc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 126.3 %

Procedure:
To a solution of 2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole from Example 1 (1.5 g, 5.2 mmol) and 3,5-dimethyl-4-methoxy-2-pyridylmethyl chloride (0.465 g, 5 2 mmol) in dimethylformamide (7 mL) at 0° C. under nitrogen was added dropwise triton-B (5 mL of a 40% solution). The solution was stirred at ambient temperature for 72 hours, then at 50° C. for 48 hours. Evaporation of the solvent gave a residue which was dissolved in CH2Cl2, washed with water and dried over Na2SO4. Evaporation of the solvent and flash chromatography of the resultant oil (10% Et2O/CH2Cl2, Merck Kieselgel) gave 1.1 g of 1-(3,5-dimethyl-4-methoxy-2-pyridylmethyl)-2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole (free base) which was converted to its oxalate salt (1.36 g). m.p. 76°-80° C. NMR (DMSO-d6) δ7.93(s,1H), 7.5(m,1H), 7.1(m,3H), 5.4(s,2H), 5.37(m,1H), 5.07(m,1H), 3.93(m,2H), 3.70(s,3H), 2,27(s,3H), 2.15(s,3H), 2.0(m,4H), 1.6(s,3H), 1.53(s,3H), 1.07(s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:6]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(CO)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-chloro-4-hydroxybenzoate (4.43 g) and 2,6-lutidine (6.64 mL) in DCM (50 mL) cooled with an ice bath was added triisopropylsilyl trifluoromethanesulfonate (7.66 mL). After being stirred at 0° C. for 1 h, saturated aqueous NaHCO3 was added thereto. The mixture was diluted with Et2O and layers were separated. The aqueous layer was extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was dissolved in diethyl ether (175 mL). To the solution cooled with an ice bath was added lithium aluminum hydride (1.08 g). After being stirred at 0° C. for 30 min, sodium sulfate decahydrate was added thereto. The mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (6.87 g).
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9][CH:10](C)C)(C)C.[CH3:13][N:14]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:23](=[O:26])[CH2:24][CH2:25][C:15]1=2.[I-].[CH3:28]C=[N+]=CC>C1COCC1>[CH3:6][N:9]([CH2:10][CH:24]1[CH2:25][C:15]2[N:14]([CH3:13])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]=2[C:23]1=[O:26])[CH3:28]
Reactant: Cn1c2c(c3ccccc31)C(=O)CC2
Reactant: CC=[N+]=CC
Reactant: CC(C)NC(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CC1Cc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (1.6M in hexane; 3.4 ml) was added dropwise, under nitrogen, at 0° to a stirred solution of diisopropylamine (0.76 ml) in THF (15 ml) and the resulting solution was stirred at 0° for 10 min. before cooling to -78°. A solution of 4-methyl-3,4-dihydrocyclopent[b]indol-1(2H)-one (1 g) in THF (120 ml) was added dropwise at -78° to -70° and the resulting solution was stirred at ca. -78° for 10 min. before N,N-dimethylmethyleneammonium iodide (ca. 1 g) was added. The resulting mixture was allowed to warm to room temperature over 1.5 h and was then partitioned between 2N sodium carbonate (100 ml) and ethyl acetate (2×100 ml). The combined, dried organic extracts were evaporated in vacuo to give an oil which was purified by FCC eluting with System A (100:8:1) to give the title compound (0.14 g) as an oil, t.l.c. (System A 100:8:1) Rf 0.2.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=1>CS(C)=O.[OH-].[Na+]>[OH:25][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:2][C:3]2[NH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14][CH:15]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(O)c1ccc(O)nc1
Reactant: ClCc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCC(O)c1ccc(OCc2cc3ccccc3[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
2-Chloromethyl indole (8 g, 0,048 mol) and 2-hydroxy-5-(1-hydroxyhexyl)pyridine (9.36 g, 0.048 mol) were dissolved in DMSO (250 ml) and to this mixture, 2N sodium hydroxide solution was added (25 ml, 0.05 mol). The clear, homogeneous reaction mixture became warm, and this mixture was stirred at room temperature overnight. The solution was poured into warer (500 ml), and was extracted thoroughly with ethyl acetate (4×50 ml). The combined extract was washed with 1N sodium hydroxide sclution, water and brine. After drying the organic extract over MgSO4, all volatiles were removed to leave a brown oil (9 g). This crude product was purified by HPLC (silica gel, 20% ethyl acetate in hexane) to yield the pure product (8.6 g, 55%) as a yellowish semi-solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>O1CCCC1.CCCCCC>[S:4]1[CH:5]=[CH:6][C:2]([C:15]2([OH:19])[CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]2)=[CH:3]1
Reactant: CC1CCCC(=O)C1
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCC(O)(c2ccsc2)C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 36.3 g (0.223 mol) of 3-bromothiophene in 50 mL of dry tetrahydrofuran was cooled to -78° C. in a dry ice-acetone bath. To this solution was added dropwise 139.4 mL (14.3 g, 0.223 mol, 1.6 M in hexane) of n-butyllithium in hexane over 30 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for 1.5 hours, then 25.0 g 0.223 mol, of 3-methylcyclohexanone was added dropwise during 20 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for two hours. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature during 1.5 hours, then was stirred for an additional one hour. Diethyl ether saturated with water (50 mL) was added with stirring, and the mixture was poured into a mixture of 50 g of ice and 20 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous layer was washed with two portions of 200 mL each of diethyl ether. The washings were combined with the organic layer, and the whole was washed with 300 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 44.0 g of 1-(3-thienyl)-3-methylcyclohexanol. Volatile components were removed from the product by distillation at 50° C./0.25 mm using a Kugelrohr distilling system.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH3:13])[C:7]=2[CH:26]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>O>[Cl:2][C:3]1[C:4]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH2:21][CH2:22][N:23]([S:53]([CH3:52])(=[O:55])=[O:54])[CH2:24][CH:25]=3)[CH3:13])[C:7]=2[CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1ccccc1C1=CCNCC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](c1ccccc1C1=CCN(S(C)(=O)=O)CC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To round bottom flask was added (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (34-6) (10 mg, 0.018 mmol), followed by NMP (1 ml), then DIPEA (50 μl, 0.286 mmol), followed by METHANESULFONYL CHLORIDE (6.80 μl, 0.087 mmol). The reaction mixture was then capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 2 minutes; the reaction mixture was diluted with H2O, then MeOH, & purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & concentrated to yield (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo-[d]oxazole-6-sulfonamide hydrochloride (36-1). MS [M+H] calculated; 596.1 observed; 596.0. 1H NMR (499 MHz, DMSO): δ 8.47 (s, 1H); 7.94 (s, 1H); 7.73 (d, J=7.8 Hz, 1H); 7.37 (d, J=7.6 Hz, 2H); 7.13 (d, J=9.8 Hz, 2H); 5.77-5.73 (m, 2H); 5.46 (s, 1H); 3.75-3.51 (m, 3H); 3.04-2.95 (m, 1H); 2.89 (s, 3H); 1.89-1.74 (m, 4H). Note: Peaks overlapping with water or solvent can not be accurately accounted for.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:25]=[N+]=[N-])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([NH2:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCc2ccc(C(N)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 18 h

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-azido-methyl}-benzonitrile (1.77 g, 4.02 mmol), triphenylphosphine (1.16 g, 4.42 mmol), water (0.5 mL) and tetrahydrofuran (25 mL) is stirred 18 hr. The mixture is concentrated, diluted with water (100 mL) and extracted to ethyl acetate (3×50 mL). The combined extracts are dried over sodium sulfate, filtered, and concentrated to a bright yellow residue. The compound is used without further purification. LCMS M−1 413.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[N:15]=[C:16]([C:28]#[N:29])[C:17](C#N)=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8]1)([CH3:6])[CH3:5].Cl.O>CO.C(Cl)(Cl)Cl>[CH:4]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[N:15]=[C:16]([C:28]#[N:29])[C:17]([O:2][CH3:1])=[N:18][C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8]1)([CH3:5])[CH3:6]
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1nc(-c2ccccc2)c(-c2ccc(=O)n(C(C)C)n2)nc1C#N
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a solution of sodium methoxide (81.5 mg) in MeOH (3 ml), 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (172 mg) was added and the mixture was stirred at 25-30° C. for 10 hours. After addition of conc. HCl (1.5 ml), the reaction mixture was stirred at 25-30° C. for 20 hours. Water and CHCl3 were added to the mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (43 mg) and with elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained methyl 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarboxylate as a solid (67 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccccc1N
Yield: 104.6 %

Procedure:
In a pressure vessel a mixture of 133 g of o-nitro-N,N-diethylbenzenesulfonamide, 5 g of 10% palladium on carbon, and 500 ml of ethyl acetate was shaken at 130° under 500 psi hydrogen pressure until hydrogen was no longer absorbed. The reaction mixture was cooled and the catalyst filtered off. Evaporation of the solvent in-vacuo gave 123 g of o-amino-N,N-diethylbenzenesulfonamide as a viscous oil which slowly crystallized to a solid, m.p. 45°-51°.