Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].CCCCCC>CO.C(OCC)(=O)C>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Yield: 91.3 %

Procedure:
In 20 ml of methanol were dissolved 2.570 g of 2,3-diphenyl-5,6-dihydropyrazine, 1.060 g of benzaldehyde and 0.672 g of potassium hydroxide. The solution was heated under reflux for 1 hour. Methanol was removed from the reaction solution by distillation under reduced pressure, and to the residue was added 50 ml of water. The resulting mixture was extracted three times with ethyl acetate. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel. A crude product was obtained from the eluates with an 8:1 hexane : ethyl acetate mixture. The crude product was recrystallized from hexane to give 2.940 g of 2,3-diphenyl-5-benzylpyrazine as colorless prisms. M.P. 118°-119° C. Physical properties of the product support a chemical structure of the below formula (VII).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2C=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.[N:41]1C=CC=CC=1>>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:9]2[N:41]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:39])[CH2:37][OH:36])=[N:6][C:5]3=[CH:7][CH:8]=2)[CH:13]=[CH:14][C:15]=1[CH3:32])=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: c1ccncc1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: CC(=O)OCC(=O)Cl
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.451 mmol) produced in Example C33(iv) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (78 μL, 0.722 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was added, and the mixture was washed with water (50 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (4.0 mL), 1N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (112 mg, 50%) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:13])([F:12])[F:11])[N:9]=[N:8]2)[CH:2]=1.[Br:15]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:1]1[CH:2]=[C:3]([C:7]2([C:10]([F:12])([F:11])[F:13])[N:9]=[N:8]2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C2(C(F)(F)F)N=N2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
To a solution of intermediate 63, 3-m-tolyl-3-trifluoromethyl-3H-diazirine, (200 mg, 1 mmol) in CCl4 (4 mL) was added N-bromosuccinimide (200 mg, 1.1 mmol, re-crystallized from water), and the stirred mixture heated at 85° C. To this was added AIBN (50 mg) and the mixture heated at reflux for an additional 2.5 hrs. After cooling, the mixture was purified by column chromatography (SiO2, pentane) to provide 150 mg (Yield 54%) of the title compound as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm: 4.42 (2H, s) 7.10–7.17 (2H, m) 7.31–7.45 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(Cl)(Cl)Cl>ClC=CCl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCN
Solvent: ClC=CCl
Solvent: ClC(Cl)Cl
Product: NCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 64698.7 %

Procedure:
26.4 g (0.3 mol) of 1,4-diaminobutane was dissolved in 100 ml of 1,2-dichloroethene and stirred together with 6.3 g (0.03 mmol) of 4-chlorophenylsulfonyl chloride at room temperature for 4 hours. After addition of chloroform, the reaction solution was filtered through celite, and the filtrate was washed with water three times and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent to give 5.1 g of the title compound in a yield of 65%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[CH2:12][CH2:11]3)=[CH:4][C:3]=2[O:2]1.[C:13](OC(=O)C)(=O)C.Cl[C:21](Cl)([F:26])[C:22]([O:24][CH3:25])=[O:23]>[Zn].[Cu]Cl.O1CCCC1>[F:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:10]1([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:12][CH2:11]1
Reactant: c1cc2c(cc1C1CC1)OCO2
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 51 %

Procedure:
The method of Example 1 was repeated using zinc powder (2.94 g), copper (I) chloride (0.45 g) molecular sieve 4A (3 g), tetrahydrofuran (54 ml), 1-formyl-1-(3,4-methylenedioxyphenylcyclopropane (3.09 g), acetic anhydride (1.5 ml) and methyl dichlorofluoroacetate (2.36 g) to yield the title compound (2.2 g, 51%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([NH:15]/[C:16](/[CH3:21])=[CH:17]\[C:18]([O-:20])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2=[C:14]3[C:13](=[CH:12][CH:11]=[C:9]2[N:10]=1)[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]3[OH:20]
Reactant: C/C(=C/C(=O)[O-])Nc1ccc2nc(-c3ccco3)[nH]c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(O)c2c(ccc3nc(-c4ccco4)[nH]c32)n1
Temperature: 230 °C

Procedure:
Dowtherm A (500 mL) is preheated to 230° C. and to it is added 3-[[2-(2-furyl)-5-benzimidazolyl]amino]crotonate (38.5 g, 0.1 mol) in small portions. After the addition is complete, the reaction mixture is maintained at 230° C. for 15 min and then poured into a beaker and allowed to cool.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([NH:38][CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:18][CH:19]=1)[C:36]([NH:38][CH3:39])=[O:37])#[N:34]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CNC(=O)CC#N
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Yield: 95.7 %

Procedure:
To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.0005 mole) and 2-cyano-N-methylacetamide (0.22 g, 0.0022 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (1.0 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 2 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate. Combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.255 g of 2-cyano-N-methyl-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide which was converted to the title compound as described in Example 1, Step 2 above.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=O)N.[CH3:11]C1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.[CH3:75][C:76]1[N:81]=[C:80]([NH:82][CH:83]([C:93]2[CH:102]=[CH:101]C3C(=C(O)C=CC=3)N=2)[C:84]2[CH:89]=[CH:88][C:87]([N+:90]([O-:92])=[O:91])=[CH:86][CH:85]=2)[CH:79]=[CH:78][CH:77]=1>CS(C)=O>[CH3:75][C:76]1[N:81]=[C:80]([NH:82][CH:83]([C:84]2[CH:85]=[CH:86][C:87]([N+:90]([O-:92])=[O:91])=[CH:88][CH:89]=2)[C:93]2[C:8]([OH:10])=[C:2]3[C:3]([CH:4]=[CH:5][CH:11]=[N:1]3)=[CH:101][CH:102]=2)[CH:79]=[CH:78][CH:77]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: Cc1cccc(NC(c2ccc([N+](=O)[O-])cc2)c2ccc3cccc(O)c3n2)n1
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(NC(c2ccc([N+](=O)[O-])cc2)c2ccc3cccnc3c2O)n1

Procedure:
H9c2 rat embryonic myocardial cells (from ATCC, Rockville, Md., USA) were grown in Dulbecco's modified eagle's medium containing 10% cattle serum, 4 mM L-glutamine (Sigma-Aldrich, Hungary), 100 IU/ml penicillin and 100 ug/ml streptomycin. To the H9c2 supernatant sample, 30 uM of the compound according to Example 1 (7-((6-methylpyridin-2-ylamino (4-nitrophenyl)methyl)quinolin-8-ol from a stock solution containing 30 mM of DMSO (1000-fold dilution) was added before electrophoresis. To the control, DMSO not containing the compound according to Example 1 was added. After electrophoresis, the gel was cut in two halves following renaturation one half was incubated in such a way that 30 uM of the compound, according to Example 1 was added to it at the final concentration, while the second half (control) was incubated without it. The compound according to Example 1 completely inhibited the 72 kDa gelatinase (MMP-2) if the substance was present during incubation. It inhibited the 92 kDa gelatinase (MMP-9) as well, hut to a less extent than the 72 kDa gelatinase,
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([N:13]=[C:14]=[O:15])([CH3:12])([CH3:11])[CH3:10]>[OH-].[Na+].O1CCCC1>[C:9]([NH:13][C:14]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)NC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 76.2 %

Procedure:
4.69 g of L-valine was dissolved in 40 ml of a 1N sodium hydroxide aqueous solution, and 5 ml of tetrahydrofuran was added to the solution. While stirring, 4.00 g of tert-butyl isocyanate was added, and the stirring was continued overnight at room temperature. After 10 ml of a 1N sodium hydroxide aqueous solution was added to the reaction mixture, the mixture was washed twice with 50 ml of ethyl acetate and acidified with 6N hydrochloric acid. Then, the reaction mixture was extracted twice with 100 ml of ethyl acetate. The extracts were washed twice with 50 ml of a saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate and then concentrating under reduced pressure, recrystallization was carried out from an ethyl acetate-hexane mixture to obtain 6.6 g of N-tert-butylcarbamoyl-L-valine as white crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[C:12]([CH3:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.1 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-t-butoxycarbonylaminopyrrolidine (200 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (110 mg, DBU) and anhydrous acetonitrile (2 ml) was refluxed for 18 hours. The reacting mixture was concentrated under reduced pressure. The resulting residue was dissolved in chloroform (20 ml), washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the solution of the resulting residue in methanol (2 ml) was added concentrated hydrochloric acid (2 ml) and stirred at room temperature for 15 minutes. After the reacting mixture was neutralized with concentrated aqueous ammonia, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting chloroform-methanol-concentrated aqueous ammonia (10:10:3) and recrystallized from dichloromethane-methanol further to give the title compound (30 mg) as yellow powder, mp 187°-190° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:22]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-Formylbenzoic acid (15.0 g, 0.1 mol, Aldrich) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol, Indofine) was dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a solid was obtained as the desired (E)-3-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6): 13.18 (br, 1H), 10.39 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.95 (m, 4H), 7.75 (d, 1H), 7.60 (m, 1H), 6.95 (d, 1H), 2.20 (s, 3H). MS (EI) for C17H14O4: 283 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:31]#[N:32])=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(Oc2nc(C#N)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 15 %

Procedure:
A mixture of Compound 1e (0.4 g; 0.92 mmol), Zn(CN)2 (0.11 g; 0.92 mmol), and Pd(PPh3)4 (0.106 g; 0.092 mmol) in DMF (2.4 mL) was irradiated at 160° C. in a CEM microwave reactor for 16 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6a (0.059 g; 15% yield). MS: m/z 426.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22]1>>[ClH:19].[OH:20][CH:21]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22]1
Reactant: NCCCN1CCC(O)C1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN3CCC(O)C3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 40 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with [3-(3-hydroxy-pyrrolidin-1-yl)-propyl]-amine as described in Step 5, Example 24 to give the title compound (40% yield). LC/MS: RT 2.25 min; m/e 426 (M+H).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1>O.CO>[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([O-:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)[O-])cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.0108 g, 0.27 mmol) in water (0.1 mL) was added to the solution of Example 7 (0.104 g, 0.27 mmol) in methanol (5 mL) and stirred at 25° C. for 15 min, the solvent was removed and dried to obtain the title compound. Yield: 0.11 g, (100%); 1H NMR (DMSO-d6, 300 MHz): δ 2.58 (s, 3H, CH3), 5.16 (s, 2H, CH2), 7.69 (d, 1H, Ar), 7.87 (d, 1H, Ar), 7.95 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.30 (s, 1H, CHO), 10.78 (s, 1H, NH); MS: m/e (ES−) 380 (M-Na); analysis: C16H11ClNNaO6S.2H2O requires C, 43.70; H, 3.44; N, 3.81; Cl, 8.06; S, 7.29. found: C, 42.88; H, 3.19; N, 3.04; Cl, 8.69; S, 7.67%.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 7.2 g. 3-propylthio-1,2,4-triazole, 6.8 g. diethylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 9 ml. dry triethylamine was refluxed under anhydrous conditions for 72 hours. The reaction mixture was worked up as described in Example 1 to produce a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 118° - 121° C./0.2 mm. (89.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)N=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].[CH2:27]1COCC1>[Pd]>[CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)n2)CC1
Reactant: C1CCOC1
Reactant: [H][H]
Agent: [Pd]
Product: CN1CCN(c2ccc(N)c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzyl-[6-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-2-yl]-amine E-3.1′ (600 mg; 1.833 mmol) is dissolved in THF and palladium on carbon is added. The reaction mixture is stirred for 2.5 h at 25° C. and 4 bar hydrogen pressure. The catalyst is filtered off under celite, the filtrate is concentrated and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[OH:18][CH2:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:27][C@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][OH:18])=[O:10]
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Reactant: N[C@H](CO)c1ccccc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 2-(3-chloro-phenoxy)-nicotinic acid (0.25 grams, 1.0 mmole) in thionyl chloride (10 ml) was heated to reflux. After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a solution of (S)-2-hydroxy-1-phenyl ethylamine (0.14 grams, 1.0 mmole) in pyridine (5 ml) at 0° C. After 30 minutes the mixture was warmed to room temperature. After 1 hour the mixture was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The combined organics were washed with 1 N hydrochloric acid followed by brine and dried over Na2SO4. Concentration under reduced pressure resulted in a yellow oil that was purified by chromatography on silica gel eluting with 1:1 ethyl acetate/hexane to give a colorless oil. Anal. calcd. for C20H17N2O3Cl: C, 65.13; H, 4.65; N, 7.60. Found: C, 65.20; H, 4.78; N, 7.38; M.S. m/z [M+] 369; 1H NMR (400 MHz, CDCl3) d 2.54 (s, broad, 1H), 3.95 (m, 2H), 5.32 (m, 1H), 7.23 (m, 10H), 8.22 (m, 1H), 8.58 (m, 2H).