Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30].Br[CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: ClCCBr
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(O)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Propyl 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (80 mg) and 1-bromo-2-chloroethane (0.082 ml) were dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (274 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (85 mg, yield 91%).
Reaction SMILES: [N:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:31][CH:30]=1.C(N(CC)CC)C.O>C(C(C)=O)C>[CH2:39]([N:36]([CH2:37][CH3:38])[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:15][CH2:16][CH:11]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:3][C:2]3=[O:10])[CH2:12][CH2:13]2)=[CH:30][CH:31]=1)=[O:41])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCBr)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.8 %

Procedure:
4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)piperidine (49 mg) was dissolved in methyl ethyl ketone (1.8 ml), added with the 1-bromo-3-[2-(4-diethylcarbamoylbenzyl)-phenoxy]propane (91 mg) obtained in Reference Example 1 and triethylamine (47 μl) and stirred at room temperature for 17 hours. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=20:1) to obtain 49.7 mg of the title compound. Yield: 41%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
To a suspension of 1-(4-Hydroxyphenyl)-4-tert-butoxycarbonylpiperazine (3 g) and potassium carbonate (0.82 g) in N,N-dimethylformamide (15 ml) was added octyl bromide (1.87 ml). The mixture was stirred for 10 hours at 70° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel, and eluted with (hexane : ethyl acetate=9:1). The fractions containing the object compound were combined, and evaporated under reduced pressure to give 1-(4-n-Octyloxyphenyl)-4-tert-butoxycarbonylpiperazine (2.71 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6]CC)=[O:5].[CH3:18][N:19]([CH3:21])N>>[CH3:18][N:19]([CH3:21])[NH:6][C:4](=[O:5])[C:3]1[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Reactant: CN(C)N
Product: CN(C)NC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Yield: 81 %

Procedure:
The acid prepared in Example 203 was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 1,1-dimethylhydrazine using General Method E1 to afford the title compound. Purification by recrystallization from ether/hexanes gave 0.62 g of the title compound as off-white crystals in 81% yield. m.p. 144-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Temperature: 13 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (1.0 g, 3.93 mmol) in DCM (20 mL) was added triethylamine (796 mg, 7.87 mmol) followed by CbzCl (808 mg, 4.72 mmol) at 0° C. The reaction mixture was stirred at about 0 to 26° C. for 1.5 hours. After the solvent was removed, the residue was purified by silica gel column chromatography (PE/EtOAc=10:1) to give the title compound as a yellow oil (1.44 g, 94.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].CCCC[Sn]([C:36]1[N:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(CCCC)CCCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][N:41]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CCOC(=O)c1nc(-c2ccccn2)c2onc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 12 from 7-Bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-(1,1,1-tributylstannyl)pyridine; ESI MS (m/z): 362.31 (M+H+); 360.34 (M−H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH:30]=O>>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH2:30][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13](=[O:18])[CH2:14]1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1CC=O
Product: Cc1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (2-Methyl-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 413 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12]([OH:14])=[O:13].[H-].[Na+].[CH:17]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O>[CH:17]1([CH2:23][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc2c(C(=O)O)c[nH]c12
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
The damp solid was suspended in 4 M aqueous sodium hydroxide (1700 ml) and heated to reflux with stirring for 2 h. The mixture was cooled and washed with diethyl ether (2×400 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-methoxy-1H-indole-3-carboxylic acid as a pink solid (42.7 g). To a solution of 7-methoxy-1H-indole-3-carboxylic acid (42.7 g, 224 mmol) in di-methylformamide (1250 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 23.0 g, 575 mmol) portionwise over 20 minutes, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 minutes. Cyclohexylmethyl bromide (64.7 ml, 464 mmol) was added. The mixture was heated at 60° C. with stirring for 3 h. The mixture was cooled to 10° C. and poured into water (3600 ml). The emulsion was washed with diethyl ether (3×500 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (55 g) as a white solid. Oxalyl chloride (12.4 g, 97.4 mmol) was added dropwise to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (7.0 g, 24.4 mmol) and dichloromethane (150 ml) under ice-water cooling and the resulting mixture was stirred at room temperate for 18 h. Dichloromethane and excess oxalyl chloride were removed by evaporation and the obtained residue was mixed with dichloromethane (150 ml). Ammonia gas was bubbled into the resulting mixture for 30 min under ice-water bath cooling. The reaction mixture was concentrated in vacuo, then the obtained solid was triturated sequentially with 0.5 M hydrochloric acid, 5% aqueous sodium carbonate, and water, and dried under reduced pressure to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (5.1 g) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][CH2:16][CH2:17][CH2:18][NH2:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=1)=[O:29]
Reactant: COc1cc2nccc(OCCCN)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(OCCCNC(=O)Nc3ccc(F)cc3)c2cc1OC
Reaction time: 0.25 h

Procedure:
6,7-Dimethoxy-4-(3-aminopropoxy)quinoline 150 mg (0.57 mM) and ethyl acetate (20 ml) were stirred at room temperature, and then 4-fluorophenyl isocyanate (0.078 ml, 0.68 mM) was added and the mixture was further stirred for 15 minutes. The precipitated solid was filtered out to obtain the target substance (92 mg) as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Mg]Cl)CCC.[C:21]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22].Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][CH2:3][CH2:2][CH2:1][CH2:26][CH2:25][O:24][C:21]([CH3:22])=[O:23]
Reactant: CC(=O)OCCBr
Reactant: C=CCCC=CCCC=CCCCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCCC[Mg]Cl
Agent: Cl
Product: CCCC/C=C\CC/C=C\CCCCCCOC(C)=O
Temperature: 0 °C
Yield: 11 %

Procedure:
1,5,9-Tetradecatriene (10 g, 0.052 mol), n-butylmagnesium chloride (24.8 mL of 2.5M in tetrahydrofuran; 0.062 mol) and titanium tetrachloride (0.52 g, 0.0027 mol) were stirred under an inert atmosphere at about 65° C. for about 4.5 hours. The reaction mixture was then cooled to 0° C. and cuprous bromide (0.14 g, 1.0 mmol) was added. 2-Bromoethyl acetate (6.9 mL, 0.063 mol) was then added dropwise and the mixture allowed to warm slowly to room temperature and stirred for several hours at room temperature. Reaction temperature was then raised to 60° C. for 4 hours before the mixture was cooled, acidified with aqueous HCl, then extracted with hexane. The hexane extract was washed with saturated sodium bicarbonate solution, dried over MgSO4, filtered and solvent removed on the rotary evaporator. GLC analysis of this crude reaction product indicated an 11% yield of gossyplure. It should be recognized that while this reaction represents successful production of gossyplure from 1,5,9 -tetradecatriene in one reaction vessel, the reaction parameters have not been optimized. Consequently, significantly improved yields of gossyplure can be expected upon optimization of various reaction parameters.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]2=[CH:8][CH:7]=1
Reactant: Cc1ccc2sc(Cl)cc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc2nc(CBr)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of the product of Step 1 (0.371 g, 2.0 mmol), N-bromosuccinimide (0.396 g, 2.2 mmol), and benzoyl peroxide in 10 mL of carbon tetrachloride was refluxed under a sun lamp for 1 hr. After cooling to room temperature, the solvent was removed and the title bromide was purified by flash chromatography on silica (eluted with 5% EtOAc in hexane) to yield 0.284 g (46%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20]1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:25](=[O:26])[CH2:24][CH:21]3[CH2:22][CH2:23][O:19][CH2:20]3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)CC1CCOC1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(CC1CCOC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product from Example 1B and 2-(tetrahydrofuran-3-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.44-8.46 (m, 1H), 8.27-8.29 (bs, 1H), 7.89-7.94 (m, 1H), 7.80-7.86 (m, 1H), 7.74-7.79 (m, 1H), 3.91-3.98 (m, 6H), 3.70-3.82 (m, 1H), 3.57-3.61 (m, 1H), 3.21-3.23 (m, 4H), 2.77-2.81 (m, 1H), 2.51-2.54 (m, 2H), 2.15-2.30 (m, 1H), 1.68-1.78 (m, 1H); MS (APCI+) M/Z 359 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3](OC)=[O:4].Cl.[NH2:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O>[CH:16]1[C:11]([CH2:10][C@H:9]([NH:8][C:3]([CH2:2][NH2:1])=[O:4])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=1
Reactant: COC(=O)CN
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: O
Product: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Gly-OMe.HCl was added to the L-Tyr-TBP prepared by converting L-Tyr into its ionic liquid form according to the method described in Example 4 such that the concentration of the former was set at a level of 1.000 mmol/kg-L-Tyr-TBP (the amount of water present in the reaction system relative to the total mass of the system: 2% by mass). Then, the mixture was stirred enough to ensure the mixture uniform. Thereafter, the mixture was heated to 37° C. or 60° C., while stirring the same in a water bath. The reaction was finished 48 hours after the initiation of the reaction, and samples, which were collected at appropriate intervals of time during the reaction, were analyzed according to the HPLC technique to confirm the formation of the intended dipeptide, i.e., L-Gly-Tyr. The results are listed in the following Table 3.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][C:15]#[N:16].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](O)=[O:24]>>[C:15]([CH2:14][N:13]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1)#[N:16]
Reactant: Cc1ccccc1-c1ccncc1NCC#N
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(CC#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (4-o-tolyl-pyridin-3-ylamino)-acetonitrile and 3,5-bis-trifluoromethyl-benzoic acid (CAS RN 725-89-3) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated until a suspension formed. The colorless solid was filtered off and washed with a small amount of a mixture of EtOAc:n-heptane (1:6). Colorless solid (37%). MS (ESI): m/z=464.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[C:4]([CH3:16])[C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].S(=O)(=O)(O)O.[N:29]([O-])=O.[Na+].[NH2:33][C:34]1[C:39]([OH:40])=[CH:38][C:37]([Br:41])=[CH:36][N:35]=1>O.N1C=CC=CC=1>[NH2:33][C:34]1[N:35]=[C:36]([N:29]=[N:1][C:2]2[S:6][C:5]([C:7](=[O:15])[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=3)=[C:4]([CH3:16])[C:3]=2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:37]([Br:41])=[CH:38][C:39]=1[OH:40]
Reactant: Cc1c(C(=O)c2cccc(O)c2)sc(N)c1C(=O)OC(C)(C)C
Reactant: Nc1ncc(Br)cc1O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(C(=O)c2cccc(O)c2)sc(N=Nc2nc(N)c(O)cc2Br)c1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72 %

Procedure:
A slurry of t-butyl 2-amino-5-(3-hydroxybenzoyl)-4-methyl-3-thenoate in 150 ml of 1:5 acid (see Example 1-C) was cooled to 0° to 5° C. and 9 ml of concentrated sulfuric acid was added below 5° C. A solution of 4.21 g (0.61 mole) of sodium nitrite in 10 ml of water was slowly added, holding the temperature at 0° to 5° C. during the addition. The diazonium was stirred for 1.5 hours at 0° to 5° C. and then was added below 10° C. to a solution of 11.34 g of 2-amino-5-bromo-3-pyridinol (Example 2-L) dissolved in 30 ml of pyridine and 25 ml of 2:5 acid. The mixture was stirred for 2 hours at 0° to 5° C., then poured into cold water. The resulting mixture was filtered, washed with water, air dried and recrystallized from ethyl cellosolve to give 23 g (72 percent) of a red solid, used without further purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[C:15]([CH3:52])([CH3:51])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1>C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[C:15]([CH3:52])([CH3:51])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (9 mL) was stirred at 50° C. for 30 min, 4′-({4-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.98 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (9 mL). N,N′-Carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.52 g, 48%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([SH:13])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[N:3]([CH2:1][CH3:2])[C:4]2[N:9]=[C:8]3[S:10][C:11]([SH:13])=[N:12][C:7]3=[CH:6][CH:5]=2)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCNc1ccc2nc(S)sc2n1
Reactant: CCCCOc1ccc(N=C=O)cc1
Solvent: c1ccncc1
Product: CCCCOc1ccc(NC(=O)N(CC)c2ccc3nc(S)sc3n2)cc1
Reaction time: 3.5 h
Yield: 13.2 %

Procedure:
Into 13×100 mm pyrex reaction vial were added 5-ethylamino-thiazolo[5,4-b]pyridine-2-thiol (105 mg, 0.49 mmol), anhydrous pyridine (2 ml), and 4-butoxyphenyl isocyanate (135 μl, 0.74 mmol). The reaction mixture was stirred 3.5 h, then concentrated. Purification by preparative TLC (40% EtoAc in Hexanes) gave 26 mg (13%) of the title compound. 1H NMR (DMSO-d6) δ=0.91 (t, 3H), 1.10 (t, 3H), 1.39 (m, 2H), 1.61 (m, 2H), 3.91 (m, 1H), 6.80 (d, 2H), 7.30 (m, 3H) 7.99 (br d, 1H), 9.43 (s, 1H); ESIMS: m/z 401 (M−H); mp 134.3-135 C.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[NH:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.