Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+].[OH-].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:12])=[O:11])#[N:4]>[Ni].CO.C1COCC1>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[S:10]([N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:3][NH2:4])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])(=[O:11])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)N(CCCC#N)CCCCC#N)c(C)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCN)CCCCCN)c(C)c1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Raney nickel (W-2 grade, 7.60 g) and concentrated NH4OH (10 mL) were successively added to 38 (5.06 g, 14.6 mmol) in CH3OH (30 mL) and THF (30 mL) in a 200 mL Parr bottle, and a slow stream of NH3 was bubbled through the mixture for 30 minutes at 0° C. After hydrogenation in a Parr bottle was carried out at 50-55 psi for 8 hours, the suspension was filtered through Celite, and the solvents were removed in vacuo to give 4.70 g (91%) of 41 as an oil: NMR δ 1.14-1.24 (m, 10 H), 2.25 (s, 3 H), 2.6 (s, 6 H), 3.05-3.25 (m, 8 H), 3.45 (s, 4 H), 6.9 (s, 2 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH:10]([C:13]1[CH:19]=[C:18](Br)[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[C:14]=1[NH2:15])([CH3:12])[CH3:11]>C1(C)C(C)=CC=CC=1.[Cu](Cl)Cl>[CH:10]([C:13]1[CH:19]=[C:18]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[C:14]=1[NH2:15])([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: Cl[Cu]Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N

Procedure:
48.9 g of phenol are dissolved in 500 ml of xylene, and to this solution are added 30.2 g of pulverised potassium hydroxide in an atmosphere of nitrogen. The reaction mixture is stirred and heated to boiling point, while continuously distilling off the water that is formed. After addition of 0.6 g of copper chloride and 100 g of 2,6-diisopropyl-4-bromoaniline, the mixture is stirred for 8 hours at 150°-155° C., then cooled, and filtered with suction. The filtrate is washed with 15% sodium hydroxide solution (150 ml) and with two 150 ml portions of water. The organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation and the product is distilled, affording the compound of the formula ##STR5## with a boiling point of 103°-104° C./0.01 torr and a melting point of 71°-72° C. (after recrystallisation from hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]([F:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]([F:18])[CH3:17])[CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21]
Reactant: CCCOC(=O)N1CCNCC1
Reactant: CC(F)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)C(NC(=O)OCc2ccccc2)C(C)F)CC1
Reaction time: 12 h

Procedure:
To a solution of 500 mg 2-Benzyloxycarbonylamino-3-fluoro-butyric acid in 3 ml DMF were added 310 mg 1-propoxycarbonylpiperazine, 0.50 ml N-ethylmorpholine and 643 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was used without further purification in the next step. Yield: 591 mg
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1.C(Cl)Cl>[S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cc2ccsc2cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OB(O)c1cc2ccncc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of thieno[2,3-c]pyridine (2.040 g, 15.09 mmol) in anhydrous THF (50 mL) was added n-butyllithium (6.64 mL, 16.60 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of triisopropyl borate (4.16 mL, 18.11 mmol) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a 2 hour period. TLC showed the reaction was complete. Aqueous HCl (1N, 1000 mL) and DCM (500 mL) were added to the reaction mixture. The aqueous and organic layers were separated. The aqueous layer was concentrated to a volume of 500 mL and a solid precipitate was filtered and dried to give the title compound as off-white, needle-shaped crystals (2.4 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 8.41 (d, J=4.80 Hz, 1H), 8.66 (d, J=6.32 Hz, 1H), 9.10 (br s, 2H), 9.72 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of (2R,3R)-3-(benzyloxy)-2-(tritylamino)butan-1-ol (4.33 g, 9.91 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (1.52 mL, 10.9 mmol), tert-butyldimethylsilyl chloride (1.65 g, 10.9 mmol) and DMAP (122 mg, 1.00 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed successively with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 3.26 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylbutan-2-amine as a white solid.
Reaction SMILES: CS(C)(=O)=O.Cl.[C:7](Cl)(=[NH:9])[NH2:8].C([O:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[NH:18][C:17]=1[NH2:26])=O)C.O.N>C(Cl)(Cl)Cl.O>[NH2:8][C:7]1[NH:9][C:14](=[O:13])[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:25])[NH:18][C:17]=2[N:26]=1
Reactant: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Methyl sulfone (1 g) was heated to melting. Compound 7 (106.22 mg, 1.37 mmol) was added and the resulting mixture was stirred and heated at 110-120° C. to dissolve completely. 5 (200 mg, 0.837 mmol) was added in one part to the reaction mixture. Stirring was continued for 30 minutes. About 10 mL water was added to quench the reaction. Ammonia water was added to neutralize the reaction mixture. Solid precipitated out. This solid was filtered. Obtained solid was dissolved in chloroform and methanol, dried (using Na2SO4) and recrystallized. The overall yield was 78%. TLC Rf 0.33 (chloroform-methanol 1:1); mp>250° C.; 1H NMR (DMSO-d6) δ 6.57 (bs, 2H, 2-NH2, exch); 7.04-7.17 (m, 3H, phenyl); 10.41 (s, 1H, 9-NH, exch); 11.64 (s, 1H, 3-NH, exch). Anal. Calculated (C10H7ClN4O. 0.3CH3OH): C, 50.65; H, 3.38; N, 22.94; Cl, 14.52. Found: C, 50.91; H, 3.34; N, 22.60; Cl, 14.77.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1)=O.O.[NH2:19][NH2:20]>CO>[OH:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:3]([NH:19][NH2:20])=[O:2])[CH:14]=1
Reactant: NN
Reactant: COC(=O)c1cc(O)c2ccc(OC)cc2n1
Solvent: CO
Solvent: O
Product: COc1ccc2c(O)cc(C(=O)NN)nc2c1
Yield: 80 %

Procedure:
To a solution of 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid methyl ester (2.0 g, 8.58 mmol) in methanol (85 mL) was added hydrazine mono hydrate (1.7 g, 34.3 mmol) and the mixture was refluxed for 6 hours. The crude reaction mixture was concentrated in vacuo and the residue was taken up in methanol and poured onto an ice/water mixture (800 mL). A white precipitate formed, which was collected by filtration and washed with cold water. The filter cake was then dried on house vacuum by passing air through in sintered glass funnel, and then dried on vacuum oven at 45° C. overnight to afford 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid hydrazide (1.6 g, 80% yield). 1H NMR (DMSO-d6, 300 MHz) δ 11.57 (s, 1H), 10.28 (s, 1H), 7.95 (d, 1H), 7.43 (d, 1H), 7.01-6.91 (m, 1H), 6.54 (s, 1H), 4.72 (br s, 2H), 3.82 (s, 3H). LCMS found 234.18 [M+H]+.
Reaction SMILES: [C:1]([O:11]N1C(=O)CCC1=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:19][C:20]([NH2:27])([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH3:21]>C1COCC1>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][C:20]([NH:27][C:1](=[O:11])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:21])[CH3:19]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CCC(C)(C)N
Solvent: C1CCOC1
Product: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.1 %

Procedure:
Solid CbzOSu (15.6 g, 1 equiv, 48.8 mmol) was added in one portion to a solution of N1,N1-3-trimethylbutane-1,3-diamine (8.15 g, 62.6 mmol) in THF (100 mL). The reaction was left to stir at room temperature for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (500 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fractions were collected and concentrated to give a colorless oil (11.49 g, yield: 69.6%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.67-1.72 (t, J=6.6, 2H), 2.23 (s, 6H), 2.36-2.40 (t, J=7.2, 2H), 6.46 (s, 1H), 7.27-7.36 (m, 5H), LRMS (ESI+) for C15H24N2O2 (264.2); Found: 265 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Product: COC(=O)c1ccc([C@H](C)N2CCCS2(=O)=O)cc1

Procedure:
Using methyl (S)-4-(1-aminoethyl)benzoate (0.61 g) and 3-chloropropane-1-sulfonyl chloride (0.54 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (0.90 g) was obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=O.[CH3:8][C:9]([CH3:11])=[O:10]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[CH:8][C:9](=[O:10])[CH3:11]
Reactant: CCC=C(C)C=O
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: CCC=C(C)C=CC(C)=O
Yield: 29.1 %

Procedure:
Into a 2 liter autoclave are charged 2-methyl-2-pentenal (196 grams), acetone (580 grams) and zinc acetate dihydrate. The reaction mixture is heated at 170°-180° C. for a period of 5 hours. After filtering the catalyst the organic layer is washed with 10% salt solution. Distillation and bulking fractions 4-8 gives 80.3 grams of product, B.P. 91°-98° C. at 5-7 mm Hg. pressure. The bulked fractions or separate fractions are useful for augmenting or enhancing the aroma or taste of the foodstuff.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+].[N+]([C:15]1C=CC([O-])=CC=1)([O-])=O.[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH3:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([O-])c1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Product: COc1cccc([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The procedure and reactants of Example 1 were used except that sodium m-nitrophenolate was substituted for sodium p-nitrophenolate. 0.6 grams of m-nitroanisole (about 85 percent) were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=1>>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CN)o1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1

Procedure:
The method described in Example 23 was repeated except that 4-chloro-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine was used in place of 4-chloro-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and methyl 5-aminomethyl-2-furancarboxylate was used in place of ethyl (4-aminomethyl)benzoate to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([OH:33])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-]>ClCCl.CN(C)C1C=CN=CC=1>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([O:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (4.40 mL) and methanesulfonyl chloride (1.95 mL) was added to a cold (0° C.) stirred solution of cis-4-hydroxy-N-tert-butoxycarbonyl-L-proline 4-phenoxyphenylamide (C, 5.02 g) in dichloromethane (100 mL). The mixture was stirred at 0° C. for 2 hr and at room temperature for 45 min. Triethylamine (4.40 mL) and mehanesulfonyl chloride (1.95 mL) was added to the cold (0° C.) stirred mixture. The mixture was stirred at 0° C. to room temperature for 2 hr, and 4-dimethylaminopyridine (1.54 g) was added at 0° C. The mixture was stirred at room temperature for 1 hr and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.49 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), triethylamine (420 μL; 3.0 mmol) and 2-chloro-4-methyl-5-nitro-pyridine (346 mg; 2.0 mmol) is irradiated in a mono-mode microwave oven for 10 hours at 120° C. The mixture is then cooled to room temperature, water is added (5 mL) and the pH is adjusted to pH 4-5 by addition of aq. 1N hydrochloric acid. After extraction with dichloromethane (2×10 mL), the combined organic layers are dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0; 12:1; 2:1) to afford the desired product (480 mg; 1.43 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47](Cl)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:24]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)=[CH:37][CH:36]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43 %

Procedure:
Prepared using General Procedure 20. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 (786 mg, 2.33 mmol) and DIEA (448 μL, 2.56 mmol) in dioxanes (15 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (591 mg, 2.56 mmol), at room temperature. After 30 min the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (100 mL). The organics were concentrated in vacuo and the crude product purified by chromatography (MeCN/DCM) to afford 518 mg (43%) of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>CC(C)=O>[CH3:15][O:16][CH:17]([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:19]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: COC(C)C(=O)Cl
Solvent: CC(C)=O
Product: COC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 70.6 %

Procedure:
20.3 g (107 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone were stirred with 14.7 g (0.12 mole) of 2-methoxypropionyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 20.8 g (76%) of 6-[p-(2-methoxypropionylamino)-phenyl]4,5-dihydro-3(2H)-pyridazinone were obtained. Mp.: 245°-247° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[N-:32]=[N+:33]=[N-:34].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:34][N:33]=[N:32][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3C#N)cc1)C(C)C(=O)N2
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C)C(=O)N2
Yield: 45 %

Procedure:
A solution of 0.2 g of 7-butyl-6-((2'-cyanobiphenyl-4-yl)methyl]-3-methylimidazo[1,2-a]pyrimidin-2,5-dione in 4 ml of toluene and 1 ml of DMF is added with 38 mg of sodium azide and 0.17 ml of tributylstannyl chloride. After 72 h under reflux, the solvent is evaporated under reduced pressure and the residue is taken up in a NaOH diluted solution and extracted with toluene. The aqueous phase is acidified to pH 5 with AcOH, to separate a white solid which is filtered off and washed first with H2O, and then with a mixture of hexane-toluene to obtain g 0.1 of a white solid, after crystallization (45% yield).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.[F:16][C:17]([F:27])([F:26])[CH2:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)Cl>[N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)=[O:12])[CH:6]=[N:1][CH:2]=1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(CC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-(2,2,2-trifluoroethyl)aniline (105 mg, 0.60 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in water (20 mL) filtered and dried under vacuum to afford the title compound. LC-MS (Condition 4) tR=1.05 min, m/z=375.8 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ ppm 3.40 (q, J=10.76 Hz, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.65-7.71 (m, 3H) 7.80 (d, J=7.82 Hz, 1H) 7.87-7.98 (m, 2H) 8.15 (s, 1H) 9.03 (s, 2H) 9.28 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1nc(C=O)n(C)n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(Cl)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1): where 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from step 5 below, was substituted in place of 6-[2-(3-chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.47-1.74 (m, 8 H), 1.79 (s, 6 H), 2.01-2.11 (m, 8 H), 2.36-2.42 (m, 1 H), 2.56 (d, J=16 Hz, 1H), 2.60-2.66 (m, 2 H), 2.77 (d, J=16 Hz, 1 H), 3.53 (d, J=16 Hz, 1 H), 3.62 (d, J=16 Hz, 1 H), 7.25 (dd, J=8.2, 1.8 Hz, 1 H), 7.4 (d, J=1.8 Hz, 1 H), 7.45 (d, J=8.2 Hz, 1 H). Anal. Calcd. For C27H33ClN4O3.0.25H2O: C, 64.66; H, 6.73; N, 11.17. Found: C, 64.88; H, 6.74; N, 10.86. ESIMS (MH+): 498.