Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2F)[CH2:5][CH2:4]1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:30]2[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]2)[CH2:7][CH2:8]1
Reactant: F[C@@H]1CCNC1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(F)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2,3-difluoro-4-methylamino-5-nitro-benzoic acid amide (200 mg, 0.52 mmol), (R)-3-fluoropyrrolidine×HCl (72 mg, 0.57 mmol), DIPEA (0.76 mL, 4.4 mmol) and MeCN (5 mL). Yield: 230 mg. HPLC Rt=1.52 min (method A). MS m/z: 451 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=C.C(N(C(C)C)C(C)C)C>C(#N)C1C=CC=CC=1.[Pd](C#N)C#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:6]=[CH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: N#C[Pd]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: N#Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC)cc(OC)c1
Yield: 49.4 %

Procedure:
0.0792 g (5 millimols) of palladium(II) cyanide, 10.03 g (50 millimols) of 3,5-dimethoxybenzoyl chloride, 6.26 g (62.5 millimols) of ethyl acrylate and 6.46 g (50 millimols) of N-ethyldiisopropylamine, in 100 ml of benzonitrile, are stirred for 70 minutes at 140° C. The crude product is distilled in vacuo. Working up affords 5.83 g (49% of theory) of ethyl 3,5-dimethoxycinnamate as a colourless liquid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([NH2:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[O:6]=[C:1]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([NH2:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.9 %

Procedure:
Valeryl chloride (6.0 mL, 50 mmol) was added to a mixture of anthranilamide (6.8 g, 50 mmol) and triethylamine (7.0 mL, 50 mmol) in tetrahydrofuran (100 mL) at 25° C. A rapid, exothermic reaction was observed, but no external cooling was required to prevent reflux. The mixture was stirred at ambient temperature for 19 hours, after which it was poured into excess aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried (magnesium sulfate), and concentrated in vacuo. The residue was triturated with hexane/ether to give the title compound as a tan solid (9.9 g, 90%); M.p. 119° C.-120° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[CH3:38])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[SH:43][CH2:44][CH2:45]O.B(F)(F)F.CCOCC>ClCCl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:29][CH2:28][C:27]4([O:30][CH2:45][CH2:44][S:43]4)[CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC3(CC2)OCCS3)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 0.20 g (0.34 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 5 ml dichloromethane were added 0.03 g (0.4 mmol) 2-mercaptoethanol and 0.11 g (0.34 mmol) boron trifluoride etherate at 0° C. After 1 h the reaction mixture was allowed to warm to room temperature and stirred over night. Dilution with a 2 N aqueous sodium hydroxide solution was followed by extraction with 3 portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.22 g (98%) of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20]>C(CC(C)(C)C)(C)C>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)CC(C)(C)C
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of iso-octane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:31][C@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1.C(N(CC)CC)C>C1COCC1>[N:34]12[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35]1)[C@H:32]([N:31]1[C:10](=[O:12])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C:14]1=[O:16])[CH2:33]2
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of N-benzyliminodiacetic acid (2.23 g, 10.0 mmol) in THF (30 mL) was added 1,1′-carbonylbis-1H-imidazole (3.57 g, 22.0 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at reflux temperature for 30 min (until the evolution of C02 gas ceased, giving a clear solution), then cooled to room temperature. To the resulting mixture was added a solution of (3S)-3-aminoquinuclidine dihydrochloride (2.00 g, 10.0 mmol) and triethylamine (3.06 mL, 22.0 mmol) in THF (10 mL) stirred at room temperature under nitrogen atmosphere for 30 min via a cannula. The combined reaction mixture was stirred under reflux for 24 h, then cooled to room temperature and quenched with H2O (10 mL). The organic layer was extracted with EtOAc (50×2 mL) and the combined organic layers were dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (NH gel, 200-350 mesh, 150 g, EtOAc) to give a product (2.17 g, 69%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17](=[O:18])[CH2:16][CH2:15][CH:14]3[C:19]([OH:21])=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([NH2:71])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1>CN(C=O)C>[Br:58][C:59]1[CH:60]=[C:61]([NH:71][C:19]([CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:13]2[CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[CH2:8][CH2:9]2)=[O:21])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1
Reactant: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)O)CC2)ccc1Cl
Reactant: Cn1nnnc1-c1cc(N)cc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(Br)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid as DIPEA salt (2.6 g) in DMF (100 ml) was added DIPEA (2.1 g), and HATU (4 g). 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine (1.4 g) was added and the reaction stirred overnight at rt. The reaction mixture was filtered and the filtrate partitioned between water and EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (DCM:MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). Rf=0.19 (95:5 DCM:MeOH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1c(F)cccc1F
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(NC(=O)c3c(F)cccc3F)nc2n1
Temperature: 4 °C
Yield: 40.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (5.1 g), N,N'-carbonyldiimidazole (5.2 g) and 2-amino-7-methoxy-1,8-naphthyridine (4.4 g). The product produced by precipitation in water (4.5 g; m.p. 215°-217° C.) is dissolved in boiling ethanol (70 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (3.2 g) is produced, m.p. 219°-220° C.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][NH2:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CN(C)C=O>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][NH:15][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 10.0 g (0.043 mol) of (1f) and 10.3 g (0.036 mol) of N-BOC-L-alanine, N-hydroxysuccinimide ester in anhydrous N,N-dimethylformamide (50 ml) was cooled with an ice bath. To this was added 7.6 ml (0.054 mol) of triethylamine in anhydrous N,N-dimethylformamide (20 ml) over a period of 30 minutes. The reaction was stirred at ca. 5° C. for 1 hour, then at room temperature for 1 hour. The N,N-dimethylformamide was removed in vacuo and the resulting residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) and finally, with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 12.4 g (94% yield) of N-BOC-L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1g) as a white solid. TLC: Rf 0.67 (chloroform-isopropanol 9:1); 1H NMR(CDCl3) δ 1.27(d, 3H), 1.40(s, 9H), 3.32(m, 4H), 4.15(m, 1H), 5.06(s, 2H), 5.51(d, 1H), 5.90(m, 1H), 7.19(m, 1H), 7.31(bs, 5H); 13C NMR (CDCl3) δ 18.5, 28.2, 39.6, 40.5, 50.1, 66.5, 79.8, 127.9, 128.3, 136.3, 155.4, 156.9, 173.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24](SC)=[N:25][CH:26]=2)=[CH:18][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:24]2[NH:23][C:22](=[O:29])[C:21]([CH2:20][C:19]3[CH:30]=[CH:31][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:26][N:25]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(Cc2cnc(SC)[nH]c2=O)cc1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: COc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cc1
Yield: 70.8 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.875 g) and 5-(4-methoxybenzyl)-2-methylthio-4-pyrimidone (0.786 g) were refluxed in pyridine (3 ml) for 20 hours. The pyridine was evaporated in vacuo. Residual pyridine was removed from the residue by azeotroping with water in vacuo and dried by azeotroping with ethanol. Addition of water (10 ml) and ethanol (1 ml) gave a colourless solid. This was recrystallised from ethanol and then from methanol to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(4-methoxybenzyl)-4-pyrimidone (0.97 g) m.p. 149°-50° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([NH:21][C:22]2[N:26](C3CCCCO3)[N:25]=[C:24]([C:33](=O)[NH:34][C:35]3[CH:39]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[N:37](C4CCCCO4)[N:36]=3)[CH:23]=2)=O)=[N:8]1.CO.Cl>C1COCC1>[C:43]1([CH3:46])[CH:42]=[CH:41][C:40]([C:38]2[NH:37][N:36]=[C:35]([NH:34][CH2:33][C:24]3[CH:23]=[C:22]([NH:21][CH2:19][C:9]4[CH:10]=[C:11]([C:12]5[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=5)[NH:7][N:8]=4)[NH:26][N:25]=3)[CH:39]=2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(NC(=O)c4cc(-c5ccc(C)cc5)n(C5CCCCO5)n4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CNc3cc(CNc4cc(-c5ccc(C)cc5)[nH]n4)n[nH]3)n[nH]2)cc1
Temperature: 0 °C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-ylcarbamoyl)-1H-pyrazol-5-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (28 mg, 0.04 mmol) was suspended in anhydrous THF (500 μL) and borane dimethylsulfide complex (26 μL, 0.27 mmol) was added dropwise. The reaction mixture was stirred under reflux for 16 hrs. The reaction mixture was then cooled down to 0° C. and MeOH (50 μL) was added and the mixture was stirred for 10 min. Concentrated hydrochloric acid (12 N) was added until pH<2 was obtained The resulting mixture was stirred at 50° C. for 16 hrs. The mixture was cooled to room temperature and the solvent was evaporated. The residue was resuspended in THF and the precipitate was filtrated and washed with cold THF. 5-p-Tolyl-N-((5-((5-p-tolyl-1H-pyrazol-3-yl)methylamino)-1H-pyrazol-3-yl)methyl)-1H-pyrazol-3-amine was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[OH:10])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(C2=CCOCC2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2-Bromo-4,6-dimethylphenol (430 mg, 2.14 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (494 mg, 2.35 mmol), Pd(dbpf)Cl2 (69.7 mg, 0.11 mmol) and sodium carbonate (680 mg, 6.45 mmol) were dissolved in dimethoxyethane:water=3 mL:1 mL, followed by stirring in microwave at 120° C. for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 2-(3,6-dihydro-2H-pyran-4-yl)-4,6-dimethylphenol (160 mg, 37%) as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl)([O-:17])=[O:16]>[O-]CC.[Na+]>[CH:1]([NH:3][C:4]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N+:15]([O-:17])=[O:16])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC=O)C(=O)OCC
Yield: 75.4 %

Procedure:
Diethyl (formylamino)malonate (20.3 g, 0.1 mol) was added to a stirred solution of sodium ethoxide (250 mL of 0.4 M). 2-Nitrobenzyl chloride (17.2 g, 0.1 mol) was added, the mixture was refluxed for 2 hours and the solvent was then removed under reduced pressure. The material was partitioned between ethyl acetate and water, the ethyl acetate was separated and evaporated to give 40.3 g of crude product. The compound was crystallized from ethyl acetate:hexane to give 25.5 g of diethyl (formylamino)((2-nitrophenyl)methyl)propanedioate; mp 129°-132° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:31]1[C:35]([CH2:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:38])=[N:34][N:33]=[N:32]1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (50.7 mg, 0.122 mmol), (1H-tetrazol-5-yl)-acetic acid (15.6 mg, 0.122 mmol), triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were reacted as above to give a clear oil. The crude product was crystallized from methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide as off-white crystals (11 mg, 17%). ES-MS calcd for C25H22F3N7O3 (m/e) 525.49, obsd 526 (M+H).
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Reactant: Fc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[OH-].[Na+].O>CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoroaniline (11.1 g, 100.0 mmol) in 100 ml of dry ether cooled in an ice bath is added ethyl chloroformate (7.1 ml, 8.1 g, 75.0 mmol). After addition, the mixture is allowed to warm to RT and is stirred at RT for 3 hours. Then a 10% sodium hydroxide solution (54 ml, 2.8M, 150.0 mmol) is added, followed by another 7.1 ml of ethyl chloroformate. The mixture is stirred at RT for 3 hours, and is then poured into water and ether. The organic layer is separated, washed with 5% HCl and with brine, and dried. The solvent is removed to give ethyl N-(2-fluorophenyl)carbamate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:24]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[C:21]=2[C:22]#[N:23])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cccc(F)c2C#N)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.6 g; 2.6 mmol) was added to a suspension of sodium hydride (125 mg; 3.1 mmol) in 5 mL of anhydrous dimethylformamide at 0° C. Mixture was then heated to 40° C. for 2 hours. Anion was cooled to room temperature and added to a 0° C. mixture of 2,6-difluorobenzonitrile in 5 mL of dimethylformamide. After 16 hours at room temperature, reaction was quenched over 20 g of ice, mixture was extracted 4×50 mL with ethyl acetate. Combined organics was washed with 6×40 mLs water, brine and dried over MgSO4. Crude oil was obtained after filtration and concentration. Material was purified by flash chromatography using 2-3.5% methanol/dichloromethane gradient to obtain 660 mg of title compound. (73% yield).
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]2[N:13]=[N:12][NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:15].[CH3:21][N:22](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[Cl:20][C:3]1[C:4]([O:5][C:6]2[C:14]3[N:13]=[N:12][NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[Cl:15])=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=1[C:21]#[N:22]
Reactant: Clc1cc(Br)c(Cl)c(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(3-bromo-2,5-dichlorophenoxy)-5-chloro-1H-1,2,3-benzotriazole (2.55 g, 6.49 mmol), tetrakis triphenylphosphine palladium(0) (2.25 g, 1.95 mmol) and zinc cyanide (0.915 g, 7.79 mmol) were suspended in dry DMF (50 mL) under N2 and placed in an oil bath at 90° C. for 24 hours, after which the reaction mixture was allowed to cool to room temperature. The cooled mixture was then diluted with EtOAc (200 mL) and washed with water (4×100 mL), the aqueous layer was extracted with EtOAc (100 mL) and then washed with water (4×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated with silica gel. The concentrate was purified by automated column chromatography on silica gel (40 g) eluting with 0-30% EtOAc/hexanes to afford the title compound. LRMS (M+1)=340.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH:10]([CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(Cl)nc1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 2-chloro-5-aminopyridine (500 mg, 3.88 mmol) and acetone (250 μL, 4.27 mmol) in dichloroethane (13 mL) was added NaBH(OAc)3 (989 mg, 4.66 mmol) and AcOH (330 μL, 5.82 mmol). The reaction was stirred for 24 hours and was diluted with 1N NaOH. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 505.2 mg of (6-chloro-pyridin-3-yl)-isopropyl-amine. 1H NMR (CD3OD) δ 7.64 (d, 1H), 7.10 (d, 1H), 6.99 (dd, 1H), 3.55 (m, 1H), 1.17 (d, 6H).