Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>CCCCCC>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in hexane (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in hexane was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:25])=[O:24])=[CH:21][CH:20]=1>>[ClH:25].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: COc1ccc(C(=O)Nc2ccc(N3CCN4CCC3CC4)cc2)cc1
Product: Cl

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 4-methoxybenzoyl chloride. Mp. >275° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(=O)C(C)C.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)(C)(C)C.C(O)C.[Pd]>[CH2:1]([CH:14]([CH2:13][C:12]([OH:21])=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]([CH3:5])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Pd]
Agent: CC(C)C=O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)O)CC(C)C

Procedure:
49.4 g of potassium tert.butoxide in 350 ml of tert.butanol were stirred and heated under reflux under nitrogen. A mixture of 36.4 ml of isobutyraldehyde and 83.2 ml of diethyl succinate was added over a period of 0.25 hour and the mixture was heated under reflux for 1.5 hours. The solution was evaporated to a small volume, acidified with 2N hydrochloric acid and the evaporation was continued. The residue, diluted with water, was extracted three times with 300 ml of diethyl ether each time and the ether solutions were combined, washed with water and extracted three times with 200 ml of 10% potassium carbonate solution each time. The basic solution was acidified with concentrated hydrochloric acid and the product was extracted into diethyl ether, washed with water, dried over anhydrous magnesium sulfate and evaporated to give an oil. This oil was dissolved in 400 ml of ethanol and the solution was hydrogenated for 2 hours in the presence of 5 g of 5% palladium/carbon. After filtration and evaporation of the filtrate there were obtained 69.8 g of crude 1-ethyl hydrogen 2(RS)-isobutylsuccinate.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN.[CH3:31]O>[Ni]>[NH2:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([C:13]3[CH2:14][CH2:15][CH:10]([N:2]([CH2:1][CH3:31])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:11][CH:12]=3)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reactant: CO
Agent: [Ni]
Agent: NN
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(N)ccc23)CC1

Procedure:
A solution of compound 127 (0.2 g, 0.518 mmol) in dry MeOH (3 mL) was treated with Ra—Ni (0.02 g) followed by hydrazine hydrate (0.16 mL, 5.188 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 2 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2×15 mL). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to obtain compound 130 as a foam. 1H NMR (DMSO-d6) δ 1.08 (t, 3H, J=6.9 Hz), 1.41 (s, 9H), 1.72-1.89 (m, 2H), 2.18-2.60 (m, 4H), 3.10-3.20 (m, 2H), 4.01 (brs, 1H), 4.71 (s, 2H), 6.02 (brs, 1H), 6.39 (dd, 1H, J=1.5, 8.5 Hz), 6.51 (d, 1H, J=1.8 Hz), 6.99 (d, 1H, J=2.1 Hz), 7.43 (d, 1H, J=8.4 Hz), 10.44 (s, 1H); ESI-MS (m/z, %): 378 (M+Na, 8), 356 (MH+,4), 300 (100).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.C(O[CH:11]=[NH:12])C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH2:25])[NH:23][N:24]=1.[C:26]([OH:29])(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([OH:29])(=[O:28])[CH3:27].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH:25][CH:11]=[NH:12])[NH:23][N:24]=1
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N=CNc1cc(-c2ccccc2Cl)n[nH]1

Procedure:
To a vigorously stirred solution of saturated aqueous Na2CO3 (50 mL) and methylene chloride (50 ml) was added solid ethylformimidate hydrochloride salt (8.98 g, 82 mol). After stirring for several minutes the aqueous layer was separated and extracted with additional methylene chloride (3×50 ml). The combined organic layers were dried (MgSO4) and filtered. To the stirred solution was added 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-9a; 5.27 g, 27 mmol) in methylene chloride (50 mL) and then glacial acetic acid (2.67 ml, 46.6 mmol), dropwise. A cloudy precipitate began to form as the acetic acid was added. After stirring overnight, the solids were collected by vacuum filtration, washed with methylene chloride, and then dried, in vacuo, to give intermediate I-3A-9b, contaminated with ˜25% of the corresponding dimer (MW=396; 2 pyrazoles+1 formamidine), as a solid (5.7 g, 75%): +APcI MS (M+1) 221.1; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.62-7.30 (m, 4H), 6.48 (s, 1H), 1.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[CH2:28]([O:30][CH2:31][C:32](Cl)=O)[CH3:29].C(N(CC)CC)C>>[CH2:28]([O:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:29]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCCN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCN1CCCC1=O
Yield: 56.7 %

Procedure:
1-[3-(3-Amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (2.21 g, 6.13 mmol) was treated with ethoxyacetyl chloride (0.95 mL, 8.76 mmol) according to the methods described in Parts C and D of Examples 152-156. Triethylamine (8.6 mmol) was added in Part C. The product from Part D was purified by column chromatography on silica gel (eluting with acetone and then chloroform:methanol in a gradient from 95:5 to 90:10) to provide 1.49 g of 1-[3-(2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]pyrrolidin-2-one as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:46][CH2:47][CH:48]([OH:52])[CH:49]([CH3:51])[CH3:50]>ClCCl>[OH:52][CH:48]([CH:49]([CH3:51])[CH3:50])[CH2:47][NH:46][C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(O)CNC(=O)CCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
46.00 g (206.07 mmol) 3-benzyloxycarbonylamino-propionic acid, 51.37 g (267.95 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 27.85 g (206.07 mmol) hydroxybenzotriazole (HOBT) and 37.14 ml (267.95 mmol) triethylamine are placed in 700 ml dichloromethane, the mixture is stirred for 0.5 hours at 0°, then 23.70 g (229.73 mmol) 1-amino-3-methyl-butan-2-ol are added. The reaction mixture is stirred for 16 hours at ambient temperature. Then it is extracted with potassium carbonate solution and dichloromethane. The organic phase is washed with 1 molar sodium hydroxide solution, dried and evaporated to dryness. The residue is extracted with diethyl ether, then recrystallised with acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1Br.[C:13]([Cu])#[N:14].O.N>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(N)ccc1Br
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N)ccc1C#N
Temperature: 150 °C

Procedure:
The mixture of 5-amino-2-bromobenzoic acid methyl ester (14.27 g, 62.0 mmol) and CuCN (6.11 g, 68.2 mmol) in DMF (130 ml) was heated at 150° C. for 1 h 10 min under nitrogen atmosphere. The mixture was cooled to 70° C. and poured into the mixture of water (250 ml) and 12.5% NH3 (500 ml). The product was extracted into ethyl acetate (3×250 ml). The organic phase was washed several times with 12.5% NH3 and water, dried over Na2SO4 and concentrated under vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:21]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(NCC(F)(F)F)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2,2,2-trifluoroethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 10.4 mg of 254. MS (Q1) 462.7 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])[CH3:4].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[NH2:30][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: CCCCCCCCc1ccc(CCC(C(=O)OCC)C(=O)OCC)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1ccc(CCC(N)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
60% Sodium hydride (0.38 g) was suspended in dry dimethyl-formamide (30 ml) and ethyl 2-ethoxycarbonyl-4-(4-octylphenyl)-butyrate (3.0 g) was added thereto. The mixture was stirred at room temperature for 2 hours. O-(2,4-Dinitrophenyl)hydroxyl-amine (1.14 g) was added thereto and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into cool water and extracted with toluene. The extract was washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled away under reduced pressure to give 3 g of the subject compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][NH2:21])=[CH:16][C:15]([N+:22]([O-:24])=[O:23])=[CH:14][CH:13]=3)[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(N(CC)CC)C.NC[CH2:34][C:35]1[C:43]2C(=CC=CC=2)N[CH:36]=1.[C:44]([O:47]CC)(=[O:46])C>C(Cl)Cl>[C:35]([O:47][C:44](=[O:46])[NH:21][CH2:20][CH2:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=2)[NH:11][C:10]=1[C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:2])[CH:4]=1)([CH3:43])([CH3:36])[CH3:34]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN)c1
Reactant: CCOC(C)=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]-ethylamine hydrochloride salt (1 g) was suspended in dry methylene chloride (25 mL) and dry triethylamine (0.806 mL) was added and stirred for 5 minutes at room temperature. [2-(tert-butoxycarbonyloxyimino)phenylacetronitrile] (890 mg) was added in small portions over 5 minutes to the tryptamine and the reaction mixture left to stir overnight at room temperature. The reaction was partitioned between methylene chloride and 5% citric acid. The methylene chloride layer was separated and washed with brine and dried over anhydrous sodium sulfate powder. The extract was filtered and evaporated to dryness. The product was isolated by column chromatography using silica gel and an eluant of ethyl acetate and hexanes (35:65 v/v). The yield of the title compound was 1 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([Cl:11])[CH:3]=1.[Cl:12]C1C=CC(C(=O)C)=C(C)C=1>>[Cl:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1.[C:8]([Cl:12])(=[O:10])[CH3:5]
Reactant: CC(=O)c1ccc(Cl)cc1C
Reactant: CC(=O)c1ccc(C)cc1Cl
Product: CC(=O)Cl
Product: Cc1cccc(Cl)c1

Procedure:
A mixture of 4'-methyl-2'-chloroacetophenone and 4'-chloro-2'-methylacetophenone (98 g), [obtained by reaction of 3-chlorotoluene with acetyl chloride using the conditions of C R Noller and R Adams, J.Amer.Chem.Soc., 46, 1892 (1924)], methylamine (33% w/w solution in industrial methylated spirit, 130 ml), copper powder (3 g) and industrial methylated spirit (150 ml) was stirred in a sealed pressure vessel at 100° overnight. After cooling, further methylamine solution (130 ml) was added, the pressure vessel resealed and the mixture stirred at 100° overnight. The cooled mixture was washed out of the pressure vessel with industrial methylated spirit (2×200 ml) and then heated to 60°. Aqueous sodium sulphide nonahydrate (6.1 g in 60 ml water was added, the mixture stirred at 60° for 15 minutes and filtered through diatomaceous earth (sold under the trade name CELITE). The filter bed was washed with industrial methylated spirit (2×100 ml) and the combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was stirred with hydrochloric acid (5M, 400 ml) for 2.75 hours and the resultant aqueous solution basified to pH 8 to 9 with aqueous sodium hydroxide (specific gravity 1.5). The mixture was extracted with dichloromethane (600 ml, then 2×400 ml), the combined extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was dissolved in diethyl ether (500 ml) and the solution extracted with hydrochloric acid (5M, 3×150 ml). The diethyl ether solution was discarded. The aqueous extracts were basified to pH 8 with aqueous sodium hydroxide (specific gravity 1.5) and then extracted with diethyl ether (2×250 ml). The combined diethyl ether extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was distilled under reduced pressure to give the novel compound 4'-methyl-2'-(methylamino)acetophenone, m.p. 47°.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CO>[ClH:12].[C:25]([NH:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:16]1[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]1=[NH:2])(=[O:27])[CH3:26]
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CC(=O)Nc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)Nc1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.70 g) and N-[3-(aminomethyl)phenyl]acetamide hydrochloride (1.20 g) in methanol (10 ml) was added triethylamine (1.66 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (10 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the aqueous layer was basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.30 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[NH2:13][OH:14].C1(C)C=CC=CC=1>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[OH:14])/[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C/C(=N/O)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 97 %

Procedure:
1-(2,4-Dihydroxyphenyl)ethanone (4.5 g, 29.6 mmol) was dissolved in pyridine (17 mL). Hydroxylamine hydrochloride (2.1 g, 29.6 mmol) was added in small portions over 10 minutes. The reaction mixture was stirred at room temperature over night, partitioned between ethyl acetate and H2O. The organic layer was washed with H2O and 0.2 M aqueous HCl respectively. The oily residue was treated with H2O, evaporated in vacuo to yield a white semi-solid residue which was treated with toluene and then evaporated in vacuo to give the sub-title compound (4.8 g) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C1(C2C=CC=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]=[O:35])=[N:30][C:31]=1[O:32][CH3:33]>O1CCCC1.O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[OH:35])=[N:30][C:31]=1[O:32][CH3:33]
Reactant: Brc1ccc(C2CC2)cc1
Reactant: COc1nc(C=O)ccc1Cl
Agent: [Li]CCCC
Agent: c1ccc(C2CC2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C(O)c2ccc(C3CC3)cc2)ccc1Cl
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.65 M, 3 mL) was added dropwise to a solution of the mixture of 4-bromo-1-cyclopropylbenzene and cyclopropylbenzene (976 mg) in tetrahydrofuran (20 mL) at −78° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (732 mg) in tetrahydrofuran (9 mL) was added to the reaction solution at −78° C., and the mixture was stirred at the same temperature for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→1:10) to give (5-chloro-6-methoxypyridin-2-yl)(4-cyclopropylphenyl)methanol (765 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[C:40](O)(C(F)(F)F)=[O:41]>CN(C=O)C>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:40]=[O:41])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide (Example 212) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (11 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.24 (1H, m), 7.17 (2H, dt, J=8.4; 1.6 Hz), 7.14 (1H, m), 7.11 (1H, m), 5.82 (1H, s), 4.68 (1H, t, J=8.0 Hz), 4.56 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.05 (2H, m) ppm.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[C:14]([CH:15]=O)=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)(=O)C>[OH:4][C:5]1[C:14]([CH:15]=[N:2][OH:3])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc2ccc(O)c(C=O)c2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2ccc(O)c(C=NO)c2n1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Referring to FIG. 19, hydroxylamine hydrochloride (0.106 g, 1.52 mmol) was added to a mixture of 6 (0.200 g, 1.06 mmol) in a solution of NaOH (0.3 in 6 mL water). The reaction was stirred at 95° C. for 15 min followed by the addition of glacial acetic acid until it reached pH 6. The resulting mixture was cooled in an ice bath and vacuum filtered to afford 7 (0.176 g, 0.869 mmol, 82% yield) as a yellow solid, which was carried to the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([C:16]([N:18]([CH2:20][C:21]([OH:23])=O)[CH3:19])=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[CH3:19][N:18]([CH2:20][C:21](=[O:23])[N:55]1[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]1)[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)=[O:17]
Reactant: CN(CC(=O)O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
DIPEA (216 mg, 0.3 mL, 1.6 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid (100 mg, 0.37 mmol) in DMF (3 mL). HOBT (55.2 mg, 0.4 mmol) and EDCI (178 mg, 0.92 mmol) were then added at room temperature. After 2 minutes piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (131 mg, 0.44 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 135 mg (71.3% yield) of biphenyl-4-carboxylic acid methyl-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 96.56%. 1H NMR (DMSO-d6): δ 7.9-7.6 (m, 7H), 7.6-7.45 (q, 4H), δ 7.45-7.3 (q, 2H), 4.5-4.2 (m, 2H), 4.15 (s, 1H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.25-3.1 (m, 2H), 3.0 (s, 3H).