Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:32]([CH3:33])[CH:29]1[CH2:30][CH2:31][N:26]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:51]([C:48]4[C:49](=[O:50])[N:44]([C:41]5[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=5)[N:45]=[CH:46][CH:47]=4)=[O:52])=[CH:20][C:19]=3[F:25])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[N:9]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (25.63 mg, 0.1095 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.95 mg, 0.3649 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol), N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707 (M+1).
Reaction SMILES: [OH:1][C@@:2]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]([NH:44][CH3:45])=[O:43])[CH:38]=2)[CH:33]=1)([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[CH2:3][C:4](OC)=[O:5].O.Cl>C(OCC)(=O)C>[OH:1][C@@:2]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42]([NH:44][CH3:45])=[O:43])[CH:36]=[CH:35]2)([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
0.188 g (0.314 mmol) of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 0˜5° C., and the mixture was stirred for 30 minutes. The mixture was stirred at room temperature for 4.5 hours. 7 mL of water was added dropwise at 35° C. or lower. 2.5 mL of 1N hydrochloric acid was added dropwise, followed by dilution with 10 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 2 mL of an aqueous saturated sodium bicarbonate solution and 2 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, the concentration residue was loosened with 2 mL of IPE, crystals were filtered, and washed with 1 mL of IPE. Vacuum drying (40° C.) to a constant weight afforded 0.16 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 90%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[NH2:32][NH2:33]>C(O)C.O>[CH2:25]([C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]2[C:11]([C:12]=1[CH2:27][C:28]([NH2:30])=[O:29])=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[CH:17][CH:16]=2)[CH3:26]
Reactant: NN
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)NN)ccc2n1Cc1ccccc1
Yield: 87 %

Procedure:
A mixture of 211 mg (0.05 mmol of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of hydrazine in 5 mL of ethanol was heated to maintain reflux for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with MeOH and the insoluble material filtered to give 177 mg (87% yield) of 2-ethyl-5-(4-hydrazino-4-oxobutoxy)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 176°-179° C.
Reaction SMILES: [Na].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[CH:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.C(OCC)C>[Br:9][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)COc1ccc(Br)cc1

Procedure:
2.76 g of sodium are dissolved in 100 ml of anhydrous ethanol and 20.8 g (0.120 mol) of p-bromophenol are added. 22.1 g (0.132 mol) of ethyl bromoacetate are run into this solution over the course of 20 minutes and the mixture is then heated under reflux for 1 hour. The ethanol is driven off under reduced pressure and the residue is dissolved in diethyl ether; after washing with water and then with a potassium carbonate solution, and evaporating the solvent, 30.2 g of a white powder are obtained. After purification of this product by crystallisation from petroleum ether, 23 g of a white, water-insoluble powder are obtained.
Reaction SMILES: [OH:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].[CH2:22]([O:24][P:25]([CH2:30][S:31][CH2:32][CH2:33]O)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:22]([O:24][P:25]([CH2:30][S:31][CH2:32][CH2:33][O:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O:26][CH2:27][CH3:28])=[O:29])[CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Reactant: CCOP(=O)(CSCCO)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CSCCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Yield: 45.8 %

Procedure:
A mixture of 9-hydroxy-6-phthalimidopurine (0.5 g, 2.2 mmol). diethyl-2-hydroxyethylthiomethylphosphonate (0.45 g. 2 mmol) and triphenylphosphine (0.52 g, 2 mmol) was dissolved in dry tetrahydrofuran (20 ml) and cooled to 0°-5° C. A solution of diethylazodicarboxylate (0.348 g, 2.0 mmol) in dry tetrahydrofuran (10 ml) was added dropwise with stirring, and after the addition was completed the reaction was stirred at room temperature for 18 hours. The solvent was then removed in vacuo, and the residue was purified by column chromatography on silica using ethyl acetate: methanol (98:2) as eluent to give 9-[2-(diethoxyphosphorylmethylthio)ethoxy]-6-phthalimidopurine (0.45 g 56%) as a white solid after crystallisation from acetone/diethyl ether, m.p. 115°-116° C.; γmax (EtOH) 271mm (s 14020) υmax (KBr) 3100, 3060, 2960, 2900, 1780, 1725, 1650, 1600, 1580, 1453, 1400, 1380, 1360, 1320, 1280, 1240, and 1200 cm-1 ; δH [(CD3)2SO] 1.25 (6H, t, J 7Hz 2 × CH3), 3.0 (2H, d, J 13Hz, PCH2S), 3.1 (2H, t, J 7Hz CH20, 4.0 (4H, m, 2 × CH2), 4.7 (2H, t, J 7Hz, CH2S), 8.1 (4H, m, Ar H), 9.0 (1H, s, 2H), 9.1 (1H, s, 8-H). (Found C, 48.65; H, 4.55; N, 14.23%. C20H22N5O6PS requires C,48.87; H, 4.51; N, 14.25%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 140 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argon at 140° C. for 2 hours. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. MH+: 377.9721
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[CH:20]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)nc(N2CCN(c3ccc(O)cc3)CC2)c1C#N
Temperature: 110 °C
Reaction time: 10 h
Yield: 51.1 %

Procedure:
12.26 g (36 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 8.24 g (36.1 mmol) of 2-chloro-3-cyano-4-methyl-6-phenylpyridine and 7.46 g (54 mmol) of powdered K2CO3 in 135 ml of absolute DMF were reacted at 90° C. according to the procedure described in Example 20. The mixture was subsequently stirred for 10 hours at 110° C. After removal of the DMF by distillation, the residue was taken up in CH2Cl2 /water. After thorough mixing, separating the phases and extraction of the aqueous solution, the CH2Cl2 extracts were combined, dried and evaporated. The crystalline residue (14.6 g) was recrystallized three times as follows. The substance was dissolved in a boiling mixture of CH2Cl2 /CH3OH 1:1, and the majority of the CH2Cl2 was then removed by distillation. A product crystallized out of the CH3OH solution obtained, and was filtered off under suction and again recrystallized in this fashion. Further impure substance was isolated from the mother liquors by concentration etc, and this was finally recrystallized again as described above. In this fashion, 6.82 g (=51% yield) of 1-(4-hydroxyphenyl)-4-(3-cyano-4-methyl-6-phenylpyrid-2-yl)piperazine, melting point 207°-08° C., were obtained;
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1>>[CH2:2]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(CC(=O)c2ccccc2)c2ccccc12
Yield: 56.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.88 g of bromoacetophenone and 2.00 g of indole-3-carbaldehyde as a starting material to give 2.06 g of 1-phenacylindole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 57%.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].[Cl:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>C(N(CC)CC)C>[Cl:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:4][CH2:3][CH:2]([CH3:5])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2-Methylpropylamine (0.5 mL) was added to a suspension of 2,4-dichloro-3-nitroquinoline (1 g) and triethylamine (15 mL) at 40° C. over a period of 40 min. The solution was then heated at 70° C. for 1 h. The triethylamine and 2-methylpropylamine were removed by distillation and the residue was slurried for 1 h in aqueous 1N HCl. The solid product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine was collected by filtration, washed with water and recrystallized from petroleum ether.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH2:22][CH:23]=[CH2:24])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:22]([N:17]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:20][N:19]([CH2:2][C:3]2[N:4]=[CH:5][NH:6][C:7]=2[CH3:8])[C:18]1=[O:21])[CH:23]=[CH2:24]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: Cc1[nH]cnc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2nc[nH]c2C)c1=O
Temperature: 25 °C

Procedure:
100 mg (0.89 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 252 mg (1.07 mmol) of the compound from Example 12A and 370 mg (2.68 mmol) of potassium carbonate were dissolved in 4.5 ml of DMF and 4.5 ml of water, and the mixture was stirred in a microwave oven at 200° C. for 75 min. After cooling to RT, for work-up, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 1:1, then dichloromethane/methanol 10:1). This gave 153 mg (52% of theory) of the target compound in a purity of 73%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CC(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[CH:59]=2)[CH:54]=[C:53]1[C:71](O)=[O:72])=O)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:71]([C:53]2[NH:52][C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:68])([CH3:67])[CH3:69])[CH:59]=3)=[O:72])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (0.090 g, 0.237 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.0491 g, 0.158 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-2-carboxylic acid (0.048 g, 0.158 mmol) and diisopropylethylamine (0.041 mL, 0.237 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.055 g, 58%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 9.81 (s, 1H), 8.89 (t, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.39-7.53 (m, 4H), 7.36 (t, 1H), 7.03-7.12 (m, 2H), 4.52 (d, 2H), 3.57 (t, 2H), 2.36-2.49 (m, 2H), 1.10 (s, 9H). ES MS: m/z 597 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[C:24]([NH2:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.Cl>>[C:13]([O:17][C:18]([N:20]1[C:24]([NH:25][C:6](=[O:8])[CH:5]([CH3:9])[CH2:4][CH2:3][CH2:2][Br:1])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(Cl)cc2)cc1N
Reactant: CC(CCCBr)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCCBr)C(=O)Nc1cc(-c2ccc(Cl)cc2)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-2-methyl-pentanoic acid (1.79 g, 9.2 mmol, 1 eq) in anhydrous DCM (8 mL) oxalyl chloride (1.0 mL, 12.0 mmol, 1.3 eq) was added dropwise and the mixture was stirred at room temperature for 16 hours. After evaporation of the solvent and the excess oxalyl chloride, the residue was dissolved in anhydrous DCM (8 mL) and a solution of 5-amino-3-(4-chloro-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (2.7 g, 9.2 mmol, 1.0 eq) and triethylamine (1.7 mL, 12 mmol, 1.3 eq) was added dropwise at 0° C. The mixture was allowed to reach room temperature and stirred at room temperature for 24 hours, after which another 0.5 eq of activated 5-bromo-2-methyl-pentanoic acid was added. HCl 1M was added; the crude was extracted with DCM and purified through SiO2 column (eluent DCM) to give 3.3 g (yield 97%) of the title product.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:19](#[N:21])[CH3:20].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C:4]([CH3:16])([CH3:17])[C:3](=[O:18])[CH2:20][C:19]#[N:21])=[CH:13][CH:12]=1
Reactant: CC#N
Reactant: COC(=O)C(C)(C)COCc1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COCC(C)(C)C(=O)CC#N)cc1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of 3.66 g (14.5 mmol) of 2,2-dimethyl-3-(4-methoxybenzyl-oxy)-propionic acid methyl ester and 1.07 mL (20.5 mmol) of acetonitrile in anhydrous toluene (10 mL) is added dropwise to a refluxing suspension of 0.83 g (20.5 mmol) of sodium hydride (60% dispersion in mineral oil) in toluene (20 mL). After the addition is complete, the mixture is stirred at reflux for 3 h, then allowed to cool to room temperature. The reaction mixture is then diluted with 1M aqueous HCl solution to neutral pH, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water and brine, then dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 3.95 g of 5-(4-methoxy-benzyloxy)-4,4-dimethyl-3-oxo-pentanenitrile, which is used in the next step without further purification. Yield: assumed quantitative, no spectroscpic analysis performed.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[C:18]1[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:29]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1CCCCN1CCOc1ccc(N)cc1-c1ccnn1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of 4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.1 mmol), 3,4-difluorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 459 as a white solid in 88.2% yield. LCMS m/z (%)=455.5 (M+H, 100).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[CH:12][CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a mixture of 1-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (10.04 g, 27 mmol) and HCOOK (15.87 g, 189 mmol) in THF/H2O (54 mL, THF/H2O=4:1) was added catalytic amount of Pd/C (5%, 53%˜55% water content, w/w). The reaction was stirred at 45° C. for 5 hours, and then diluted with THF/H2O (40 mL, v/v=1:1). The resulted mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with EtOH/H2O (30 mL×3, v/v=5:1), and dried in vacuo at 45° C. for 24 hours to give the title compound as a light gray solid (8.1 g, 87%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:54][N:55]=[CH:56]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:54][N:55]([CH3:56])[C:9](=[O:10])[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1
Agent: N
Product: CN(O)C(=O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 3-cyclohexyl-2-[4-(pyrid-2-yl-methoxy)phenyl]propionic acid for {[1-(3-[2-naphthylmethoxyl]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 0.85 (m, 2H), 1.1 (m, 4H), 1.43 (m, 1H), 1.6 (m, 5H), 1.8 (m, 1H), 3.04 (s, 3H), 4.25 (m, 1H), 5.24 (s, 2H), 6.93 (d, J=7Hz, 2H), 7.2 (d, J=7Hz, 2H), 7.33 (m, 1H), 7.5 (d, J=7Hz, 1H), 7.82 (dt, J=7Hz, 2Hz, 1H), 8.58 (m, 1H), 9.8 (bs, 1H). IR (CDCl3): 3620, 3440, 1610 with shoulder 1660 cm-1. MS (DCI/NH3) m/e 369 (M+H)+.