Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH:21]=[CH:22][N:23](C)C)=[CH:16][CH:15]=3.[CH3:32][NH:33]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:33]([CH3:32])[N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CNN
Product: Cn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 37 above, with the compound from preparation 1.10F, 3-(2,4-dichlorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and methylhydrazine
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C1(C)C=CC=CC=1>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=1[OH:10])=[O:23])([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)c1cccc(O)c1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1

Procedure:
2-(2′-Carboxybenzoyl)-5-diethylaminophenol was prepared as follows. A mixture of m-diethylaminophenol (1 mole) and phthalic anhydride (1.2 moles) was refluxed in toluene (2.0 L) for about 16 hours, cooled, and the resulting solid filtered, washed with toluene and dried to give 2-(2′-carboxybenzoyl)-5-diethylaminophenol in 70% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.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>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: NCCN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1N
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: COc1cc(C(=O)NCCN2CCOCC2)ccc1N
Reaction time: 24 h

Procedure:
4-amino-3-methoxybenzoic acid (Aldrich; 5 g, 29.9 mmol) was stirred and dissolved in DMF (100 mL) at ambient temperature. 4-(2-aminoethyl)morpholine (Aldrich; 4.7 mL, 35.8 mmol) was added followed by DIPEA (15.6 mL, 89.7 mmol) and HATU (13.7 g, 36.0 mmol) causing a slight exotherm. The brown solution was stirred for 24 h and the solvent evaporated to a brown gum.
Reaction SMILES: C(OC(N1[CH2:11][CH:10]([N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:13][CH3:14])C1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][CH2:35][NH2:36]>>[CH2:13]([N:12]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:36][CH2:35][CH2:34][C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C@H:11]1[CH2:17][CH2:16][CH2:15][NH:12][CH2:10]1)[CH3:14]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CN(C(=O)OC(C)(C)C)C1
Reactant: NCCc1cccs1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccs3)n2)c1)C[C@H]1CCCNC1

Procedure:
Intermediate 105 was coupled with 2-thiophen-2-yl-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 437. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.71 (s, 1H), 8.40 (d, 2H), 7.98 (d, 1H), 7.75 (s, 2H), 7.21 (d, 1H), 6.93 (d, 2H), 4.61 (s, 2H), 4.03 (s, 2H), 3.13 (m, 6H), 2.85 (t, 2H), 2.67 (t, 1H), 2.39 (m, 2H), 1.81 (m, 4H), 1.29 (t, 3H).
Reaction SMILES: C[O:2][B:3]([C:6]1[C:11](=[O:12])[C:10]([O:13]CC2C=CC=CC=2)=[CH:9][N:8]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH:7]=1)[O:4]C>C1COCC1.CO.CO.[Pd]>[C:23]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=[C:21]([N:8]2[CH:9]=[C:10]([OH:13])[C:11](=[O:12])[C:6]([B:3]([OH:2])[OH:4])=[CH:7]2)[CH:22]=1
Reactant: COB(OC)c1cn(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(O)cn(-c2cccc(-c3ccccc3)c2)cc1B(O)O

Procedure:
The solution of crude dimethyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-3-yl]boronate (2.4 mmol) in THF/MeOH from the preceeding step and 10% Pd/C (52 mg, 0.49 mmol) was stirred under H2 (1 atm) for 18 h. The reaction mixture was diluted with MeOH (20 mL), filtered through a pad of Celite (MeOH wash), and concentrated under reduced pressure, The residue was diluted with DMF (10 mL) and 0.5 M aq, HCl (0.4 mL) and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added, fractions were lyopholized) to provide [1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid. ′H NMR (599 MHz, DMSO, 75° C.): S 8.19 (d, J=2.3 Hz, 1H); 7.89 (d, J=2.3 Hz, 1H); 7.83 (s, 1H); 7.79-7.74 (m, 3H); 7.67-7.61 (m, 1H); 7.56 (d, J=8.1 Hz, 1H); 7.49 (t, J Hz, 2H); 7.46-7.38 (m, 1H). HRMS (ES) calc (M+H)+ −308.1089. found 308.1092.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:21])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.C(=O)([O-])O.[NH4+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C>[NH2:22][C:18]([CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]([CH3:21])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenylacetic acid (2.0 g, 6.79 mmol) is dissolved in acetonitrile (15 mL). Subsequently, pyridine (0.34 mL, 4.22 mmol) and ammonium hydrogencarbonate (699 mg, 8.84 mmol) were added thereto, and the mixture was stirred for 10 minutes at room temperature. Thereafter, di-tert-butyl dicarbonate [Boc2O (2.03 mL, 8.84 mmol)] was added thereto, and the resultant mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (1.07 g, 3.65 mmol, 53.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:3]=1[CH2:4][O:5][C:6]1[CH:44]=[CH:43][CH:42]=[CH:41][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15].C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:3]=1[CH2:4][O:5][C:6]1[CH:44]=[CH:43][CH:42]=[CH:41][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]2[OH:20])=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2cc(C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C)c(COc2ccccc2Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-1,2-dihydropyrazol-3-one (152 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 18 mg), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added a solution of acetobromo-α-D-glucose (214 mg) in N,N-dimethylformamide (1 mL), and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 0.400 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2 mol/L hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH3:21])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([Br:22])=[N:19][N:18]=[C:17]2[CH3:21])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 75.5 %

Procedure:
To a suspension of 4.5 g of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone in 450 ml of carbon tetrachloride was added 3.1 g of N-bromosuccinimide and the mixture was heated under reflux for 3 hours. Then, the reaction mixture was filtered and the filtrate was cooled. The resulting crystals were filtered, washed with carbon tetrachloride and dried to obtain 4.3 g of brown 5-chloro-2-(3-methyl-5-bromo-4H-1,2,4-triazol-4-yl)benzophenone. A part of the product thus obtained was recrystallized from ethyl acetate to give colorless needles, m.p. 198° - 199° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[CH:13]([CH3:15])[OH:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[O:14][CH:13]([CH3:15])[C:12]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
2,4-Difluoronitrobenzene (16.9 g; 0.10 mole), ethyl lactate (11.8 g; 0.10 mole), and anhydrous potassium carbonate (13.8 g, 0.10 mole) are combined in dioxane (200 ml) and the temperature is brought to 95° C. over a 1.5 hour period and maintained at 95° C. for 3 hours. The reaction mixture is cooled to room temperature, the inorganic solids removed by filtration and the solvent removed under vacuum to afford a dark colored oil, from which low boiling fractions are removed by distillation (bp., 79° C./0.5 mm). The pot residue is then cooled to afford 15.9 g of crude product, which is recrystallized from ligroin/acetone to afford ethyl 2-(5-fluoro-2-nitrophenoxy)propionate as yellow needles, m.p. 64°-65° C. Elemental anal. Calcd for C11H12FNO5 : C, 51.4; H, 4.70; F, 7.38; N, 5.45. Found: C, 51.35; H, 4.74; F, 7.60; N, 5.44.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23]>>[NH2:16][C:15]1[CH:14]=[C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COCCOc1cc(N)ccc1OC
Reactant: O=Cc1ccccc1Cl
Product: COCCOc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC

Procedure:
(2-amino-5-methoxy-4-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xgg) was prepared by reacting 2-chlorobenzaldehyde with 0.0296 moles of 4-methoxy-3-(2-methoxyethoxy) aniline in a manner analogous to Example 1. MH+/Z=336.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)(=[O:12])[CH3:11]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(CCO)CC1
Temperature: 80 °C

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (5.5 ml; 42.3 mmol) in toluene (50 ml) was added acetic anhydride (4.0 ml; 42.4 mmol). The mixture was heated to 80° C. overnight. The solvent was removed under reduced pressure and the residue was washed several times with a mixture of diethyl ether and petroleum ether (1:1 v/v) to leave 6q1 as an oil (5.2 g; 72%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N:14]1([C:19]2[N:24]=[C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH2:31][NH2:32])[CH:22]=[C:21]([CH3:33])[N:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:32][CH2:31][CH2:30][N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[C:23]3[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:14]4[CH:18]=[CH:17][N:16]=[CH:15]4)[N:24]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2CCCN2CCN)nc(-n2ccnc2)n1
Reactant: O=CCc1ccc2c(c1)OCCO2
Product: Cc1cc(C2CCCN2CCNCCc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1

Procedure:
[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine was prepared following the procedures described in the preparation of Example 127 using (2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetaldehyde and 2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethylamine. [M+H]+ 435.54; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.75 (d, 1H), 6.70-6.60 (m, 2H), 4.18 (s, 4H), 3.54 (t, 1H), 3.15 (m, 1H), 2.94-2.74 (m, 5H), 2.52 (s, 3H), 2.40-2.20 (m, 4H), 1.95-1.66 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.[CH2:28](I)[CH:29]([CH3:31])[CH3:30]>>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:3][C:4]=1[Cl:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)CI
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Product: CC(C)Cc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1

Procedure:
In the same manner as in Preparation Example 70-2, the objective compound (1.644 g, 76%) was obtained as a colorless oil from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene and isobutyl iodide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=4)=[CH:23][C:22]=3[CH3:37])[N:11]=2)=[CH:5][CH:4]=1)#[N:2].C1C=[N:42]C2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl-].[NH4+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([NH2:42])=[O:35])=[CH:32][CH:33]=4)=[CH:23][C:22]=3[CH3:37])[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: On1nnc2cccnc21
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(-c2ccc(C(N)=O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Temperature: 80 °C

Procedure:
To a solution of 4′-(2-(4-cyanophenylamino)-9-methyl-9H-purin-6-yloxy)-3′,5′-dimethylbiphenyl-4-carboxylic acid (40 mg, 0.082 mmol), HOAt (23 mg, 0.18 mmol), and EDCI (35 mg, 0.18 mmol) was added ammonium chloride (25 mg, 0.47 mmol) followed by TEA (0.1 mL, 0.72 mmol) at rt. The reaction mixture was heated at 80° C. for 1 h and added H2O. The solid material which precipitated was collected by filtration and purified on silica gel preparative TLC to yield the desired compound. NMR (DMSO-d6): δ 10.10 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 8.03 (d, 2H), 7.87 (d, 2H), 7.66 (s, 2H), 7.62 (d, 2H), 7.43 (s, 1H), 7.35 (d, 2H), 3.80 (s, 3H), 2.18 (s, 6H); MS (ESI): m/z 490 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1F>C1COCC1.CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) was suspended in anhydrous THF (50 ml) under nitrogen and the resulting mixture is cooled to 0° C. To above suspension was added dropwisely (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol), followed by a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). The reaction mixture was then stirred at room temperature for another 4 hours. The reaction mixture concentrated under vacuum to about 40 mL, and was poured into 200 ml of ice:water. The resultant solid was isolated by filtration, washed with water (50 ml), and air dried to yield a yellow solid, 2-Chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene (5.8 g). The solid was suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture was stirred under hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite plug and the solvent is removed under reduced pressure to yield 5.2 g of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:11]([CH2:16][C:17]([OH:19])=[O:18])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)CN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: CC(C)CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), [(4-fluoro-benzenesulfonyl)-isobutyl-amino]-acetic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=140-143° C.
Reaction SMILES: [CH2:1]=O.[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Na].N>ClCCl.CO>[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:1])[CH2:28][CH2:29]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)cccc2o1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5c(F)cccc5o4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
37% aqueous formaldehyde (0.015 ml) at 0° C., was added to a stirred solution of 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine dissolved in dichloromethane (6 ml) and methanol (6 ml) over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 10 minutes. Sodium triacetoxyhydroborate (233 mg) was added at 0° C. to the mixture and stirred at 0° C. for 1 hour. A solution of 7N ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and tritured in hot acetonitrile, filtered and dried under reduce pressure to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (268 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:8][C:7]1[C:6]([F:10])=[CH:5][C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of N′-(3-chloro-5-fluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (600 mg, 2 mmol) in DCM (10 mL) at 0° C. were added PPh3 (1.06 g, 4.06 mmol) and CBr4 (1.3 g, 4.06 mmol). The resulting solution was stirred at room temperature for 30 min, concentrated, and purified by column chromatography (silica, DCM/EtOAc=20:1) to afford N′-(4-(bromomethyl)-3-chloro-5-fluorophenylsulfonyl)-N,N-dimethylformimidamide (673 mg, 92%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.11 (m, 1H), 7.78 (d, 1H), 7.57 (dd, 1H), 4.64 (d, 2H), 3.22 (d, 3H), 3.10 (t, 3H); MS (EI) m/z 379 (M+Na+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6]C=CC=1.NC1CCC[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>>[C:36]([O:35][C:33]([N:29]1[CH2:6][CH2:7][CH2:2][CH:1]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH2:28]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2sccc2Nc2ncnc3[nH]ccc23)C1
Yield: 14 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using tert-butyl 3-aminopiperidine-1-carboxylate instead of benzylamine and obtained in 14% yield. 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.39 (br s, 1H), 8.47 (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 8.09-8.01 (m, 1H), 7.78 (d, J=4.8 Hz, 1H), 7.38-7.14 (m, 1H), 6.48-6.43 (m, 1H), 3.91-3.75 (m, 3H), 2.80-2.62 (m, 3H), 1.92-1.84 (m, 1H), 1.75-1.66 (m, 1H), 1.65-1.54 (m, 1H), 1.40 (s, 9H); MS (m/z) 443 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[N:3][C:4]2[C:9](=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=2)[N:10]=1
Reactant: COc1cc2nc(N)c(OC)nc2cc1OC
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.9 %

Procedure:
2-Amino-3,6,7-trimethoxyquinoxaline (2.60 g, 11.0 mmol) and ethyl chloroformate (2.40 g, 22.1 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.75 g, 22.1 mmol) was added. The mixture was stirred at room temperature for 22 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 3.04 g of the titled compound (yield, 90%).