Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(N3CCOCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCOCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 70 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-morpholinopyrimidin-4-amine (34 mg, 0.080 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-morpholinopyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (22 mg, 0.056 mmol, 69.8% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.91 (s, 1H); 9.16 (s, 1H); 8.50 (s, 1H); 8.08 (d, J=4.97 Hz, 1H); 7.67 (s, 1H); 7.51 (s, 1H); 6.85 (d, J=8.77 Hz, 1H); 3.85 (s, 3H); 3.74 (s, 4H); 3.66 (s, 4H); 2.36 (s, 3H). m/z (ESI, +ve ion) 396.0 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.CI.O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C)c1ccccc1
Temperature: 0 °C
Yield: 70 %

Procedure:
5 0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.5 g (3.5 mmol) of methyl iodide is then added and then the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated. The product crystallizes when triturated in 10 ml of diisopropyl ether. It is filtered and then dried under vacuum. 0.73 g (yield: 70%) of Compound 22 is thus obtained in the form of a pale-yellow powder melting at 124° C.
Reaction SMILES: [H-].[K+].[C:3]1([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[C:15]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: NC(=O)CCc1ccccc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of potassium hydride (from 46 grams of 35% potassium hydride in oil washed three times with hexane)in 50 ml of THF is added with stirring under nitrogen to 20 grams of 3-phenylpropionamide in 350ml of THF. After addition of the hydride is complete, the reaction is allowed to warm to room temperature and is stirred for 30 minutes. The thickened reaction mixture is cooled to 0° to 5° C. and is then added dropwise over 30 minutes to a solution of 30 grams of p-pivaloylbenzoyl chloride in 50 ml of dry THF. The resulting solution is stirred for 15 minutes at 0° to 5° C. and is then quenched with 150 ml of saturated ammonium chloride solution. The THF phase is decanted off, and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extract is combined with the THF phase, dried with magnesium sulfate, filtered, and then evaporated almost to dryness. The resulting solids are triturated with ether, and the white crystals obtained are filtered, washed with ether and dried to yield the title product (m.p. 137°-138° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NC(=O)c1nc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
3-amino-6-bromo-pyrazine-2-carboxamide (500 mg, 2.304 mmol) was dissolved in pyridine (5 mL) and treated with POCl3 (666 μL, 7.145 mmol) dropwise at 0° C. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for 1.5 hours. The solvent was removed in vacuo and the reaction carefully treated with NaHCO3 to basify. The mixture was diluted with EtOAc and the layers separated. The aqueous layer was further extracted with EtOAc (1×) and the combined organics washed with brine (1×), 0.1 M HCl (1×) and water (1×), dried (MgSO4), filtered and concentrated to furnish the product as a brown solid (197 mg, 43% Yield). 1H NMR (DMSO) d 7.62 (2H, br s), 8.45 (1H, s) ppm
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:9]1[CH2:10][O:11][CH:19]([C:18]2[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(CO)CO
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC1COC(c2ccc(O)cc2)OC1
Yield: 45.7 %

Procedure:
A mixture of 2-n-octylpropane-1,3-diol (5.64 g, 0.03 m), 4-hydroxybenzaldehyde (3.66 g, 0.03 m), benzene (60 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected (about 16 hours). The solvent was evaporated and the residue was crystallized from 50% aqueous ethanol to yield p-(5-n-octyl-1,3-dioxan-2-yl)phenol (4 g, 48%) mp 96°-97° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:21])([F:20])[CH:15]([OH:19])[CH2:16][CH:17]=[CH2:18].[H-].[Na+].Cl>O1CCOCC1>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:19][CH:15]([CH2:16][CH:17]=[CH2:18])[C:14]([F:21])([F:20])[F:13])[CH:11]=1
Reactant: C=CCC(O)C(F)(F)F
Reactant: COC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCC(Oc1cc(F)ccc1C(=O)OC)C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 2,4-difluorobenzoate (1.72 g, 9.99 mmol) was dissolved in dioxane. To this was added 1,1,1-trifluoropent-4-en-2-ol (1.40 g, 9.99 mmol) followed by 60% (mineral oil) NaH (0.40 g, 9.99 mmol). The resulting mixture was heated to 90° C. and stirred overnight. After cooling to RT, 1N HCl was added and the mixture transferred to separatory funnel. The mixture was extracted with ethyl acetate after which the organic solution was washed with 1N NaOH (2 times) and sat'd NaCl. The solution was dried over Na2SO4, filtered and the solvent removed to yield the title compound as an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.C(OC(=O)C)(=O)C.CCN(CC)CC>>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])=[CH:12]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.3 %

Procedure:
A mixture of phenylacetic acid (0.0376 mol., 5.1 g) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.0376 mol., 5.5 g) in acetic anhydride (0.1881 mol., 17.7 ml) and Et3N (0.0376 mol., 5.2 ml) was stirred at 100° C., for 6 hrs. The obtained solution was cooled to 50° C., quenched with conc. hydrochloric acid (10 ml) and extracted with EtOAc. The organic phase was extracted with 1 N NaOH. 3-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid was then precipitated from the aqueous layer with conc. hydrochloric acid with ice-cooling. Filtration and recrystallization from isopropyl alcohol of the crude product afforded 4,4 g of the desired compound as a white solid (44%), m.p. >230° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>CN(C)C=O>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[F:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(CCl)c(F)c1OC
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(C)=O)c(F)c1OC
Temperature: 0 °C

Procedure:
5.5 g of α-chloro-2-fluoro-3,4-dimethoxytoluene and 4.05 g of potassium acetate are stirred at 80° for 25 hours in 50 ml of dimethylformamide. The reaction mixture is subsequently poured into 150 ml of ice-water and extracted with ether. The ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. 2-fluoro-3,4-dimethoxybenzyl acetate is obtained as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C=CC2N(O)N=[N:28]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:28])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Temperature: 30 °C
Reaction time: 17 h
Yield: 49.4 %

Procedure:
To a solution of 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxylic acid (1.42 g, 5 mmol) in DMF (70 mL) was added HOBt (0.75 g, 5.5 mmol), NH4Cl (0.27 g, 5.0 mmol), DIPEA (1.94 g, 15.0 mmol) and EDCI (1.15 g, 6.0 mmol). The mixture was stirred at 30° C. for 17 hr. To the resulting mixture, water (10 mL) was added and 1N aqueous hydrochloric acid to pH=3, then filtered, the filtrate was washed with saturated sodium bicarbonate solution (100 mL×2), brine (100 mL×2) and dried in vacuum to get a crude product. The crude product was re-crystallized in THF to obtain 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (700 mg, yield 49%); LC-MS (ESI) m/z 284 [M+1]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Cl[C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[IH:18]>>[I:18][C:11]1[CH:16]=[C:15]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccnc1
Reactant: I
Product: Ic1cc(-c2cccnc2)ncn1

Procedure:
The compound was prepared according to Example 1 using pyridine-3-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].Cl[C:8](OC1C=CC([N+]([O-])=O)=CC=1)=[O:9].CCN(C(C)C)C(C)C.[CH:29]1([CH2:32][O:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[C:40]([CH:44]2[CH2:49][O:48][CH:47]([CH2:50][CH2:51][CH2:52][NH2:53])[O:46][CH2:45]2)=[CH:39][CH:38]=[CH:37]3)[CH2:31][CH2:30]1>ClCCl.ClCCCl>[CH:29]1([CH2:32][O:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[C:40]([C@@H:44]2[CH2:49][O:48][C@@H:47]([CH2:50][CH2:51][CH2:52][NH:53][C:8](=[O:9])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:46][CH2:45]2)=[CH:39][CH:38]=[CH:37]3)[CH2:30][CH2:31]1
Reactant: OCC(F)(F)F
Reactant: NCCCC1OCC(c2cccc3cc(OCC4CC4)ccc23)CO1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1)OCC(F)(F)F
Temperature: 60 °C

Procedure:
0.075 ml (1.01 mmol) of 2,2,2-trifluoroethanol is added, dropwise and at ambient temperature, to a suspension of 0.205 g (1.01 mmol) of 4-nitrophenyl chloroformate and 0.555 g (2.02 mmol) N,N-diisopropylaminoethylpolystyrene (Ps-DIEA, 2% DVB, titre=3.66 mmol/g) in 7.1 ml of dichloromethane. The mixture is stirred with orbital shaking and at ambient temperature for 16 hours. The resin is filtered through a cartridge equipped with a sintered glass funnel and rinsing is carried out with 4 ml of dichloromethane. The filtrate is concentrated under reduced pressure and the oily residue thus obtained is taken up in 3.5 ml of 1,2-dichloroethane. 0.134 ml (0.78 mmol) of N,N-diisopropylethylamine and 0.205 g (0.6 mmol) of 3-[5-(6-cyclopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamine are successively added. This reaction mixture is heated at 60° C. for 16 hours. After cooling, washing is carried out with 20 ml of a 1N sodium hydroxide solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.076 g of white solid is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate (0.13 g) in methanol (1.5 mL) and ethyl acetate (3.0 mL), 10% palladium-carbon (0.063 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.084 g of tert-butyl 2-(2-hydroxy-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=3[F:30])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)[CH2:4][CH2:5][C:6]1=[O:22]
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reaction time: 3.5 h

Procedure:
A A mixture of 24 mg of 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1), 28 mg of 2,4-difluorophenylboronic acid, 3 mg of Pd(Ph3P)4, and 0.15 mL of a 1M aqueous Na2CO3 solution in 2 mL of toluene and 0.2 mL of EtOH in a 10 mL flask equipped with a reflux condenser was evacuated and purged three times with Ar. The mixture was heated to reflux and stirred at this temperature for 3.5 h, then cooled and diluted with 15 mL EtOAc and 10 mL of saturated aqueous NaHCO3. The phases were separated and the organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by preparative thin-layer chromatography, eluting with 3:1 hexanes-EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone. Mass spectrum (ESI) 434.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J=8.0 Hz, 2H); 7.35 (t, J=8.0 Hz, 1H), 7.32 (m, 1H); 6.96, (m, 2H); 6.52 (d, J=2.5 Hz, 1H); 5.89 (d, J=2.5 Hz, 1H); 3.69 (s, 3H); 2.64-3.00 (m, 4H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][CH2:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:38][CH2:39][NH:40][S:41]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)(=[O:43])=[O:42])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CO.Cl>O.C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]([CH2:38][CH2:39][NH:40][S:41]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)(=[O:43])=[O:42])=[C:16]2[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 94.8 %

Procedure:
A solution of ethyl 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoate (0.50 g, 0.65 mmol), LiOH (0.24 g, 10.0 mmol), methanol (5 mL), THF (5 mL) and water (5 mL) was stirred for 18 h at rt, then diluted with water (200 mL). 1 N HCl (10 mL) was added. The reaction mixture was extracted with EtOAc (2×50 mL). The organic extracts were dried over Na2SO4. The solvent is evaporated to give a white solid (0.46 g, 96%). 1H NMR (DMSO-d6): δ12.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d, 1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m,2H), 2.96 (m,2H), 2.76 (m, 4H), 1.90(m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[CH2:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:27][O:26][CH2:25][C:24]4[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:23]=4[F:22])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Product: O=C(NOCc1c(F)c(F)c(F)c(F)c1F)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-[(2,3,4,5,6-pentafluorobenzyl)oxy]amine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ; 8.69 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.33–7.32 (m, 2H), 7.07–7.02 (m, 2H), 5.56 (s, 2H), 5.09 (s, 2H). LCMS (API-ES, M+H+): 467.0. HRMS calcd for C21H13F6N4O2 (M+H) 467.0943. found 467.0942. HPLC: >80% purity.
Reaction SMILES: Br[C:2]1[C:3]([OH:15])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:8]=[CH:7]2.[N:16]([O-:18])=[O:17].[Na+].O>O1CCCC1.C(O)(=O)C>[OH:14][C@H:12]([CH3:13])[CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([OH:15])[C:2]=2[N+:16]([O-:18])=[O:17])[CH:7]=[N:8]1
Reactant: O=N[O-]
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(Br)c21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)Cn1ncc2ccc(O)c([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of the product from Step A (6.99 g, 24.8 mmol) in a mixture of tetrahydrofuran (20 mL) and acetic acid (20 mL) was cooled in an ice bath. Sodium nitrite (5.13 g, 74.4 mol) was added and the mixture was stirred for one hour, warmed to room temperature and stirring continued for one hour. Water (200 mL) was added to the reaction mixture, which was extracted with ethyl acetate (200 mL). The organic layer was washed with aqueous saturated sodium bicarbonate (100 mL, to pH 7), dried (magnesium sulfate), filtered and saturated sodium bicarbonate (100 mL, to pH 7), dried (magnesium sulfate), filtered and evaporated to an oil (4.75 g). Purification by chromatography gave a bright yellow solid (2.96 g, 50%): mp 70–74° C.; LC/MS m/z 238.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.FC(F)(F)C([O-])=O.[NH4+:33].O.C(Cl)(Cl)[Cl:36]>>[ClH:36].[ClH:36].[C:20]1([C:2]2[N:33]=[C:5]([CH:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClC(Cl)Cl
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Cl
Product: c1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 4-[(2-oxo-2-phenylethyl)carbamoyl]piperidine-1-carboxylate (5.0 g) and ammonium trifluoroacetate (18.9 g) was stirred at an exterior temperature of 170° C. for 30 minutes. After leaving to be cooled, water and chloroform were added thereto, and the aqueous phase was separated. The aqueous phase was adjusted to a pH of about 10 with a 24% aqueous sodium hydroxide, and extracted with chloroform. The combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure, and dissolved in DCM (20 mL) and methanol (10 mL), and 4 M hydrogen chloride/dioxane (5.3 mL) was added thereto. The solvent was concentrated under reduced pressure, to the residue was added diisopropyl ether/methanol, and the resulting solid was collected by filtration, and dried under reduced pressure to obtain 4-(4-phenyl-1H-imidazol-2-yl)piperidine dihydrochloride (3.29 g).