Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]=[S:27]>CS(C)=O.O>[CH3:24][C:23]1[C:18]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[S:27])=[N:7][CH:6]=2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Yield: 77 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (1.84 g, 5.75 mmol) in DMSO (20 mL) was added dropwise with stirring under ice-cooling ethyl isothiocyanatoformate (0.75 mL, 6.35 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25%→40% ethyl acetate-hexane) to give the title compound (2.00 g, 77%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13][CH2:14]S(C)(=O)=O)[C:8]1=[O:27].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:8]1=[O:27]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(CN2CCC(CCCS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonylpropyl)-2-oxopyrrolidine (0.32 g, 0.63 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.30 g, 0.63 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/30% ethyl acetate/methanol to give the title compound: Rf=0.55 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:2]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([O:7][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Oc2ccc(OCC(O)CCc3cccnc3)cc2)cc1
Yield: 14 %

Procedure:
Prepared according to the method described in Example 5 from 4,4'-dihydroxydiphenyl ether (1.68 g), (±)-3-(2-oxiranylethyl)pyridine (1.24 g) and sodium hydride (60% dispersion in oil; 0.319 g) in dimethylformamide (20 ml) at 100° C. for 2 hours to give the title compound as a white solid (0.41 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.CN(C)C=O.[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])/[C:24]/2=[CH:35]/OC>C(N(CC)CC)C>[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])[C:24]2=[CH:35][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1
Reactant: CCCOc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3cc(OC)c(Br)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-Aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, x mmole) were stirred for 15 minutes. Then (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The product is isolated as before, to give an off-white solid, 119 mg, (51%), mp 212-214° C. dec; MS (ESI): m/z 459.1, 461.2 (M−H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]([CH2:19][CH:20]([OH:23])[CH2:21][F:22])[CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:22][CH2:21][CH:20]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:19][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][CH2:17][O:18][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(Cc1ccccc1)CC(O)CF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Yield: 108.6 %

Procedure:
7.27 g (0.072 mole) of triethylamine were added to a solution of 6.75 g (0.03 mole) of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine [prepared as described in step (a) above] in 200 ml of ethyl acetate. Whilst stirring and ice-cooling the mixture, 8.24 g (0.072 mole) of methanesulfonyl chloride were added to it. After the resulting mixture had been stirred for 3 hours at the same temperature, an aqueous solution of sodium bicarbonate was added to it. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 12.49 g of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]([O:64][C:65]1[CH:70]=[CH:69][C:68](O)=[CH:67][CH:66]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:68]3[CH:69]=[CH:70][C:65]([O:64][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:66][CH:67]=3)=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(COc2ccc(OCc3ccccc3)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 6 (from Example A) (1 mmol) is added to a solution of diethylazodicarboxylate (1 mmol) and triphenylphosphine (1 mmol) in dry THF (10 mL). 4-Benzyloxyphenol (7) (1 mmol) is then added, and the progress of the reaction is monitored by tlc. When the reaction is complete, water is added and the product is extracted with ethyl acetate. The extract is dried and evaporated and the title compound 8 is then purified by HPLC.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])(C1C=CC(C)=CC=1)(=O)=O.[I-:25].[Na+]>CC(C)=O>[C:22]([O:21][CH:15]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][CH2:12][I:25])(=[O:24])[CH3:23]
Reactant: CCCOCC(CCCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCOCC(CCCI)OC(C)=O
Reaction time: 18 h

Procedure:
A solution of 4-acetoxy-5-propoxy-1-pentanol tosylate (61.5 g., 0.179 mole) and sodium iodide (79.5 g., 0.53 mole) in acetone (500 ml.) is allowed to stand at 25°-27° C. for 18 hours. The precipitated sodium tosylate is filtered off. Most of the acetone is evaporated from the filtrate and the residue is treated with 300 ml. of water. The oily product is taken up in ether, washed with dilute sodium thiosulfate solution, water, and brine, and dried over sodium sulfate. The solvent is distilled in vacuo to give a quantitative yield of the crude title compound as a yellowish oil which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[CH:15]([OH:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH3:27]O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[CH:15]([O:17][CH3:27])[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1nc(-c2ccccc2)c(C(C)O)c(Nc2cccc(Cl)c2)c1=O
Reactant: CO
Solvent: O
Product: CCn1nc(-c2ccccc2)c(C(C)OC)c(Nc2cccc(Cl)c2)c1=O
Temperature: 120 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of the title product of example 1 (111 mg, 0.3 mmol mmol) in methanol (5 mL), PPA (600 mg) was added and the mixture was stirred in a sealed tube at 120° C. for 10 h. Then it was let to cool down and was diluted with water. The final product was isolated by filtration (96% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].[O:17]1[CH:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>CO.O>[ClH:1].[OH:17][CH:19]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CNCC(O)COc2ccccc2)cc1

Procedure:
To a solution of 18.0 g (0.76 mmol) of N-[4-(aminomethyl)phenyl]methanesulfonamide hydrochloride in 200 mL of methanol, add a solution of 3.04 g of sodium hydroxide in 10 mL of water. Stir for fifteen minutes. Add 11.14 g (0.076 mmol) of 1,2-epoxy-3-phenoxy propane and reflux for 4.5 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Remove the solvent in vacuo. Chromatograph the oil on 800 g of silica gel using a mixture of methylene chloride:methanol:triethylamine (97:2:1) initially and changing to methylene chloride, methanol, triethylamine (95:4:1). Combine the fractions containing product and remove the solvent in vacuo. Dissolve the product in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 55.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577 intermediate 4D, 1 g, 1.877 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 1, 1.279 g, 5.63 mmol), Pd(PPh3)2Cl2 (0.066 g, 0.094 mmol), copper(I) iodide (0.018 g, 0.094 mmol), triphenylphosphine (0.049 g, 0.188 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 mins. The solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column 40+M and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent to afford the title compound (750 mg, 1.036 mmol, 55.2% yield) as a white solid. UPLC: Rt 1.02 min, m/z 724 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[CH2:8][C:7](=[O:11])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[N+:12]([O-])([O-:14])=[O:13].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[OH:1][CH:2]1[CH:10]([N+:12]([O-:14])=[O:13])[C:9]2[CH2:8][C:7](=[O:11])[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: O=C1C=CC2=C(C1)CC(O)C2
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=CC2=C(C1)C([N+](=O)[O-])C(O)C2
Reaction time: 24 h
Yield: 38.4 %

Procedure:
2-Hydroxy-5-indanone(3.00 g, 20.0 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.95 g, 21.0 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.5 g, 39%). 1H NMR (CD3COCD3): δ 7.70 (d, 1H), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow solid. MS: 485.3 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13][CH3:14])=[N:5][C:6]([OH:12])=[C:7]([CH:11]=1)C(O)=O)#[N:2].C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:12][C:6]1[CH:7]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([S:13][CH3:14])[N:5]=1
Reactant: CSc1nc(O)c(C(=O)O)cc1C#N
Solvent: C1CCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1nc(O)ccc1C#N
Yield: 60.6 %

Procedure:
A solution of 6 g (28.5 mmol) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in 35 ml of diphenyl ether is stirred at 250° C. for 4 hours. After returning to room temperature, 100 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then dried under vacuum to yield 2.87 g (60%) of 6-hydroxy-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: C[C:2]1(C)OC(=O)CC(=O)[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:25][C:26](=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[Cl:17][C:18]1[C:23]([Cl:24])=[C:22]([O:3][CH3:2])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26](=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC(=O)Cc1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Product: COC(=O)CC(=O)Cc1ccc(OC)c(Cl)c1Cl

Procedure:
24.1 g (0.17 mol) of Meldrum's acid, 30.4 g (0.38 mol) of pyridine and the acyl chloride described under Intermediate 8.4 were reacted by the method of Intermediate 1. Yield: quantitative;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Reactant: COc1ccnc(N)c1
Product: COc1ccn2c(C3CCN(C(=O)OC(C)(C)C)CC3)cnc2c1

Procedure:
The title compound was prepared from 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) and 2-amino-4-methoxypyridine (prepared using procedures analogous to those described by R. J. Sundberg et al, Org. Preparations & Procedures Int. 1997, 29, (1), 117-122) using a procedure similar to that described in Example 235 Step A. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 1.63˜1.75 (m, 2H), 2.05 (br d, J=13 Hz, 2H), 2.85˜3.00 (br, 3H), 3.88 (s, 3H), 4.15˜4.35 (br, 2H), 6.58 (d, J=7.4 Hz, 1H), 6.93 (br s, 1H), 7.25 (br s, 1H), 7.79 (d, J=7.5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H-].[Na+].F[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:18][C:2]([O:1][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)(O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 16.4 %

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxy-2-methylpropyl)pyridin-2-ylcarbamate (26) (292 mg, 1.10 mmol) in DMF (5.0 mL), at 0° C. under nitrogen, was added sodium hydride (132 mg, 3.29 mmol, 60 wt %). The resulting orange mixture was stirred at 0° C. for 45 min, and then a solution of 1-fluoro-4-nitronaphthalene (210 mg, 1.10 mmol) in DMF (5.0 mL) was added dropwise, over 2 min. The dark-brown mixture was stirred at 0° C. for 5 min, and then at RT. After 90 min, the reaction was quenched by addition of 4.0 mL aqueous NH4Cl solution. Diethyl ether (40 mL), EtOAc (40 mL) and water (40 mL) were added, and the layers separated. The aqueous layer was extracted with a mixture of diethyl ether and EtOAc (1:1, 30 mL×2). The combined organic extracts were washed with brine (50 mL), dried and the solvents removed under reduced pressure. The crude mixture was purified by column chromatography (40 g) eluting with 0 to 70% EtOAc in iso-hexane, to give tert-butyl 4-(2-methyl-2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (27) (79 mg, 15%) as an orange foam: m/z 438 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OC[C@@H]2F)c1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2-methyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (CAS 128694-63-3) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=418.3 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[C:27]1([Li])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6]([CH:1]([OH:3])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: [Li]c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(C(C)C)c(C(O)c2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.23 (m, 7 H), 7.06 (m, 2 H), 5.71 (d, J=5.14 Hz, 1 H), 4.38 (d, J=5.5 Hz, 2 H), 3.47 (septet, J=6.6 Hz, 1 H), 3.12 (septet, J=6.6 Hz, 1 H), 2.12 (d, J=5.1 Hz, 1 H), 1.57 (s, 1H), 1.29 (m, 10 H), 0.797 (d, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H28NFO2) 393, found 394 (M+H). Anal. Calcd for C25H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204° C. Rf=0.2 (20% ethyl acetate/hexane).