Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:34])([F:33])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.Cl.C(OCC)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:33])([F:34])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 14 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.100 mmol) in DCM (10 mL) was added 1M HCl in diethyl ether (0.100 mmol) at room temperature and the solution stirred for 14 h. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in methanol. The purification afforded (2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (10 mg, 0.023 mmol, 23% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=5.2 Hz, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.98 (d, J=5.2 Hz, 1H), 6.97 (s, 1H), 6.45 (m, 1H), 3.9 (m, 1H), 3.87 (m, 1H), 3.09 (m, 1H), 1.83 (m, 1H), 1.33 (m, 2H), 1.31-1.26 (m, 6H); LCMS (ESI) m/e 401.2 [(M+H), calcd for C19H21ClF3N2O2 401.1]; LC/MS retention time (Method C): tR=1.69 min; HPLC retention time (method A): tR=5.80 min, 5.87 min (diastereomeric mixture); HPLC retention time (method B): tR=6.41 min, 6.45 min (diastereomeric mixture).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (0.6 ml), and a solution of 4-fluorobenzoyl chloride (0.8 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[O:3]1.[CH2:12](Br)[CH:13]=C.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)C>[CH3:11][C:2]1([CH3:1])[O:3][C:4](=[O:10])[CH:5]([CH2:9][CH:12]=[CH2:13])[C:6](=[O:8])[O:7]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CCC1C(=O)OC(C)(C)OC1=O
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 7.7 g (0.0632 mol) of allyl bromide, 21 g (0.152 mol) of potassium carbonate and 200 mL of acetone. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl ether and filtered through a bed of Celite/activated charcoal. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to yield 11 g of 2,2-dimethyl-5-allyl-1,3-dioxane-4,6-dione compound as shown in Formula (IV)) as a clear, colorless oil.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+].Cl>CCO.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:34][CH2:35][OH:36])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: OCCBr
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(CCO)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.1 mmol, 49 mg) in EtOH (1 mL) was added 2-bromoethanol (0.3 mmol, 22 μL), and potassium carbonate (0.4 mmol, 56 mg). The mixture was stirred at room temperature for 3 hours and then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1 mL), 1N HCl in ether (1 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (12 mg). LCMS: m/z 456 [M+2]. 1H NMR (400 MHz, CD3OD): δ 7.78 (1H, s), 7.45-7.49 (2H, m), 7.12-7.17 (2H, m), 5.38-5.57 (1H, m), 4.41-4.48 (1H, m), 3.91-3.95 (2H, m), 3.60-3.81 (2H, m), 3.32-3.47 (4H, m), 3.12-3.17 (2H, m), 2.10-2.59 (5H, m), 1.98-2.04 (2H, m), 1.78-1.84 (2H, m), 1.35-1.63 (7H, m), 1.26-1.33 (2H, m), 0.82 (3H, t).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:14][C:13]2[C:15]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[N:4]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:16][C:12]1[C:11]([O:18][CH3:19])=[CH:10][C:9]2=[C:15]3[C:13]=1[CH:14]=[C:3]([CH3:2])[N:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]3=[N:6][CH:7]=[N:8]2
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccccc1
Temperature: 120 °C

Procedure:
To a solution 5-iodomethyl-7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalene (0.1 g, 0.22 mmol) (from Example 15, Step F, supra) in toluene (20 mL) was added DBU (73 μL, 0.49 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 7,8-dimethoxy-5-methyl-4-phenyl-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 50 mg, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.CC1C=CC(C(C)C)=CC=1.O>C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[OH:9])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)c1ccccn1
Solvent: O
Solvent: CCO
Solvent: Cc1ccc(C(C)C)cc1
Product: COc1ccc(CC(O)c2ccccn2)cc1
Yield: 65 %

Procedure:
Ketone starting material for A-077 was prepared from picolinic acid and 4-methoxybenzaldehyde. To a solution of 50 g. (0.37 moles) of 4-methoxybenzaldehyde and 50 ml. p-cymene (heated to dissolve) in a 3-neck flask with reflux condenser and refluxed until boiling, 10 g. (0.08 moles) picolinic acid was added dropwise and then refluxed for three hours. The solution changed in color from reddish to brown at the end. The solution was cooled and extracted in a separatory funnel with 2 N HCl (twice with 50 ml.). The above acid layer was washed twice with 100 ml. diethyl ether. The ether layer was discarded. The acid layer was basified with ice cold concentrated ammonium hydroxide at 0° C. The basic layer was extracted with diethyl ether (3×100 ml.) until clear. The ether washings were collected and dried over anhydrous sodium sulfate. The filtered ethereal solutions were evaporated (under roto-vacuum) at room temperature until an oil formed. The oil was dissolved in minimal ethanol to solubilize, and hot water dropwise was added until turbidity was produced and then disappeared on further heating. On cooling, a cloudy layer formed an oil which was removed by hand aspiration rapidly because it precipitated quickly. The 4-methoxybenzyl(2-pyridyl) carbinol oil was recrystallized from ethanol-water (80:20) as a white powder, 65% yield, mp 110°-112° C. Calc. for C14H13NO2 : C, 74.01; H, 5.73; N, 6.16. Found: C, 74.09; H, 6.01; N, 6.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH:10]([C:25](N2C(C3C=CC=CC=3)COC2=O)=[O:26])[CH2:11][CH2:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][Si](C)(C)C)=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:25](=[O:26])[CH:10]([CH2:11][CH2:12][CH:13]([OH:14])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:9]2[C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(C#N)cc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: COC(C)(C)C
Product: N#Cc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
2.7 g of 4-[1-(4-fluorophenylamino)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-5-phenyl-5-trimethylsilanyloxypentyl]benzonitrile in 30 ml of tert-butyl methyl ether, 1.6 ml of bistrimethylsilylacetamide and 0.2 g of tetrabutylammonium fluoride trihydrate are heated at reflux for 3 hours. The mixture is allowed to stand overnight, 0.2 ml of glacial acetic acid are added, and the mixture is stirred for 15 min and then substantially concentrated. 15 ml of a mixture of isopropanol/2N sulfuric acid=10:1 are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then treated with a little solid sodium bicarbonate and again substantially concentrated and the residue is taken up in ethyl acetate and washed with water. The residue of the dried organic phase is purified by column filtration (SiO2, ethyl acetate/n-heptane=1:1). This gives the product of molecular weight 400.5 (C25H21FN2O2); MS (DCl+): 401 (M+H+), 383 (M+H+−H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].Cl.[C:19]([NH:26][CH2:27][C:28](O)=[O:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:22]([O:21][C:19](=[O:20])[NH:26][CH2:27][C:28](=[O:29])[NH:17][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][C:2]=1[F:1])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of 2-fluoro-4-(4-fluoro-benzyloxy)-phenylamine (1:1) hydrochloride (272 mg, 1 mmol), Boc-glycine (263 mg, 1.5 mmol), N,N′-dicylcohexylcarbodiimide (206 mg, 1 mmol) and pyridine (127 mg, 1.6 mmol) in ethyl acetate (6 mL) was stirred at room temperature for 3 h. After this time, the reaction mixture wa poured into sodium hydrogen carbonate (saturated), and the mixture extracted with ethyl acetate. The combined organic layers were then washed with brine and dried. Filtration and evaporation afforded the title compound (180 mg, 46%) as a light brown solid after chromatography on silica gel eluting with ethyl acetate:heptane (1:1 to 4:1). MS: m/e=393.1 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A solution of 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid (0.15 g, 0.46 mmol) in methylene chloride (4.6 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.25 mL, 0.50 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (0.10 g, 1.01 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) in tetrahydrofuran (2.3 mL). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (119.4 mg, 63.5%) as a white solid: mp 48-50° C.; EI-HRMS m/e calcd for C24H26N2O2S (M+) 406.1715, found 406.1716.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)(O)[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29](/[C:21](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)=[CH:22]\[CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: COc1cnc2c(c1)cc(C(O)(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(/C(=C/C3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 62.7 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethanol (110 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2.0 mL, 2.0 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo the residue was treated with methanol to afford 2-[(E)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 64.1%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.05-8.09 (m, J=8.1 Hz, 2H), 7.94 (d, J=2.5 Hz, 1H), 7.60-7.64 (m, J=8.1 Hz, 2H), 7.43 (d, J=2.5 Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 5.86 (s, 1H), 4.11-4.24 (m, 1H), 3.97 (q, J=7.0 Hz, 1H), 3.85 (s, 3H), 3.73-3.81 (m, 1H), 3.22 (s, 3H), 2.03-2.13 (m, 2H), 1.79-1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][C:19]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:5]=[C:4]([CH:18]=[CH2:19])[N:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)[C@H](C)NC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)N[C@@H](C)C(=O)OC)nc(Cl)n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 49.8 %

Procedure:
To a mixture of (S)-methyl 2-(2,6-dichloropyrimidine-4-carboxamido)propanoate (0.921 g, 3.31 mmol) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.65 mL, 3.8 mmol), Na2CO3 (0,704 g, 6.64 mmol), and PdCl2(dppf) (0.142 g, 0.17 mmol). The reaction vessel was flushed with argon, sealed, and heated at 80° C. overnight. Additional 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.65 mL, 3.8 mmol) was added. After 7 hours at 80° C., additional 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.65 mL, 3.8 mmol) was added. After stirring at 80° C. for 4 more days the reaction was concentrated in vacuo to a residue and chromatographed over silica gel using 0-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2-chloro-6-vinylpyrimidine-4-carboxamido)propanoate as a yellow oil (0.444 g, 1.65 mmol, 50% yield). LC/MS: m/z=270.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:12]2([CH2:21][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)[C:13]3[C:5](=[N:4][CH:3]=[CH:2][CH:1]=3)[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]23)=[CH:17][CH:16]=1
Reactant: c1cnc2c(c1)Cc1cccnc1-2
Reactant: ClCc1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: c1cnc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1cccnc1-2

Procedure:
The title compound was prepared following the procedure of Example 1 from 0.43 g (2.56 mmole) of 4,5-diazafluorene, 0.84 g of 4-picolylchloride hydrochloride, 29.0 mg of benzyltriethylammonium chloride, 3 ml of 50% sodium hydroxide, and 30 ml toluene by reaction at 50 for 6 hrs. The crude product was chromatographed (Ethylacetate/Methanol, 99:1) and recrystallized from isopropyl alcohol. NMR (CDCl3, 200 MHz) δ: 3.42(s,4H), 6.52(d,J=5.7 Hz,4H), 7.33(dd,2H), 7.85(d,2H), 8.16(d,J=5.6 Hz,4H), 8.61(d,2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), (4-methoxyphenyl)boronic acid (3.0 g), triethylamine (6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride (50 mL) was added copper(II) acetate (3.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (3.03 g, 78%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][C@H:10]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:27][CH3:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:27][CH3:28])[CH:20]=2)[C@H:10]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(Br)ccc1C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2C(=O)C3(CC3)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc1C#N

Procedure:
Using (6S)-7-(tert-butyldimethylsilyloxy)-6-methyl-5-azaspiro[2.4]heptan-4-one (762.2 mg), 4-bromo-2-methoxybenzonitrile (724 mg), cesium carbonate (1.46 g), tris(dibenzylideneacetone)dipalladium(0) (136.6 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (345.3 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 760 mg, 66%).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:22]=1)#[N:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1.CCOCC.C(O)(=O)C>O1CCCC1.CO.C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:8]([OH:9])[C:7]2[C:3]([C:1]#[N:2])=[C:4]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:22]=3)[S:5][C:6]=2[C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C=O)c2C#N)ccn1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C(O)c3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a suspension of methyl (4-{3-cyano-4-formyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (0.1077 g, 0.2456 mmol) in anhydrous Tetrahydrofuran (6.0 mL) cooled with ice bath was added slowly 1.0 M of 4-chlorophenylmagnesium bromide in ether (2.50 mL, 2.50 mmol). The resulting clear solution was stirred with cooling for 30 min, then the mixture was quenched with methanol (0.5 mL), then with acetic acid (148 mg, 2.46 mmol). The mixture was warmed to room temperature, then rotavaped to give crude product, which was chromatograph in a silica gel column using MeOH/DCM (0/100 to 3/97) to afford a solid product (0.116 g, yield 82%). LC/MS: (FA) ES+ 551; ES− 549. 1H NMR (400 MHz, d-chloroform/d4-methanol) δ 8.36 (s, 1H), 8.29 (m, 2H), 7.43 (m, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 6.37 (s, 1H), 5.41-5.46 (m, 1H), 3.99-4.04 (m, 1H), 3.79 (s, 3H), 3.68-3.72 (m, 1H), 2.13 (m, 1H), 1.97-2.00 (m, 2H), 1.55-1.70 (m, br, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester [CAS-No. 335255-88-4] according to the general procedure M. Obtained as a light red solid (502 mg).