Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: ClCC=C(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of crude 1-(4-chlorophenyl)-1-(3-pyridyl)-2-propen-1-ol (40 mmol) in 100 ml methylene chloride was added dropwise to a suspension of phosphorus pentachloride (12.4 g, 60 mmol) at 10° C. After stirring for 1 h at room temperature the solution was washed with 50 ml water at 0° to 10° C. The solution of the crude title compound was used in the following aminations, i.e. Example 2 and 3.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23.C([Li])CCC.CN(C)[CH:47]=[O:48]>O1CCCC1.CCCCCC>[CH:47]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23)=[O:48]
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C=O)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4, 5-hexahydrobenz[cd]indole (6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 1 hour. Dimethylformamide (3 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 5.6 g of the above-titled compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][C:3]=1[F:24].C(N(CC)CC)C.[C]=O>CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:24][C:3]1[CH:4]=[C:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:6]=[CH:7][C:2]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc([C@@H]2CCCCN2C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Yield: 176.8 %

Procedure:
A mixture of EXAMPLE 87C (1.46 g, 3.7 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride (145 mg) and triethylamine (0.52 mL, 3.7 mmol) in methanol (16 mL) was stirred under 60 psi of carbon monoxide at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was concentrated and the residue purified by flash chromatography on silica gel using a gradient of 10-40% ethyl acetate in hexane to give the title compound as a colorless oil (1.215 g). [α]589=−102.2 (c=0.95 in methanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:20][CH:21]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
4-Chloro-2-phenyl quinazoline, 1 equivalent, was treated with 1 equivalent 4-aminopyridine and 1 equivalent potassium carbonate in dimethylformamide (DMF), under reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to an oil. This crude material was dissolved in ethyl acetate and chromatographed using hexane:ethyl acetate:methanol 8:2:0.5 to obtain solid product. Electron impact mass spectroscopy (EIMS) gave a molecular ion corresponding to the calculated molecular weight of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:25][CH:26]=3)[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: COC(=O)CCc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 833.6 %

Procedure:
A mixture of 2-bromomethyl-4,5-diphenyloxazole (10.00 g, 3 mmol), methyl 3-(3-hydroxyphenyl)propanoate (5.73 g, 3 mmol) potassium carbonate (4.83 g, 3.5 mmol) potassium iodide (catalytic amount) and acetonetrile (150 mL) was stirred at reflux temperature. After 30 minutes, the mixture was filtered, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (3:1) furnished methyl 3-[3-((4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoate (10.34 g, 78%) as an oil. An analytical sample was prepared by subjecting a 4 g sample to chromatography under the conditions described above to furnish pure material as an oil.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3](O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(N(CC)CC)C>C1COCC1.CCCCCC>[CH3:1][C@@H:2]1[C@@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:11]1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1N[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To (1R,2S)-(−)-norephedrine (1 g, 6.61 mmol) in THF (20 mL), triphenylphosphine (1.98 ml, 7.94 mmol), diisopropyl azodicarboxylate (1.401 ml, 7.27 mmol) and triethylamine (2.6 ml, 18.8 mmol) was added anr the rm was stirred at room temperature over night. The solvent was evaporated and the crude material was purified on silica eluting with Heptane/EtPAc 1+4 to EtOAc 100% and EtOAc/MeOH 95+5% the fractions containing product were collected giving 2.5 g of with solid containing lot of P(Ph)3O according to LC/MS. This solid was stirred in hexane (50 ml) O/N and than filtered through a pad of Celite 545 giving 0.6 g of an oil.
Reaction SMILES: [OH:1][C:2]12[CH:11]3[CH2:12][C:13]4[C:18]5[C:7]1([CH2:8][CH2:9][N:10]3[CH3:22])[C:6]([CH2:23][OH:24])([O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=4)[C:5](=[O:25])[CH:4]=[CH:3]2>C(O)C>[OH:1][C:2]12[CH:11]3[CH2:12][C:13]4[C:18]5[C:7]1([CH2:8][CH2:9][N:10]3[CH3:22])[C:6]([CH2:23][OH:24])([O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=4)[C:5](=[O:25])[CH2:4][CH2:3]2
Reactant: COc1ccc2c3c1OC1(CO)C(=O)C=CC4(O)C(C2)N(C)CCC314
Solvent: CCO
Product: COc1ccc2c3c1OC1(CO)C(=O)CCC4(O)C(C2)N(C)CCC314
Yield: 69.9 %

Procedure:
To a solution of 5-(hydroxymethyl)-14-hydroxycodeinone 4 (0.13 g, 0.379 mmol) in 5 mL of 1:1 ethanol-glacial acetic acid Pd/C (10%, 15 mg) was added. The mixture was evacuated and filled with H2 gas in a hydrogenation flask and maintained under 40 psi H2 pressure for 4 h. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was basified with aqueous ammonia prior to CHCl3 extraction. Organic phases were combined, washed with brine, dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was subjected to column chromatography (7:93 methanol-dichloromethane) to give the pure olefin reduced compound 5 as white foam (0.0915 g, 70%). 1H NMR (CDCl3, 400 MHz): δ 6.7 d (1H, J=8.6 Hz), 6.65 d (1H, J=8.6 Hz), 4.16 d (1H, J=10.9 Hz), 4.01 d (1H, J=11.7 Hz), 3.86 s (3H), 3.16 d (1H, J=18.7 Hz), 3.07 td (1H, J=5.4, 14.8 Hz), 2.96 d (1H, J=5.4 Hz), 2.67-2.51 m (2H), 2.43 s (3H), 2.40-2.29 m (2H), 2.25-2.15 m (1H), 1.96-1.87 m (1H), 1.74-1.63 m (1H), 1.47 d (1H, J=12.5 Hz). 13C NMR (CDCl3, 100 MHz): δ 210.47, 144.17, 142.88, 129.60, 124.43, 119.64, 114.49, 96.26, 70.29, 64.20, 61.74, 56.53, 50.58, 44.67, 42.65, 37.31, 31.21, 26.88, 21.91. MS (ESI): m/z 346.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1.[F:15][C:16]([F:20])([F:19])[CH2:17]N.N([O-])=O.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.[Fe](Cl)(Cl)Cl.C1(C2C3NC(C(C4C=CC=CC=4)=C4N=C(C(C5C=CC=CC=5)=C5NC(=C(C6C=CC=CC=6)C6C=CC=2N=6)C=C5)C=C4)=CC=3)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH:17]2[C:16]([F:20])([F:19])[F:15])[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: C=Cc1cnc(C2(C#N)CC2)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Agent: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: O=N[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
1.4 g 1-(3-chloro-5-vinyl-2-pyridyl)cyclopropanecarbonitrile (step 1) was dissolved in 2.0 ml toluene and 14 mg 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride was added. Then 30 ml water was added, followed by 1.4 g 2,2,2-trifluoroethanamine and 1.1 g sodium nitrite. The reaction mixture was stirred for 3 hours at ambient temperature. Then saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a dark oil, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 1.2 g of 1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropanecarbonitrile was obtained as a brown oil. 1H-NMR (CDCl3): 8.25 ppm (s, 1H), 7.44 ppm (s, 1H), 2.35 ppm (m, 1H), 1.85 ppm (m, 1H), 1.75 ppm (m, 2H), 1.60 ppm (m, 2H), 1.50 ppm (m, 1H), 1.24 ppm (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][CH:7]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(N)ccc23)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(NS(C)(=O)=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a solution of (E)-3-(4-{1-[2-(6-amino-2-tert-butyl-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.70 g, 1.6 mmol) in dichloromethane (7 mL) was added methanesulfonyl chloride (0.198 g, 1.73 mmol), triethylamine (241 μL, 1.73 mmol). The resulting solution was stirred at room temperature for 1 h, diluted with ethyl acetate, and washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution, and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.21 g, 26% yield). LCMS (m/z): 523.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:20][C:21]([C:23]3[O:27][C:26]([C:28](C)=[CH2:29])=[N:25][CH:24]=3)=[O:22])[CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[C:28]([C:26]1[O:27][C:23]([C:21]([NH:20][C@H:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:22])=[CH:24][N:25]=1)(=[O:31])[CH3:29]
Reactant: C=C(C)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-4-(3′-chlorobiphenyl-4-yl)-3-(2-(prop-1-en-2-yl)oxazole-5-carboxamido)butanoic acid (60 mg, 0.14 mmol) in DCM (2 mL) and MeOH (2 mL) at −78° C. is bubbled ozone for 30 seconds. After 30 seconds ozone is removed and oxygen is bubbled for 10 minutes. After bubbling oxygen for 10 minutes the −78° C. bath is removed and the reaction is quenched with polymer supported triphenylphosphine and the reaction is stirred at room temperature for 2 hours. After 2 hours the reaction is filtered to remove triphenylphosphineoxide on supported polymer and the filtrate is collected and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(2-acetyloxazole-5-carboxamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (13 mg). HPLC retention time=1.67 minutes (condition D); MS (m+1)=427.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.59 (m, 2H) 2.60 (s, 3H) 2.87 (dd, J=10.9, 3.3 Hz, 1H) 2.94 (dd, J=10.9, 5.1 Hz, 1H) 4.46-4.60 (m, 1H) 7.31 (d, J=8.1 Hz, 2H) 7.36-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.62 (d, J=8.3 Hz, 3H) 7.69 (t, J=1.9 Hz, 1H) 7.94 (s, 1H) 8.86 (d, J=8.6 Hz, 1H) 12.31 (br. s., 1H).
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[NH:1]1[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:9][N:3]=[N:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Temperature: 105 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Azidotrimethylsilane (161 μL, 1.215 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (225 mg, 0.607 mmol) and dibutylstannanone (30 mg, 0.121 mmol) in toluene (6 mL) at rt. It was heated to 105° C. and allowed to stir overnight. The reaction, which remained a slurry, resulted in ˜70% conversion. Additonal equiv of reagents and solvents were added and the mixture was allowed to stir overnight at 105° C. The reaction was allowed to cool and filtered to give the titled compound (205 mg, 82%). LC-MS retention time: 1.03 min; m/z (MH+): 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[C:14]([C:23](O)=[O:24])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=2)=[O:24])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 1.13 g of 3-chloro-5-trifluoromethylpicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.35 g of 3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:22]3[CH2:23][CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCc4ccccc4C3)nc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-6-(3,4-dihydro-1H-isoquinolin-2-yl)-nicotinamide was synthesized from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 1,2,3,4-tetrahydro-isoquinoline in a method similar to the one described in the synthesis of N-(3-iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. LCMS calcd for C25H27N3O (m/e) 385, obsd 386 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[F:24])=[O:5])C.[OH-].[Na+]>>[F:24][C:17]1[CH:18]=[C:19]([S:22][CH3:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[S:14][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc2ccncc2c1Nc1ccc(SC)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(Nc2c(C(=O)O)sc3ccncc23)c(F)c1
Temperature: 60 °C
Yield: 61.5 %

Procedure:
A suspension of 3-(2-fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.19 g, 0.52 mmol) in IMS (10 ml) was treated with sodium hydroxide (1M aqueous solution, 0.63 ml) and the reaction mixture heated at 60° C. for 3 hours. The resultant mixture was allowed to cool then concentrated in vacuo. The crude residue was treated with water and the mixture adjusted to pH 5 with acetic acid. The resultant suspension was filtered, the residue collected and dried in vacuo to give the title compound as a green solid (0.107 g, 56%) which was used without purification in the subsequent step.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[F:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>CCOC(C)=O>[ClH:30].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[F:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1C(=O)NN=C2COc3cc(F)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a suspension of 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.110 g, 0.271 mmol) in EtOAc (10 mL) was added an EtOAc solution saturated with hydrogen chloride (3 mL). The reaction mixture was stirred at rt for 3 h then concentrated in vacuo and the residue was purified by preparative HPLC (Table 3, Method 1)) to give 6-(azetidin-3-ylamino)-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid as a white solid (0.026 g, 31%). LC/MS (Table 1, Method 5) Rt=1.853 min.; MS m/z: 306 [M+H]+.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([F:30])[F:29])[CH2:23][NH:22]1)=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1>CO>[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([F:30])[F:29])[CH2:23][N:22]1[CH2:1][CH2:2][OH:3])=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1
Reactant: C1CO1
Reactant: CSC1OC(C(NC(=O)C2CC(CCC(F)F)CN2)C(C)C)C(O)C(O)C1O
Solvent: CO
Product: CSC1OC(C(NC(=O)C2CC(CCC(F)F)CN2CCO)C(C)C)C(O)C(O)C1O
Temperature: 4 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Ethylene oxide (0.4 mL) was added to a solution of 4-(3,3-difluoro-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, prepared as in Example 14 (29.7 mg, 0.07 mmol), in methanol (2 mL), at 0° C. The reaction mixture was stirred at 4° C. overnight. Additional ethylene oxide (0.4 mL) was added and stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (19.3 mg, 59%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:31][C:32]#[N:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCCO3)cc1OC
Yield: 86.4 %

Procedure:
(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,4-dimethoxyphenyl)methanone (3.01 g, 10.02 mmol), cyanomethylphosphonic acid diethyl ester (3.15 ml, 20.05 mmol) in anhydrous THF (20 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 20.05 ml, 20.05 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give an oil, which was lyophilized to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile as an light yellow foam (2.80 g, 86%): 1HNMR (DMSO-d6) δ 7.09-6.69 (m, 6H, Ar), 6.15 (s, 0.49H, double bond proton of one isomer), 6.09 (s, 0.45H, double bond proton of the other isomer), 4.33-4.25 (m, 4H, 2CH2CH2), 3.83-3.74 (multiple singlets, 2OCH3); 13C NMR (DMSO-d6) δ 161.0, 160.9, 150.9, 150.0, 148.6, 148.3, 145.6, 144.7, 143.2, 143.0, 131.3, 130.5, 130.1, 129.2, 122.6, 122.4, 122.3, 122.0, 118.7, 118.7, 118.0, 117.2, 117.1, 117.0, 112.7, 111.4, 111.2, 111.1, 93.1, 93.0, 64.3, 64.2, 64.0, 64.0, 55.6, 55.5. Anal. Calcd. For C19H17NO4 (+0.45H2O): C, 68.85; H, 5.44; N, 4.23. Found: C, 68.69; H, 5.31; N, 4.04.