Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[ClH:32].CCN(C(C)C)C(C)C.[C:42]([CH2:44][C:45](O)=[O:46])#[N:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:42]([CH2:44][C:45]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:46])#[N:43].[ClH:32]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.35 mL, 2.0 mmol), cyanoacetic acid (85 mg, 1.0 mmol) and BOP (379 mg, 1.0 mmol). The mixture was stirred at RT for 3 h and quenched with TFA. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C27H27FN6O2: 487.5. NMR (CD3OD): 8.03 (1H, s), 7.27 (1H, m), 7.24 (2H, d, J=8.4 Hz), 7.19 (1H, m), 7.09 (1H, m), 7.07-7.00 (3H, m), 5.78 (1H, s), 4.56 (1H, m), 4.41 (2H, s), 3.88 (1H, d, J=18.8 Hz), 3.83 (1H, m), 3.78 (1H, d, J=18.4 Hz), 3.17 (1H, m), 2.80 (1H, m), 2.72 (1H, m), 1.83 (2H, m), 1.61 (2H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([NH:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[H-].[Na+].Br[CH:24]([CH3:26])[CH3:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]3[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1
Reactant: Cn1c(Cl)nc2cccc(Nc3ccc(C#N)cc3)c21
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Product: CC(C)N(c1ccc(C#N)cc1)c1cccc2nc(Cl)n(C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
To a suspension of 4-[(2-chloro-1-methyl-1H-benzimidazol-7-yl)amino]benzonitrile (64 mg, 0.226 mmol), tetrabutylammonium iodide (8.4 mg, 0.023 mmol) and sodium hydride (18.1 mg, 0.679 mmol, 90% dry) was added 2-bromopropane (0.07231 ml, 0.679 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 extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a solution of 50% hexane/ethyl acetate to give 64 mg (84%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)=[O:10])[CH3:23]
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(N)cn1
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of 5-amino-pyridine-2-carboxylic acid (1.0 g, 5.9 mmol) in ethanol (15.0 ml) was treated with concentrated sulfuric acid (0.30 ml) and stirred at reflux overnight. The mixture was cooled to 0° C. and treated with 1M Na2CO3 until pH 8 was reached (4.0 ml). A precipitate formed, which was filtered washing with ethanol/water 2:1, and dried under vacuum, yielding 5-amino-pyridine-2-carboxylic acid ethyl ester (1.03 g, 89%) as a white solid, MS (EI): m/e=196.0 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:41])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[OH:10].C(OC(=O)C)C>CN(C=O)C>[F:41][C:8]([F:7])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[OH:10]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Morpholine (17.5 μl) is added to an ice-cold, stirring solution of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (51 mg) in anhydrous DMF (0.5 ml). The resulting solution is allowed to warm to room temperature (25° C.) and then stirred at room temperature for 4 hrs. Ethylacetate (10 ml) is added and the solution is washed with water (5×2 ml), pH 3 phosphate buffer, 5% NaHCO3, brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.[OH-:18].[Na+].Cl>CS(C)=O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:4]2[N:5]=[N:6][CH:7]=[C:2]([OH:18])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)cnn2)c1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 54 %

Procedure:
5-Chloro-3-[3-(trifluoromethyl)phenyl]pyridazine (2 g, 0.0077 mole, Compound No. 5), 2.5N NaOH (50 mL) and DMSO (100 mL) were refluxed under N2 for 2 h. The mixture was then allowed to cool and made acidic with 12N HCl and extracted 3×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude solid which was recrystallized from methanol to give 6-[3-(trifluoromethyl)phenyl]-4-pyridazinol (1 g, 54% yield, Compound No. 25) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl) oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,4-dibromobutane (0.12 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloro-phenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 47 mg (yield 44%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(#N)C.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O>[Br:13][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: Nc1cccc(F)c1F
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: Nc1ccc(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
The procedure for preparing this compound was based on that described in International Patent Publication No. WO 2010/091272. To a 100 mL round bottom flask, 2,3-difluoroaniline (1 g, 0.0077 mol) and ACN (30 mL) were added. To the flask was added the solution of tetrabutylammonium tribromide (3.71 g, 0.0077 mol, in 10 mL of ACN). The reaction mixture was stirred at room temperature for 3 h. The reaction mass was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-12 silica gel and 30% ethyl acetate in hexane to get the title compound [0.55 g, 34%]. The obtained product was immediately taken to the next step.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:49])([F:48])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[C:34]3[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[C:36]([OH:44])[C:35]=3[O:45]C)[C@H:18]2[CH3:47])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>C(Cl)Cl.O>[F:49][C:6]([F:5])([F:48])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:25]=3[C:34]3[CH:39]=[C:38]([CH:40]([CH3:41])[CH3:42])[C:37]([F:43])=[C:36]([OH:44])[C:35]=3[OH:45])[C@H:18]2[CH3:47])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cc(C(C)C)c(F)c1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(O)c(O)c1F
Reaction time: 8 h

Procedure:
Boron tribromide (17.4 mg, 6.6 μL, 0.0692 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (22.6 mg, 0.0346 mmol) in dry CH2Cl2 (1 mL) at −78° C. at room temperature under N2 and the reaction was stirred for 8 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by chiral HPLC (IA column, 20×250 mm, 15% i-PrOH in heptane) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′,3′-dihydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.24 (20% EtOAc in hexanes). LCMS calc.=640.2; found=640.2 (M+1)+. 1H NMR (600 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.85 (s, 1H), 7.70-7.62 (m, 4H), 7.41 (m, 1H), 6.52 (s, 0.5H), 6.51 (s, 0.5H), 6.20 (br s, 2H), 5.65 (d, J=7.9 Hz, 0.5H), 5.38 (d, J=8.0 Hz, 0.5H), 5.00 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=15.6 Hz, 0.5H), 4.15 (d, J=15.5 Hz, 0.5H), 4.02 (d, J=15.6 Hz, 0.5H), 3.88 (t, J=6.7 Hz, 0.5H), 3.77 (t, J=6.7 Hz, 0.5H), 3.19-3.13 (m, 1H), 1.26-1.17 (m, 6H), 0.59 (d, J=6.1 Hz, 1.5H), 0.48 (d, J=6.2 Hz, 1.5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)[CH:10]=[C:9]2[C:5]=1[C:6]([CH3:14])=[N:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (400 mg, 0.928 mmol) in DMF (20 mL) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (397 mg, 1.02 mmol) followed by sodium carbonate (246 mg, 2.32 mmol) dissolved in water (4 mL) and degassed with argon for 30 min. PdCl2(PPh3)2 (65 mg, 0.092 mmol) was added and the mixture again degassed with argon for 10 min. The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (650 mg). The crude compound was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM). The product was triturated with diethyl ether (150 mL) to afford the title compound as an off white solid (270 mg, 47%). 1H NMR (DMSO-d6, 400 MHz): δ 1.498 (s, 9H), 1.560 (d, J=6.4 Hz, 6H), 2.128 (s, 3H), 2.413 (s, 3H), 2.526 (s, 3H), 3.579 (s, 8H), 4.610 (d, J=5.6 Hz, 2H), 4.760-4.824 (m, 1H), 5.907 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 7.311-7.346 (m, 2H), 7.454 (s, 1H), 7.735 (d, J=8.8 Hz, 1H), 8.463 (s, 1H), 10.991 (brs, 1H). LCMS (ES+): 614.25.
Reaction SMILES: [F:1][C:2]([F:19])=[C:3]([F:18])[C:4]([F:17])([F:16])[O:5][C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[Br:9].[O:20]=O>>[F:10][C:8]([F:11])([Br:9])[C:7]([F:12])([F:13])[C:6]([F:14])([F:15])[O:5][C:4]([F:16])([F:17])[C:3]1([F:18])[O:20][C:2]1([F:19])[F:1]
Reactant: O=O
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Br
Product: FC(F)(Br)C(F)(F)C(F)(F)OC(F)(F)C1(F)OC1(F)F
Yield: 33 %

Procedure:
A 100-ml metal tube containing 20.0 g (0.053 mol) of perfluoro(7-bromo-4-oxa-1-heptene) from Part C and 60 ml of CF2ClCFCl2 was heated at 140° while O2 was injected incrementally over a 4 h period until absorption ceased. The mixture was cooled, gases vented, and the liquid product fractionated to give 6.9 g (33%) of perfluoro(1-bromo-6,7-epoxy-4-oxaheptane), bp 94°-95°. IR(CCl4): 6.50 (epoxide), 8-9μ (CF, C--O) with weak band indicating COF impurity near 5.3μ. NMR (CCl4): 19F -65.6 (t of m, JFF 9.8 Hz, 2F, CF2Br), -80.2 (AB multiplets 2F, CF2O), -80.4 (AB multiplets, 2F, CF2O), -121.9 (m, 2F, CF2), and -156.6 ppm (t of m, JFF 17.6 Hz, 1F, CF), with AB multiplets for ring CF at -10368 and -10409 Hz (d of d of m, JFF 18.5, 9.8 Hz, 1F) and -10596 and -10637 Hz (d, JFF 17.3 Hz, 1F).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=O)(C)(C)C.Br[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:35]1([S:32]([N:29]2[C:26]3=[N:27][CH:28]=[C:23]([C:11]4[CH:12]=[N:8][NH:9][CH:10]=4)[CH:24]=[C:25]3[CH:31]=[CH:30]2)(=[O:34])=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
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: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cn[nH]c3)cnc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a degassed (sparging with argon for 5 minutes), stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.31 g, 4.45 mmol) and 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow solid. LRMS (ESI) calculated for C16H12N4O2S [M+H]+, 325.1; found 325.0.
Reaction SMILES: B.[CH:2]([O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C@H:21]([NH2:25])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:4])[CH3:3].C1COCC1.C(ON=C(C(C)C)CCC1C=CC(OC2C=NC(OC(C)C)=CC=2)=CC=1)C1C=CC=CC=1.O1CCOB1OC(C1C=CC=CC=1)(C1C=CC=CC=1)[C@@H](N)C(C)C.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[CH:2]([O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C@@H:21]([NH2:25])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ccc(CC[C@H](N)C(C)C)cc2)cn1
Agent: B
Agent: CC(C)Oc1ccc(Oc2ccc(CCC(=NOCc3ccccc3)C(C)C)cc2)cn1
Agent: CC(C)[C@H](N)C(OB1OCCO1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ccc(CC[C@@H](N)C(C)C)cc2)cn1
Reaction time: 48 h

Procedure:
(S)-1-{2-[4-(6-isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine Borane-THF (2.87 ml, 2.87 mmol) is added dropwise under argon at 0° C. to 1-[4-(6-isopropoxypyridin-3-yloxy)phenyl]-4-methylpentan-3-one O-benzyloxime (310 mg, 0.717 mmol) in 15 ml of anhydrous THF. Then, (S)-1-[([1,3,2]dioxaborolan-2-yloxy)-diphenylmethyl]-2-methylpropylamine (23.3 mg) is added and the mixture is stirred for 2 days. Following addition of twice 1.5 ml of borane-THF stirring is continued for 4 h each time. % N hydrochloric acid is carefully added for hydrolysis, the mixture is rendered alkaline with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase is separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 160 mg (68%), M+H+: 329.3. Chiral chromatography is performed (Chiralcel OD-H, heptane:ethanol=5:1+0.1% DEA) to obtain the enantiomers (R)-1-{2-[4-(6-isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (RF: 4.442 min), Yield: 49 mg (21%), M+H+: 329.3. (S)-1-{2-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (RF: 5.965 min), Yield: 50 mg (21%), M+H+: 329.3.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH2:8]=[CH:9][C:10](=[CH2:12])[CH3:11]>C1(C=CC=C(O)C=1O)O>[CH3:11][C:10]1[CH2:12][CH:3]2[CH:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)[CH2:8][CH:9]=1
Reactant: C1=CC2CCC1C2
Reactant: C=CC(=C)C
Agent: Oc1cccc(O)c1O
Product: CC1=CCC2C3CCC(C3)C2C1
Yield: 37.9 %

Procedure:
A mixture of 715 g (7.6 M) of norbornene, 550 g (8.1 M) of isoprene and 2 g of pyrogallol was heated in a stainless steel autoclave at ca. 150° during 15 hours. An internal pressure of 20 atm. is thus reached. The reaction mixture was then distilled by means of a Vigreux column and yielded 467 g (yield 38 %) of 5-methyl-tricyclo[6.2.1.02,7 ]undec-4-ene having b.p. 90°/10 Torr.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:8][C@H:7]1[CH2:17][O:18][CH3:19])=[O:4].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)C>[CH:14]([N:12]([CH3:13])[C@@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[C@H:7]([CH2:17][O:18][CH3:19])[CH2:8]1)([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of the bis-trifluoroacetic acid salt of 2-amino-N-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (57 mg) in ethanol (4 mL) was treated with 4-chloro-6-(trifluoromethyl)quinazoline (40 mg) and triethylamine (0.08 mL). The mixture was heated at reflux overnight. The mixture was then cooled to rt and purified by reverse phase HPLC and lyopholization to provide the bis-trifluoroacetic acid salt of the title product as a white powder (42 mg). MS found: (M+H)+=468.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1.O>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN2CCOCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a solution of 4-(2-hydroxyethyl)morpholine (5.72 g, 43.62 mmol) in THF (25 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)-amide (1.0 M in hexanes) (21.80 ml, 21.80 mmol). The reaction mixture is stirred for 15 minutes, and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (30 g, 8.72 mmol). The reaction vessel is sealed and heated at 80° C. for 3 hours. The reaction is cooled to room temperature and quenched by the addition of water (200 ml). A yellow precipitate is formed. The mixture is diluted to 350 ml with water and cooled to 0° C. The yellow precipitate is collected by filtration. The solid is slurried in 100 ml of 3:1 hexane:EtOAc and stirred for 10 minutes. The mixture is filtered, and the collected solid is dried in the vacuum oven overnight to afford the title compound as a yellow solid (2.11 g, 59%). Mass (m/z): 411.1 (M++1), 409.1 (M+−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[Cl:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C#CCCc1nc2ccccc2s1
Product: Clc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 18.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloro-pyridine (395 mg, 2.67 mmol) and 2-but-3-ynyl-benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 31 mg (0.10 mmol, 19%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.