Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C)C=O>[F:45][C:44]([F:47])([F:46])[CH2:43][O:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1(CN2CCC(CCOc3noc4cccc(O)c34)CC2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a stirred mixture of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)-methyl]tetrahydro-2H-pyran-4-carboxylate (0.63 g, 1.5 mmol, EXAMPLE 7, step 6) and potassium carbonate in N,N-dimethylformamide (3.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.26 mL, 1.8 mmol) at 70° C. After being stirred at 70° C. for 3 h, the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (50 mL×2) and washed with water and brine. The extracts were combined and dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2:1) to give 0.69 g (92%) of the title compound as a colorless viscous oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=4)[N:7]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)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
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide from Step 4 (0.060 g, 0.28 mmol), 4-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (0.19 g, 0.51 mmol, Aldrich, St. Louis, Mo.), DMF (3.0 mL), and aq. sodium carbonate (0.85 mL, 1.7 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. Bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.028 mmol, Strem Chemical, Inc., Newburyport, Mass.) was added. Once again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The mixture was poured into water (75 mL) and extracted with EtOAc (3×75 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL) then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1 to 5% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an off-white solid. MS (ESI positive ion) m/z: 422 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 10.44 (s, 1H), 8.26 (s, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.77 (t, J=1.8 Hz, 1H), 7.67-7.71 (m, 3H), 7.61 (d, J=9.6 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.19 (dd, J=8.0 Hz, 1.4 Hz, 1H), 2.32 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[CH:4][C:3]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=[O:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])[CH:5]=[CH:4][C:3]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=[O:28]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CO)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 441 (3.21 g, 6.32 mmol) and TBAF.3H2O (2.99 g, 6.32 mmol) were dissolved in THF (20 ml). The obtained reaction solution was stirred at RT for 0.5 h. After reaction the solution was concentrated in vacuo. The residue was redissolved in CH2Cl2 and washed with H2O. The aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (petroleum ether/ethyl acetate 2:1) to give the title compound as reddish foam.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[N:3]=[C:2]1[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].Br[CH:24]([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:24]([N:8]1[CH2:7][CH2:6][C:5]2[N:1]=[C:2]([C:11]3[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])[NH:3][C:4]=2[CH2:10][CH2:9]1)([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(C)C)CC3)c(C)cc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4, 347 mg, 0.84 mmol), 2-bromopropane (790 μL, 8.40 mmol), N,N-diisopropylethylamine (1.46 mL, 8.4 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 4 h at 80° C., then cooled to room temperature. The resulting solution was diluted with ethyl acetate (50 mL) and washed with brine (4×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.22 g (crude) of the title compound as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([CH3:7])=[CH2:6].[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([CH3:7])[CH3:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: [H][H]
Reactant: C=C(C)c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1ccc(Cl)c(Cl)c1
Yield: 89.2 %

Procedure:
3,4-dichloro-α-methylstyrene (21.9 g, 118 mmole), approximately 100 mg platinum oxide, and 125 ml absolute ethanol were shaken on a Paar Hydrogenator for four hours, at an initial hydrogen pressure of 50 psi. The material was then filtered through celite, and the solvent removed by distillation at atmospheric pressure. The resulting residual material was distilled at reduced pressure to produce 19.9 g (95% yield) of 3,4-dichlorocumene, bp 123°-126° C.
Reaction SMILES: [CH2:1]([P:3]([OH:11])([CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])=[O:4])[CH3:2].[CH2:12](O)[CH2:13][CH2:14][CH2:15][OH:16]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])([CH2:5][CH:6]([CH3:10])[C:7]([O:9][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:8])=[O:4])[CH3:2]
Reactant: OCCCCO
Reactant: CCP(=O)(O)CC(C)C(=O)O
Solvent: Cc1ccccc1
Product: CCP(=O)(CC(C)C(=O)OCCCCO)OCCCCO
Yield: 91.9 %

Procedure:
540 g (3.0 mol) of 3-(ethylhydroxyphosphinyl)-2-methylpropionic acid (produced as in Example 17) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 894 g (92% of theory) of 4-hydroxybutyl 3-(ethyl-4-hydroxybutoxyphosphinyl)-2-methylpropionate as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.[H-].[Na+].[Br:13][CH2:14][CH2:15]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH2:15][CH2:14][Br:13])[CH:6]=1
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn1CCBr
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (Combi-Blocks, San Diego, Calif.; 5.15 g, 25.2 mmol) in DMF (25 mL) at 0° C. was added NaH (60% wt. in mineral oil, 1.81 g, 45.4 mmol) and the resulting mixture was stirred at 0° C. for 15 min. 1,2dibromoethane (4.79 ml, 55.5 mmol) was added and the reaction was stirred at RT for 10 min, then heated in an oil bath at 70° C. for 2 h. After cooling to RT, it was treated with ice cold NH4Cl solution (10 mL), extracted with 2×75 mL of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification on a silica gel column (15-35% EtOAc in hexanes) furnished methyl 4-bromo-1-(2-bromoethyl)-1H-pyrrole-2-carboxylate (3.60 g, 11.58 mmol, 46% yield) as an off-white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=1.8 Hz), 4.65 (2H, t, J=6.5 Hz), 3.75 (5H, m). m/z (ESI, +ve) 311.9 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH3:10])[CH:6]=[N:7][CH:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@@H](N)c1cncc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a 100-mL flask are added (1R)-1-(5-bromo(3-pyridyl))ethylamine HCl salt (0.5 g, 2.105 mmol), DCM (5 mL), and triethylamine (1.2 mL, 8.52 mmol). The mixture is cooled to 0° C. Ethanesulfonyl chloride (0.24 mL, 2.526 mmol, dissolved in 3 mL of DCM) is added dropwise. The mixture is stirred at 0° C. for 15 min. The ice/water bath is removed and the mixture is stirred at room temperature for 25 min. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-5% MeOH in DCM as the gradient to afford ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (482.5 mg, 78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[N:16]1.[F:22][C:23]([F:28])([F:27])[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:25][CH2:24][C:23]([F:28])([F:27])[F:22])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(O)cc2C)cc1SCC(F)(F)F
Reactant: OCCC(F)(F)F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(OCCC(F)(F)F)cc2C)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
0.6 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxy-5-methylpyrazole was dissolved in 4 mL of tetrahydrofuran, and 0.23 g of 3,3,3-trifluoropropanol, 0.75 g of triphenylphosphine and 0.71 g of 1,1′-(azodicarbonyl)dipiperidine were added, followed by stirring at room temperature for 12hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:4) to obtain 0.61 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methyl-3-(3,3,3-trifluoropropoxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[C:40]([S:41](Cl)(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1.O>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:41]([C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:45])(=[O:43])=[O:42])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3c(C)noc3C)CC2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (75 mg, 0.22 mmol, Example 59) and diisopropylethylamine (2 mL) in tetrahydrofuran (40 mL) was stirred at +5° C. To this was added dropwise 3,5-dimethyl-isoxazole-4-sulfonyl chloride (100 mg, 0.51 mmol, Maybridge). The reaction was stirred at room temperature for 2 hours, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-amino-2-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 505.1669; Calcd for M+: 505.1664.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][NH2:5].[O:9]=[C:10]1[NH:14][N:13]=[CH:12][CH:11]1[CH:15]=O>C(O)C>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][NH:5][CH:15]=[C:11]1[CH:12]=[N:13][NH:14][C:10]1=[O:9]
Reactant: NCCC(F)=C(F)F
Reactant: O=CC1C=NNC1=O
Solvent: CCO
Product: O=C1NN=CC1=CNCCC(F)=C(F)F
Yield: 68 %

Procedure:
A solution of 3,4,4-trifluoro-3-butene-1-amine (2.25 g, 0.018 mole) and 4,5-dihydro-5-oxo-1H-pyrazole-4-carboxaldehyde (1.12 g 0.01 mole) in absolute ethanol (30 mL) is heated at reflux for 15 min. The solution is concentrated and the residue is recrystallized from ether/dichloromethane to give 1.49 g of the title compound as an yellow solid, a 68% yield. m.p. 126°-130° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:32])[CH:27](O)[CH:28]([CH3:30])[CH3:29].CO>C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:32])[CH:27]([O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)C(C)C
Yield: 58 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 2-hydroxy-3-methyl-butyric acid methyl ester were reacted and subjected to flash chromatography (SiO2, gradient 0-5% methanol in ethyl acetate) to give racemic 2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-3-methyl-butyric acid methyl ester as a yellow oil (160 mg, 58%). LCMS: RT=3.60 min, [M+H]+=427
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:18])=[CH:15]/[CH:16]=[O:17])[CH:5]=[CH:4][C:3]1=2.[Br:20]Br.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Br:20]/[C:15](=[C:14](/[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)\[CH3:18])/[CH:16]=[O:17]
Reactant: C/C(=C\C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C/C(=C(\Br)C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -75 °C
Reaction time: 0.17 h

Procedure:
2.86 g of (E)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal were dissolved in 16 ml of CH2Cl2 and cooled to -75° C. 1.1 eq. of Br2 (0.63 ml), dissolved in 3 ml of CH2Cl2, was added drop by drop and the mixture kept for 10 minutes at this temperature. TLC indicated the formation of the dibromide. 4.98 ml of DBU was then added all at once and the temperature raised to 0° C. After 1/2 hour the reaction mixture was poured onto crushed ice/HCl, extracted with EtOEt, washed twice with brine, dried over Na2 SO4 and the solvents removed i.V. Flash chromatography (silica gel, hexane/AcOEt=96:4) yielded 0.95 g of the labile (E)-2-bromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal as yellow crystals of m.p. 115°-117° C. Double bond geometry was proven by NOE.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:31](I)([CH3:33])[CH3:32]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(C(C)C)c1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 83 using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and isopropyl iodide (0.11 mL) as starting materials, N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCOCC2)c1
Yield: 76.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(morpholinomethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), morpholine (0.046 mL; 0.5 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 5% methanol in dichloromethane) furnished 0.044 g (76%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:30](Cl)[O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: Cc1noc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Reactant: COCCOCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)thieno[2,3-b]-pyridine-3-sulfonamide (0.76 g, 2.3 mmoles) (see Example 3), DIEA (0.6 ml, 35 mmoles) and EtOAc (100 ml) was added MEM-Cl (0.3 ml, 2.5 mmoles). The orange-brown solution was stirred 3 hours at ambient temperature, then washed with saturated NaHCO3 (200 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.92 g (95%) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33](Br)[N:34]=3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:39][C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][C:49]=1B1OC(C)(C)C(C)(C)O1)[C:43]([O:45][CH3:46])=[O:44].C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([C:49]4[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=4[CH3:39])[N:34]=3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(Br)cs1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2csc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)n2)c(C)c1
Temperature: 90 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (46.0 mg, 0.073 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (30 mg, 0.11 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (5 mg, 7.3×10−3 mmol), THF (1 mL) and 1M K2CO3 (1 mL, 1 mmol). The mixture was degassed with N2, the tube was sealed, and the reaction was heated to 90° C. for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 mL) each, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 40% EtOAc/hexanes) afforded methyl 4-{2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-3-methylbenzoate. Rf=0.29 (25% EtOAc/hexanes). LCMS=702.9 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.97 (s, 1H), 7.92 (dd, J=8.0, 1.4 Hz, 1H), 7.85-7.86 (m, 3H), 7.69-7.72 (m, 4H), 7.53(s, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.11 (d, J=16.2 Hz, 1H), 4.95 (d, J=16.2 Hz, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 2.54 (s, 3H), 0.60 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]1([C:20]2[CH2:24][C:23]3([CH2:28][CH2:27][NH:26][CH2:25]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:24]3)[CH2:25]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(C2=NOC3(CCNC3)C2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC(c4ccccc4)=NO3)C2)cc1
Reaction time: 2 h

Procedure:
4-Tert-butylphenyl isocyanate (350 mg, 2 mmol) was added to a solution of compound R (420 mg crude product, approx. 2 mmol) in abs. THF (20 ml) under argon at RT within 10 min. After 1 h the cloudy solution was mixed with triethylamine (0.3 ml, 2.22 mmol). The reaction mixture was stirred for a further 2 h and then mixed with 2 N HCl solution (10 ml). The acidic reaction mixture was stirred for 10 min and then extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue was recrystallised from toluene (15 ml). The desired product N-(4-tert-butylphenyl)-3-phenyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide was thus obtained in a yield of 415 mg (55%) having a melting point of 207-208° C. (from EtOH, crystal transformation between 183 and 188° C.).