Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(I)cc1F
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 3,4-difluoroiodobenzene (5.00 g), copper(I) iodide (79.4 mg), triphenylphosphine (273 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (432 mg), propargyl alcohol (1.35 ml), diisopropylethylamine (14.5 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.25 g) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][C@@H:4]([CH3:7])[CH2:5][OH:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C(OCC)C.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:9])([F:8])[CH2:3][C@@H:4]([CH3:7])[CH:5]=[O:6]
Reactant: C[C@@H](CO)CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](C=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2R)-4,4,4-trifluoro-2-methylbutan-1-ol (2.90 g, 20.4 mmol) in CH2Cl2 (50 mL) at 0° C. was added Dess-Martin periodinane (10.24 g, 24.49 mmol). After 15 min, the reaction mixture was warmed to 25° C. and stirred for 1 h. This mixture was then diluted with diethyl ether (50 mL) and added to Na2S2O3 (11.29 g, 71.44 mmol) dissolved in a saturated solution of aqueous NaHCO3 (100 mL). The milky white mixture was stirred until both layers were homogeneous. The phases were separated and the organic extract was dried (MgSO4) and filtered to give a solution of (2R)-4,4,4-trifluoro-2-methylbutanal which was used in the next step without removal of solvents.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:10][CH:11]=1)[C:3]#[N:4].[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:2]/[C:3]#[N:4])=[CH:11][N:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Br)C#N)cn1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/C#N)cn1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionitrile (4.5 g), lithium bromide (LiBr) (1.14 g), lithium carbonate (Li2CO3) (2.17 g) and N,N-dimethylformamide (50 ml) was stirred for 2.5 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure to leave (E)-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]acrylonitrile (3.2, 89%), which was recrystallized from ethyl acetate--hexane to give pale yellow crystals, m.p.116°-117° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[NH:11])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([Br:1])[C:3]2[N:4]([N:11]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH:5]=1
Reactant: N=C(Nc1ncc(Br)nc1Br)c1ccco1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: Cc1ccccc1
Product: Brc1cn2nc(-c3ccco3)nc2c(Br)n1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A mixture of N-(3,5-dibromo-pyrazin-2-yl)-furan-2-carboxamidine (47 g, 0.14 mol), lead tetraacetate (95% purity, 160 g, 0.34 mol), and toluene (940 ml) was refluxed for 2 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (hexanes:EtOAc (5:1 to 3:1)) as eluent to afford 6,8-dibromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine as a yellow solid (19.2 g, 40% yield). 1H NMR (300 MHz, CDCl3) δ 6.60 (dd, 1H), 7.33 (d, 1H), 7.62 (d, 1H), 8.63 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)=[O:11].[Li+].[OH-]>CO.C1COCC1.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylate (3.7 g, 12.4 mmol) in MeOH (40 mL) and THF (40 mL), a solution of LiOH (0.7 g, 29.2 mmol) in water (10 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (100 mL), extracted with EtOAc (2×50 mL) and the aqueous layer was acidified by addition of 2 NHCl to pH 3 to give a precipitate. The precipitate was washed with water and dried in high vacuum to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][OH:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][O:31][S:39]([CH3:42])(=[O:41])=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R,5S)-2-hydroxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (500 mg, 1.14 mmol) in CH2Cl2 (5 mL) was added at 0° C. under nitrogen atmosphere Et3N (350 μl, 2.5 mmol) and mesylchloride (197 μl, 2.5 mmol) and the mixture was further stirred at RT for 3 h. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was used without further purification in the next step. MS (LC-MS): 517 [MH−Boc]+; tR (HPLC conditions b) 5.15 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:6]2.Br.C(O)(=O)C>C([O-])(O)=O.[Na+]>[CH2:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)CCN2Cc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 115 °C
Reaction time: 22 h
Yield: 93.2 %

Procedure:
To a solution of 5-methoxyindole (147 mg, 1.00 mmol) in 2.5 mL of tetrahydrofuran was added acetic acid (2.5 mL) and sodium cyanoborohydride (220 mg, 3.50 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 20 min, benzaldehyde (0.20 mL, 2.0 mmol) was added with additional stirring for 1 h. After the reaction mixture was diluted with water (20 mL) and a 1:1 solution (20 mL) of hexane and ethyl acetate, the aqueous layer was extracted with a 1:1 solution (20 mL) of hexane and ethyl acetate. The combined extracts were washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain 5-methoxy-1-benzylindoline (158 mg, 66%) as a sticky oil. To 5-methoxy-1-benzylindoline (4.30 g, 18.0 mmol) was added a solution of 50% hydrogen bromide-acetic acid solution (90 mL) at room temperature. After the reaction mixture was stirred at 115° C. for 22 h, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution (200 mL) and the solution was extracted with ethyl acetate (200 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound (3.78 g, 93%) as a sticky oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CC(C)([O-])C.[K+].Cl.Cl[CH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32]>CC(N(C)C)=O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][CH2:25][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1CCc1ccccc1O
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1CCc1ccccc1OCCC1CCCN1C
Yield: 23 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methylphenyl)ethyl]phenol (prepared as described in Preparation 24), 1.59 g of potassium t-butoxide and 1.73 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 350 mg (yield 23%) of the title compound as a solid.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[CH2:28]([C:14]1[C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:36])[N:9]([CH3:35])[C:10]=2[N:17]=[CH:16][C:15]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)c1cccc(Oc2cnc3c(c2Cc2ccccc2)c(=O)n(CCCOC=O)c(=O)n3C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(Oc2cnc3c(c2Cc2ccccc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a solution of 3-(5-benzyl-6-(3-isopropylphenoxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.10 mmol) in THF (3 ml) and water (3 mL) was added LiOH.H2O (10 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by Prep HPLC to give 5-benzyl-3-(3-hydroxypropyl)-6-(3-isopropyl phenoxy)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 45% yield) as a solid. 1H NMR (CDCl3) δ: 8.32 (s, 1H), 7.29 (s, 2H), 7.25-7.12 (m, 4H), 6.99 (d, J=7.9 Hz, 1H), 6.76 (s, 1H), 6.68 (dd, J=8.0, 2.3 Hz, 1H), 4.80 (s, 2H), 4.24 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 3.52 (dd, J=11.8, 6.2 Hz, 2H), 3.10 (t, J=7.0 Hz, 1H), 2.85 (dt, J=13.9, 6.9 Hz, 1H), 1.98-1.83 (m, 2H), 1.22 (d, J=6.9 Hz, 6H). LCMS: MH+ 460 and TR=3.376 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20]>C(O)C>[F:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]([N+:19]([O-:21])=[O:20])=[C:8]([CH:13]=1)[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1F
Reactant: NCCCCO
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1NCCCCO
Reaction time: 8 h
Yield: 79.8 %

Procedure:
With ice-cooling, 4-aminobutanol (0.72 g) dissolved in ethanol (5 ml) was added dropwise to ethanol (10 ml) solution of 1,5-difluoro-2-nitro-4-trifluoromethylbenzene (0.73 g), and the reaction was carried out overnight at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(5-fluoro-2-nitro-4-trifluoromethylanilino)butanol (0.76 g). The resulting anilinobutanol (0.66 g) and imidazole (1.5 g) were allowed to react with each other in DMF (10 ml) at 140° C. for 1 hour, the reaction solution was concentrated and then the resulting residue was purified by a silica gel column chromatography (chloroform:methanol =15:1) to give 4-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino)butanol (0.68 g).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>C1COCC1>[NH2:6][C:4](=[S:11])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: COC(=O)CCC(N)=S
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
A solution of methyl succinamate (2.5 g, 0.019 mol) in THF (60 mL) was cooled to 0° C. and P2S5 (4.2 g, 0.019 mol) was added. The reaction mixture was warmed to room temperature and stirred for 6 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 35-40% EtOAc in petroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.6 g, yield 57%). 1H NMR (300 MHz, CDCl3) δ 7.49 (br s, 2H), 3.72 (s, 3H), 2.95-2.86 (m, 4H). MS (ESI) m/z: Calculated for C5H9NO2S: 147.04. found: 248.2 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][S:15]([O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:12]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)c1cccc(O)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1cccc(OS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2.2 g of 6-isopropylsulfonyl-2-pyridinol and 1.48 g of methanesulfonyl chloride were dissolved in 30 ml of methylene chloride. 1.65 g of triethylamine was added dropwise to the solution at 10° C. or below. The mixture was stirred at room temperature for 2 hours and at 50° to 60° C. for 2 hours to complete the reaction. The reaction mixture was poured into 100 ml of chilled water to separate the methylene chloride layer. The water layer was further extracted with methylene chloride. The resulting organic layer was combined with the above methylene chloride layer. The combined layer was washed with water and chilled to remove the solvent. The resulting residue was purified by silica gel column chromatography (with ethyl acetate and n-hexane) to obtain 2.4 g of objective 6-isopropylsulfonyl-2-pyridyl methanesulfonate as a colorless crystal (yield: 76.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.C(COC)OC.[C:31]1(OB(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>O.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>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:7][N:6]4[CH:8]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
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: COCCOC
Solvent: O
Product: Clc1ccc(N2CCN(Cc3cn4cc(-c5ccccc5)ccc4n3)CC2)cc1

Procedure:
A mixture of 6-bromo-2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine. (Example 23; 0.091 g), tetrakis(triphenylphosphine)palladium (0) (Aldrich; 0.0078 g), and dimethoxyethane (2 mL) is stirred at room temperature for 10 min, at which time phenylboric acid (Aldrich; 0.0306 g) is added, followed by sodium bicarbonate (0.0565 g) in water (1 mL). The mixture is stirred at reflux for 3 h and then allowed to cool. Dimethoxyethane is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using acetone/dichloromethane/methanol (50/200/1) to give 0.027 g of the title compound. MS m/z 402; 1H NMR (CDCl3) δ2.76, 3.21, 3.80, 6.84, 7.19, 7.37-7.58, 7.61, 7.64, 8.26.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCCCC>C(OCC)(=O)C>[C:2]12([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Nc1ccccc1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
Under a nitrogen (N2) atmosphere was combined 10.0 g (46.5 mmol) of 1-bromoadamantane and 20 ml of aniline. The reaction was stirred for 20 hours at 200° C., and then cooled and fractionated on silica gel using 6:1 hexane:ethyl acetate (EtOAc) to afford, after concentration in vacuo and refractionation using toluene, 5.65 g (54%) of N-1-adamantylaniline.
Reaction SMILES: CN(C)CCN.C(N(CC)C(C)C)(C)C.[C:16]1([S:22]([O-:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(OC([N:33]1[CH2:37][CH2:36][CH:35]2[C:38]3[CH:39]=[C:40](I)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH:34]12)=O)(C)(C)C>CS(C)=O.[Cu]I.O>[C:16]1([S:22]([C:40]2[CH:41]=[CH:42][C:43]3[O:44][CH2:45][CH:34]4[CH:35]([C:38]=3[CH:39]=2)[CH2:36][CH2:37][NH:33]4)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(I)ccc3OCC21
Reactant: O=S([O-])c1ccccc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)C1CCNC1CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
Copper(I) iodide (19 mg, 0.10 mmol) was added to a stirring solution of N,N-dimethyl-1,2-ethanediamine (21 μL, 0.20 mmol) in DMSO (2 mL). The reaction was stirred at RT for 10 minutes. N,N-diisopropylethylamine (130 μL, 0.75 mmol), sodium benzenesulfinate (245 mg, 1.5 mmol) and tert-butyl-8-iodo-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate (P05, enantiomer 1,200 mg, 0.5 mmol) were then added sequentially. The reaction was stirred at 100° C. for 18 h. After cooling to RT, water (24 mL) was added and the resulting suspension was extracted with DCM (3×). The combined organic layers were washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was stirred in TFA:DCM (1:1, 2 mL) for 30 min and the solvent was evaporated. This crude product was purified by preparative LC/MS. The resulting material was suspended in DCM, washed with 1N aqueous sodium hydroxide (3×) and water (3×) and the solvent evaporated. The product was converted to the HCl salt by dissolving the free base in a small amount of DCM, adding 1.0 N HCl in diethyl ether and evaporating the solvent to provide 132 mg of 8-(phenylsulfonyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole, Enantiomer 1. MS m/z 316 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 1.91-1.97 (m, 1H), 2.53-2.60 (m, 1H), 2.98-3.02 (m, 1H), 3.19-3.22 (m, 1H), 3.72-3.77 (m, 1H), 4.09 (bs, 1H), 4.24-4.32 (m, 2H), 7.09 (d, J=2.1 Hz, 1H), 7.59-7.74 (m, 4H), 7.94-7.99 (m, 3H), 9.13 (bs, 1H), 9.79 (bs, 1H).
Reaction SMILES: C(OC(=O)CNC1C=CC=CC=1)C.C[Al](C)C.CC1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:33]([C:35]1[CH:36]=[CH:37][C:38]2[O:43][C:42]([CH3:45])([CH3:44])[C@H:41](O)[C@@H:40]([N:47]([CH2:54][C:55]([O:57]CC)=[O:56])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:39]=2[CH:60]=1)#[N:34]>ClCCCl.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>[CH3:44][C:42]1([CH3:45])[C@@H:41]2[O:56][C:55](=[O:57])[CH2:54][N:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:40]2[C:39]2[CH:60]=[C:35]([C:33]#[N:34])[CH:36]=[CH:37][C:38]=2[O:43]1
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Agent: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Agent: CCOC(=O)CNc1ccccc1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H]2[C@H]1OC(=O)CN2c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of N-phenylglycine ethyl ester (900 mg, 5.0 mmol) in 1,2-dichloroethane (10 mL) under argon at 20° C. was treated with trimethylaluminum (3.0 mL, 2.0M in toluene, 6.0 mmol) over 1-2 minutes. After 15 minutes, (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno[c][1]benzopyran-6-carbonitrile (1.0 g, 5.0 mmol, title A compound of example 3) was added at once and stirring was continued for 1.5 hours. The mixture was diluted with ethyl acetate, quenched with a few drops of water and filtered through celite to remove gelatinous aluminum salts. The filtrate was washed with 5% sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with warm methanol to give warm methanol to give the title product (392 mg), mp 241°-243° C. [α]D =-129.1 ° (c=0.35 CHCl3). Analysis calculated for. C20H18N2O3 ·0.14 H2O: C,71.29; H,5.47; N, 8.31. Found: C, 71.05; H, 5.30; N, 8.55.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[C:3]=1[CH3:29].[CH2:30]([NH2:32])[CH3:31]>CN1CCCC1=O.C(OCC)(=O)C>[CH2:30]([NH:32][C:2]1[C:3]([CH3:29])=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1)[CH3:31]
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(Cl)c3C)CCO4)cc2[nH]1
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCNc1ncnc(N2CCOc3ccc(-c4cnc5nc(C)[nH]c5c4)cc3C2)c1C
Yield: 28.4 %

Procedure:
A suspension of 4-(6-chloro-5-methylpyrimidin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (44 mg, 0.11 mmol), and ethylamine (29 mg, 0.65 mmol), in N-methylpyrrolidinone (2 mL) was stirred at 100° C. for 6 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with saturated sodium bicarbonate (75 mL) and brine (50 mL), and dried over sodium sulfate. Concentration and purification by preparatory HPLC (0.1% aqueous ammonium acetate-acetonitrile) gave N-ethyl-5-methyl-6-[7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]pyrimidin-4-amine (13 mg, 30% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H), 7.56-7.48 (m, 2H), 7.11 (d, 1H), 4.57 (s, 2H), 4.33 (d, 2H), 3.79 (d, 2H), 3.53-3.39 (q, 2H), 2.64 (s, 3H), 2.04 (s, 3H), 1.21 (t, 3H); MS (EI) for C23H25N7O: 416 (MH+).