Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: COc1ccc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(C(N)=O)c1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.64 g, 4.82 mmol) and 2-amino-5-(methyloxy)benzamide (1.0 g, 6.00 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-(methyloxy)benzamide was isolated as a white solid (1.83 g, 81% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 3.79 (s, 3 H), 6.61 (s, 1 H), 7.15 (dd, J=8.97, 2.93 Hz, 1 H), 7.31 (d, J=2.93 Hz, 1 H), 7.46 (d, J=8.05 Hz, 2 H), 7.67 (d, J=4.03 Hz, 2 H), 7.96 (ddd, J=8.60, 2.01, 1.83 Hz, 2 H), 8.08 (d, J=8.78 Hz, 1 H), 8.15 (s, 1 H), 11.48 (s, 1 H).
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.S(=O)(=O)(O)[OH:12]>>[CH2:3]([C@@H:4]([OH:5])[C@H:6]([OH:7])[C@H:8]([OH:1])[CH2:9][OH:10])[CH:2]=[O:12]
Reactant: O=S(=O)(O)O
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 35 %

Procedure:
Production of 2DG can be carried out using any known method. For example, 2-DG can be prepared from various starting materials such as D-glucose, D-mannose, calcium D-gluconate, D-arabinose, D-glucosamine hydrochloride, N-acetyl glucosamine, chitin, and chitosan and carboxymethylchitosan. Preparation methods vary with various starting materials. For example, D-glucose can be methylated and brominated, followed by debromination and acid hydrolysis to yield β-2DG. Bergmann et. al. (1992) Berichte der Deutschen Chemischen Gesellschaft Jahrg. 55:158-72. D-glucose or D-mannose can be treated with bromine and acetyl, followed by a Fischer procedure (Fischer et al. (1914) (Berichte der Deutschen Chemischen Gesellschaft Jahrg. 47:196-210), to yield 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol, which is reacted with bromine, then reduced to remove the acetyl group, yielding 2DG (Arita et al. (1972) Bull. Chem. Soc. Japan 45:567-69). The 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol intermediate can be treated with N-bromosuccinimide, followed by hydrogenation and deacetylation to yield 2DG. Monneret and Choay (1981) Carbohydr. Res. 96:299-305. D-glucose can be reacted with ethanethiol and benzoyl chloride, followed by dehydrogenation, reduction, and deprotection to give 2-DG. Wong and Gray (1980) Carbohydr. Res. 80:87-98). Glucal can be deacetylated by reacting with sulfuric acid to give 2-DG with an overall yield of 35%. Overend et al. (1949) J. Chem. Soc., 1:2841-45. D-arabinose can be treated with nitromethane and an acetylating agent, followed by treatment with diluted sodium hydroxide, to yield a-2-DG. Sowden and Fischer (1947)J. Am. Chem. Soc. 69:1048-50. D-arabinose can be condensed, reduced with acetone, then reacted with trifluoromethanesulfonic anhydride, to yield a product that is then reacted with sodium cyanide, followed by hydrogenation, reduction, and hydrolysis, yielding 2-DG. Shiue et al. (1979) Carbohydr. Res. 74:323-26.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[CH2:16][CH2:15]3)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl>[NH2:23][C@@H:21]([CH3:22])[C:20]([N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:33][CH:32]=2)[CH2:19][CH2:18]1)=[O:31]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of Example 1D (3.0 g, 6.5 mmol) in dichloromethane (30 mL) at 0° C. was treated, over a period of 10 minutes, with trifluoroacetic acid (7.5 mL, 97 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 24 hours, and concentrated. The concentrate was dissolved in dichloromethane (300 mL) and the solution was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in methanol (120 mL), treated with L-tartaric acid (1.0 equivalent based on recovered material), stirred for 18 hours at room temperature, and concentrated. The concentrate was dissolved in water (25 mL) and lyophilized to afford the desired product in 83% yield.
Reaction SMILES: C(OC(=O)[NH:10][S:11]([N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1)(=[O:13])=[O:12])C1C=CC=CC=1>[C].[Pd].CO>[OH:19][CH:16]1[CH2:17][CH2:18][N:14]([S:11]([NH2:10])(=[O:13])=[O:12])[CH2:15]1
Reactant: O=C(NS(=O)(=O)N1CCC(O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)N1CCC(O)C1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Benzyl[(3-hydroxypyrrolidin-1-yl)sulfonyl]carbamate (2.55 g) was added to MeOH, and subsequently, 10% palladium carbon (657 mg, 55% wet) was added thereto, followed by stirring at a normal temperature/a normal pressure for about 3 hours under a hydrogen atmosphere. The catalyst was collected by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 3-hydroxypyrrolidin-1-sulfonamide (1.4 g) as a colorless oily substance.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COC(=O)CCC(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL) The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g, 88% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]1=[O:29])[CH:2]=C.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5](=[O:29])[C@:4]([CH2:1][CH:2]=[O:32])([CH3:30])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 240 mg (0.54 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 71, Step E) in THF (8 mL) and water (2.8 mL) added a catalytic amount of osmium tetroxide. After 1.25 h, 323 mg (1.51 mmol) of sodium periodate were added. The resulting light brown slurry was stirred at room temperature for 18.5 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:29]([OH:31])=[O:30])[CH2:10]1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34]([CH2:33][O:30][C:29]([C@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([C:22](=[O:28])[CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C@H:11]([CH2:10][C@H:9]([OH:8])[CH2:26][CH2:25]1)[CH2:12][CH2:13]3)=[O:31])=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mmole) was added to a solution of 3α-hydroxy-5α-androstan-11-one 17β-carboxylic acid (1.025g.,) in warm acetone (50 ml.) followed by ethyl bromoacetate (6 mmole) and the reaction mixture stood at room temperature overnight. The reaction was completed by refluxing for 1 hr., evaporating to dryness and partitioning the residue between water and ether. The ethereal solution was washed with water, dried, and evaporated to give a residue (1.61g.) which was purified by preparative t.l.c. to afford the pure title compound; [α]D + 76°.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: BrCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
2,4,5-Triphenylimidazole (5 g) was added to a suspension of sodium hydride (1.0 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml ) under nitrogen. The reaction was stirred at 45° C. for 1 h, cooled and added, over 1 h to a solution of 1,8-dibromo-octane (30 g) in dry dimethylformamide (100 ml ) under nitrogen. The reaction was stirred at room temperature for 24 h, water was carefully added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 ml ), washed with water (250ml), 2N aqueous hydrochloric acid (250 ml), saturated sodium chloride solution (250 ml ), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Distillation to remove 1,8-dibromooctane and chromatography on silica gel eluted with dichloromethane gave 1-(8-bromooctyl)-2,4,5-triphenylimidazole (4.1 g, 50%) as an oil; NMR d (CDCl3) 0.9-1.7 (12 H, m, 6×CH2), 3.3 (2H, t, BrCH2), 3.9 (2H, t, N--CH2), 7.1-7.7(15H, m, 3×Ph) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>CN(C)C=O.O.C(N(CC)CC)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:3][CH2:4][C@H:5]([OH:6])[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: NC[C@H](O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a mixture of (1R)-2-amino-1-(3-pyridyl)ethanol dihydrochloride (260 g), (4-bromophenyl)acetic acid (278 g), 1-hydroxybenzotriazole (175 g) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (248 g) in N,N-dimethylformamide (1.3 l) was added triethylamine (361 l) at ambient temperature for 1 hour. The mixture was stirred at room temperature overnight. To the mixture was added water (1.3 l). The mixture was poured into water (1.6 l) and basified with 24% aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 5 hours. The precipitate was collected by filtration, washed with water and dried in vacuo to give 2-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]acetamide (335 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=[O:10])[C:3]=1[Cl:12].[OH-:13].[K+].O>C(O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2=[N+:6]([O-:13])[O:10][N:9]=[C:4]2[C:3]=1[Cl:12]
Reactant: [OH-]
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: [O-][n+]1onc2c(Cl)c(Br)ccc21
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
4-Bromo-3-chloro-2-nitroaniline (4.1 g, 16 mmol) was dissolved in 60 mL ethanol, treated with 45% potassium hydroxide solution (2.0 g, 16 mmol), cooled to −5 to 0° C. and treated drop wise with commercial bleach solution (32 mL, 6 wt. %, 31 mmol) over 20 min. The mixture was stirred for 90 min at 0-15° C. and poured into 700 mL water. The precipitated product was collected by filtration, washed well with water and then dried under vacuum at 80° C. to give the title compound (3.2 g, 81%): EIMS m/z 248.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([CH:25]([CH3:27])[CH3:26])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=2)O1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([CH:25]([CH3:27])[CH3:26])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=3)[C:3]=12
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)n(C(C)C)c(=O)c12
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1cccc2cc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)n(C(C)C)c(=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a stirred mixture of 3-((4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-isopropyl-8-methylisoquinolin-1(2H)-one (2008) (95 mg, 0.2 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (66 mg, 0.3 mmol) in DMF-EtOH-H2O (3:1:1, 20 mL), Pd(OAc)2 (16 mg, 0.075 mmol), PPh3 (39.3 mg 0.15 mmol) and Na2CO3 (132 mg, 1.25 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at 100° C. for 1 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-isopropyl-8-methylisoquinolin-1(2H)-one (2009) (53 mg, 61% yield) as a slightly yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH2:3][CH2:2]1.[BrH:14]>O>[BrH:14].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: COC(=O)CCCN1CCOCC1
Agent: Br
Solvent: O
Product: O=C(O)CCCN1CCOCC1

Procedure:
15 g. (0.052 mole) of Methyl γ-morpholinobutyrate (Cruickshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961)) was dissolved in a mixture of 45 ml. of 47% hydrobromic acid and 45 ml. of water and heated for 16 hours at reflux. The solution was taken to dryness under reduced pressure, and the solid which formed was triturated with acetone. The material was filtered and crystallized from 60 ml. of acetic acid to give 12.4 g. (95%) of product as colorless crystals, m.p. 151°-152.5°C. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3][CH:2]1[CH3:1]
Reactant: O=Cc1ncc[nH]1
Reactant: CC1COc2ccccc2N1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1COc2ccccc2N1Cc1ncc[nH]1

Procedure:
Prepared analogously to Example 1, from (RS)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine, imidazole-2-carboxaldehyde, zinc chloride and sodium cyanoborohydride in methanol. MS (ISP): 230.4 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:22])([F:24])[F:23])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Product: COC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 75, 455 mg (0.85 mmol) of the compound from Example 105A were reacted with 244 mg (1.28 mmol) of 2,3-dichlorophenylboronic acid. This gave 347 mg (57% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: FC(F)(F)COc1nnc(Cl)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)COc1nnc(Cl)cc1-c1ccc(Cl)cc1
Yield: 65.8 %

Procedure:
A mixture of 0.676 g 4-bromo-6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazine, 363 mg 4-chlorophenylboronic acid, 641 mg potassium carbonate and 134 mg tetrakis(triphenylphosphine) palladium in 15 ml tetrahydrofuran and 15 ml water was heated to reflux for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate of 95:5 to 50:50 to yield 0.493 g of the title compound as white solid. MS (EI): 323.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 67.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (213 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 194 mg (68%) of the title compound as a white solid. mp 110°-112°. FDMS: m/e=441 α[D]589 =+80.70 (c=1.05, methanol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[OH:24][CH2:23][CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:18]1
Reactant: OCCC1CCNCC1
Reactant: O=C(O)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC(CCO)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 3-phenylpropionic acid (29.5 g) and thionyl chloride (35 ml) in dry toluene (100 ml) was heated under reflux at 80°-100° C. for two hours. The mixture was then evaporated. The residue was treated with two portions of toluene and the resultant solution was evaporated on each occasion yielding an oil which was then dissolved in dry dichloromethane (50 ml). The solution was added dropwise to a stirred solution of 4-piperidine-ethanol (25.2 g) and triethylamine (22.2 g) in dichloromethane (250 ml) at 0° C. over one hour, maintaining the temperature at 0° C. The mixture was allowed to warm to 20° C. and was stirred for 18 hours and then washed with saturated sodium bicarbonate solution. The organic layer was separated and evaporated to dryness. The residue was dissolved in dioxan (20 ml) and 1M sodium hydroxide solution (20 ml) was then added. The solution was stirred at 20° C. for 20 hours and then stirred at 40° C. for a further 4 hours. The solution was evaporated and the residue treated with dilute sodium hydroxide solution and then extracted with ethyl acetate. The combined ethyl acetate extracts were washed (dilute hydrochloric acid, brine), dried and evaporated to give 4-(2-hydroxyethyl)-1-(3-phenylpropionyl)piperidine as an oil.