Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[CH2:41][CH2:40][N:32]3[C:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=[C:31]3[C:30]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[NH:21][N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[CH:24]1([C:22]2[NH:21][N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:29]5[CH2:41][CH2:40][N:32]6[C:33]7[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=7[CH:39]=[C:31]6[C:30]5=[O:42])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:23]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc(C3CC3)[nH]n2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
A mixture of 118c (350 mg, 0.62 mmol) and LiOH.H2O (260 mg, 6.2 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 118 (200 mg, 54%) as a white solid. LCMS: [M+H]+ 526. 1H NMR (500 MHz, DMSO) δ 11.83 (s, 1H), 8.48 (d, J=5, 1H), 8.05 (d, J=2, 1H), 8.03 (s, 1H), 7.38 (d, J=2, 1H), 7.31 (d, J=5, 1H), 6.58 (s, 1H), 5.81 (d, J=2, 1H), 4.95 (t, J=5, 1H), 4.49-4.51 (m, 1H), 4.38-4.40 (m, 1H), 4.19-4.21 (m, 3H), 3.85-3.87 (m, 1H), 3.58 (s, 3H), 2.61-2.62 (m, 1H), 2.56-2.57 (m, 1H), 2.48-2.49 (m, 2H), 1.81-1.82 (m, 3H), 1.70-1.71 (m, 2H), 0.88-0.89 (m, 2H), 0.63-0.64 (m, 2H)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.23 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.18 g, 46%). MS (ISP) 460.1 [(M+H)+]; mp 210° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:18]Br>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[S:7][C:8]([Br:18])=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCc1sccc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1sc(Br)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 62.3 (0.61 g, 3.58 mmol) and pyridine (0.29 mL, 3.58 mmol) in DCM (24 mL) was added bromine (3.58 mL, 1.0 M solution in DCM) dropwise at 0° C. The mixture was stirred for 30 minutes at 0° C. and warmed to room temperature over 1 hour. Upon completion, the reaction was diluted with DCM, washed with saturated Na2S2O3 and brine, dried (Na2SO4), and concentrated to afford 62.4. The crude product was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH3:31])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH3:23])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH3:31])=[CH:14][O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[CH3:23]
Reactant: ClCCl
Reactant: CCc1ccccc1C(=COCCN1CCC=C(C(=O)OC)C1)c1ccccc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccccc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
1-(2-((2,2-bis(2-Ethylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.40 g, 0.00323 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (10 ml) and 12 N sodium hydroxide solution (0.8 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.80 g, 57%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To a stirred solution of ethyl 2-(1H-benzo[d]imidazol-2-ylthio)acetate 4a (11.2 g, 47.6 mmol, 1.0 eq.) in 10:1 diethyl ether:dimethylformamide (450 mL) at 0° C., was added 60% sodium hydride in mineral oil (2.09 g, 52.3 mmol, 1.1 eq.), and the reaction was stirred at 0° C. for 20 minutes. Benzyl bromide (9.78 g, 57.1 mmol, 1.2 eq.) was added at 0° C., and the reaction was stirred with warming to room temperature for 16 hours. The reaction mixture was quenched with methanol (100 mL) and concentrated in vacuo. The residue was taken into hot chloroform (400 mL) and filtered. The filtrate was washed with water (200 mL), 1M HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (10% EtOAc:90% petroleum ether) gave 4b as a pale-yellow solid (4.82 g, 30%).
Reaction SMILES: [OH:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)[C:3]#[N:4].[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>ClCCl.CN(C)C1C=CN=CC=1.O>[Si:35]([O:1][CH:2]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:3]#[N:4])([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 2-hydroxy-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (290 mg, 0.68 mmol, 1.00 equiv) in dichloromethane (10 mL). TBSCl (153 mg, 1.02 mmol, 1.51 equiv), imidazole (92 mg, 1.35 mmol, 2.00 equiv) and 4-dimethylaminopyridine (17 mg, 0.14 mmol, 0.21 equiv) were added successively at 0° C. under nitrogen. The resulting mixture was stirred overnight at room temperature. After completion, the resulting solution was diluted with water, extracted with 3×30 mL of dichloromethane, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (1:1) to afford the desired 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propanenitrile (350 mg, 95%) as a yellow oil. MS (ES): m/z 543 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH:11](C)[CH2:12][CH:13]=O)[O:8][N:7]=1.[C:16]1([N:22]2[CH2:27][CH2:26]C[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:42]([N:49]1CCNCC1)C1C=CC=CC=1>C(Cl)Cl>[C:16]1([N:22]2[CH2:27][CH2:26][N:49]([CH2:42][CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(CC=O)c1cc(-c2cccs2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: c1ccc(N2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(N2CCN(CCCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 94.7 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)butanal (23.5 mg, 0.106 mmol) and 1-phenylpiperidine (16.2, 0.106 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (67.4 mg, 0.318 mmol), cold acetic acid (7.3, 0.127 1mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3 hr and followed the same processes as in Example 1 to obtain 36.9 mg (94.7%) of the target compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:35]2[CH2:36][CH2:37][N:32]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:33][CH2:34]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(c1cccs1)N1CCNCC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Temperature: 110 °C
Yield: 56.2 %

Procedure:
2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (2.6 g, 13 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (5.8 mL, 34 mmol), 1-(2-thiophenylsulfonyl)piperazine hydrochloride (3.0 g, 11 mmol, Example 29, step 1), and acetonitrile (22 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 110° C. for 19 h. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (50 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated, hexanes (100 mL) was added to the residue and the slurry was filtered to give 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (2.5 g) as a light tan solid. The material was used in the next step without purification
Reaction SMILES: Br[C:2](C)([C:6]1[C:7](=[C:11](C)[CH:12]=[CH:13][CH:14]=1)[C:8]([O-])=[O:9])C([O-])=O.[OH:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:27][O:26][C:23]1[CH:22]=[C:19]2[C:18](=[CH:25][CH:24]=1)[O:17][C:2]1[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8](=[O:9])[NH:21][C:20]2=1
Reactant: COc1ccc(O)c(C#N)c1
Reactant: Cc1cccc(C(C)(Br)C(=O)[O-])c1C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2oc3c4ccccc4c(=O)[nH]c3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α-Bromodimethylhomophthalate (20a) (1.16 g) and 2-hydroxy-5-methoxy-benzonitrile (0.6 g, 4 mmol, 1 eq) were dissolved by warming in acetonitrile (6 mL). Triethylamine (5.6 mL, 10 eq) was then added and the reaction was heated at reflux for 48 h under inert atmosphere, then cooled to room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (40 mL) and the resulting suspension was allowed to stir for 2 h, and was then filtered. The filtercake was washed sequentially with 1 N HCl (2×50 mL), acetonitrile (2×50 mL) and dichloromethane (50 mL), then dried in a vacuum oven at 50° C. fot three days to provide Compound 22a as an white solid. Yield=0.81 g (76%).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][CH:12]=1)=[O:9].[NH2:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12>C(Cl)Cl>[CH:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([NH:21][CH:22]2[C:40](=[O:41])[N:24]3[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]4[N:35]([CH3:36])[N:34]=[N:33][N:32]=4)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: O=CNc1cccc(CC(=O)O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(NC=O)n3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
A solution of pivaloyl chloride (1.07 g.) in methylene chloride (3 ml.) was added to a solution of 2-(6-Formamidopyridin-2-yl)acetic acid (1.6 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) in methylene chloride (25 ml.) at -20° to -25° C., and stirred at the same temperature for one hour [solution A]. On the other hand, a solution of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.24 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) in methylene chloride (60 ml.) was stirred at room temperature for 10 minutes. To the solution was added the above solution A at -20° to -25° C. and stirred at the same temperature for 1.5 hours. After removing the solvent from the resultant solution, ethyl acetate, water and sodium bicarbonate were added to the residue. The aqueous layer was separated and washed with ethyl acetate. Ethyl acetate (300 ml.) was added to the aqueous solution, adjusted to pH 2 to 3 with 5% hydrochloric acid, and then shaken sufficiently. The ethyl acetate layer was separated, washed with water and concentrated under reduced pressure to give 7-[2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.1 g, 44%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(CCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCc1ccc(OCc2ccccc2)cc1

Procedure:
5-Bromo-1-(4-benzyloxy-phenyl)-pentane (10.4) was prepared as in 10.1 using 9.4 (2.99 g, 12.3 mmol), K2CO3 (4.24 g, 30.75 mmol) and benzyl bromide (2.31 g, 13.53 mmol). The title compound (10.4) was isolated as a white semi-solid after purification by flash column chromatography (3.11 g, 76% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: CC(=O)N1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(C(C)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-acetylpiperazine. A yellow solid 104 was obtained (0.0197 g, 41%). 1H-NMR (CDCl3, 400 MHz) δ 2.17 (s, 3H), 3.68–3.72 (m, 2H), 3.73–3.78 (m, 2H), 3.82–3.89 (m, 2H), 3.83 (s, 3H), 3.94–3.99 (m, 2H), 6.95 (s, 1H), 7.00–7.05 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 7.45–7.52 (m, 3H), 7.86 (s, 1H), 8.29 (d, J=6.2 Hz, 1H). MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].FC(F)(F)S(O)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (400 mg in 6 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (209 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (9 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 6 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (320 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][CH:15]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][CH:15]2[CH3:14])=[CH:3][CH:4]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
A solution of 1-bromo-4-chlorobenzene (21.87 g, 114 mmol) in anhydrous THF (250 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (43.5 mL, 109 mmol, 1.6 M in hexanes). The mixture was stirred at −78° C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (11.6 g, 54.4 mmol) in anhydrous THF (50 mL). The reaction was stirred at −78° C. for 2 hours, then allowed to slowly warm to −20° C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3 times with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (200 mL) for 1 hour, and then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate (13.96 g, 42.8 mmol, 79% yield) as a powder. m/z=252.2 (M-tBuO)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].[CH3:29][C:30]([CH2:32]C)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:26]([CH3:28])[CH3:27])=[C:13]([O:18][CH:30]([CH3:32])[CH3:29])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Reactant: CC(C)Br
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1OC(C)C
Temperature: 40 °C
Yield: 85 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, 2-bromopropane (0.062 ml) was added and heated for 24 hours at 40° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (28 mg, productive yield 85%) was obtained.