Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:30](Br)[CH2:31][Br:32].O>CN(C=O)C>[Br:32][CH2:31][CH2:30][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@:10]2([CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:11]1=[O:19]
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(CCBr)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 40.6 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (173 mg, 0.64 m mol) in DMF (2 mL) was added KHMDS (0.5 M, 1.4 mL) dropwise at room temperature. The mixture was stirred for half an hour before adding ethylene dibromide (300 mg, 1.6 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give the title compound as white solid (98 mg, 41%). LC/MS m/e calcd. for C18H15BrClNO: 375, observed (M+H)+: 376.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:25]=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[Br:36]N1C(=O)CCC1=O.O>O1CCCC1>[Br:36][C:25]1[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:35])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2cccn2C(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
t-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (2.70 g, 5.38 mmol) synthesized in Example (13b) was dissolved in tetrahydrofuran (50 mL), and cooled to 0° C. After addition of N-bromosuccinimide (960 mg, 5.38 mmol) with stirring under nitrogen atmosphere, stirring was carried out at room temperature for 4 hours. Water (50 mL) was added, and extraction was carried out with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (2.93 g, yield 94%) as a brown oil.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 83.2 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronap hthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.0 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Yield: 91.3 %

Procedure:
A solution of 2,6-dibromopyridine 6-1 (37.3 g, 157 mmol), 4-methoxybenzylamine (21.6 g, 157 mmol), and diisopropylethylamine (22.4 g, 173 mmol) in 1,4-dioxane (150 mL) was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (125 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried (Na2SO4). The organic layer was filtered, concentrated in vacuo, and purified by flash chromatography (silica, 10% to 40% EtOAc/hexanes) affording 42 g of amine 6-2 as a white solid in 91% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfuric acid (2 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (800 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×200 mL), washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25° C.: mp 78–80° C.; EI-HRMS m/e calcd for C10H12O4S (M+) 228.0456, found 228.0451.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[CH:14][C:13]=2[Cl:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[Cl:19][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)O

Procedure:
Combine 3-(3,5-dichloro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.75 g, 0.009 mol) with aqueous sodium hydroxide (2N, 30.0 mL, 0.06 mol), ethanol (5 mL), and tetrahydrofuran (5 mL) and stir overnight at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 2.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as a light solid (2.42 g, 97%). MS(ES): (M+1)+ 273.0, 275.0 m/z.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][C:10]([C:12]1[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=1)=O.[CH3:19][C:20]1[C:21]([C:26](=[O:28])C)=N[CH:23]=[CH:24][N:25]=1>>[CH:1]1([NH:7][C:26]([C:21]2[CH:9]=[C:10]([C:12]3[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=3)[N:25]([CH2:24][CH:23]3[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]3)[C:20]=2[CH3:19])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1nccnc1C(=O)CBr
Reactant: CC(=O)c1nccnc1C
Product: Cc1nccnc1-c1cc(C(=O)NC2CCCCC2)c(C)n1CC1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using cyclohexylamine as R1R2NH, c-cyclohexyl-methylamine as R3—(CH2)m—NH2 and 2-bromo-1-(3-methyl-pyrazin-2-yl)-ethanone (available from 1-(3-methyl-pyrazin-2-yl)-ethanone [23787-80-6] following the procedure described by D. W. Robertson et. Al, J. Med. Chem., 29, 1986, 1577-1586); MS (ISP) 395.4 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][CH:59]=[C:33]34)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[OH:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:53][C:4](=[O:7])[O:5][N:3]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][CH:59]=[C:33]34)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O[Si](C)(C)C(C)(C)C)CC3)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CC3)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.26 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 5 mL), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([NH2:11])[CH3:10])=[N:6][C:7]=1[CH3:8].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][CH:9]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([CH3:8])[N:6]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Cc1nc(C(C)N)ccc1F
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)Nc2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)ccc1F
Temperature: 175 °C
Yield: 27.5 %

Procedure:
A microwave reaction vessel was charged with [1-(5-fluoro-6-methylpyridin-2-yl)ethyl]amine (Method 13; 159 mg, 1.03 mmol), 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 335 mg, 1.24 mmol) and DIEA (0.35 ml, 2.0 mmol). Anhydrous n-BuOH (1.5 ml) was added, and the tube was sealed and heated in a microwave reactor at 175° C. for 10 hours. The resulting mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, chromatography (Rf in 50:50 hexanes:EtOAc=0.25) to afford the title compound as a colourless solid (110 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.65-0.75 (m, 2H), 0.85-0.95 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.82 (tt, J=8.5, 5.1 Hz, 1H), 2.46 (d, J=2.8 Hz, 3H), 4.99-5.09 (m, 1H), 6.01 (s, 1H), 6.26 (s, 1H), 7.05 (dd, J=8.3, 3.5 Hz, 1H), 7.15-7.23 (m, 1H), 7.38-7.48 (m, 1H), 7.84 (s, 1H). Calcd.: 387. Found [M+H+] 388.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]([CH2:6][O:7][CH2:8]2)[CH2:4]1.[Li][CH2:20]CCC.CN(C=O)C.Cl>C1COCC1>[CH:9]12[NH:11][CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][C:3]1[C:10]2=[CH:20][O:1][N:2]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1onc2c1C1COCC(C2)N1
Reaction time: 0.5 h

Procedure:
To a solution of compound 104b (512 mg, 2 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry DMF (740 mg, 10 mmol, 5.0 eq) in THF (2 mL) was added dropwise, the mixture was stirred for another 2 h from −60° C. to room temperature. To it 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (332 mg) as an oil. MS: calc'd (MH+) 167, measured (MH+) 167.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)c2ccccc2NC1=O
Reaction time: 8 h
Yield: 88.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (832 mg) was dissolved in methanol (20 ml), sodium bicarbonate (445 mg) and benzyl bromide (906 mg) were added, the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue, after addition of water, was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, the crystals were washed with isopropyl ether, to thereby obtain 980 mg of the titled compound (Yield: 86.9%).
Reaction SMILES: [NH2:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[C:12]([NH:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C(N)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
27.5 parts of DL-1-amino-2-methylpropanephosphonous acid in 100 parts of water was stirred until solution occurred. The pH of the solution was adjusted to 9.5 with 4N sodium hydroxide and the mixture cooled to 0°. 34 Parts of benzyl chloroformate was added over 1 hour and the mixture stirred for 6 hours maintaining at pH 9.0-9.5 by periodic addition of 4N sodium hydroxide. The mixture was allowed to warm up to room temperature and then washed with ether. The aqueous portion was added slowly to a mixture of 120 parts of water and 80 parts of concentrated hydrochloric acid and 400 parts of ice. The solid which was obtained was dried and recrystallised from ethyl acetate/petroleum ether to give DL-1-carbobenzyloxyamino-2-methylpropanephosphonous acid, melting point 108°-111°.
Reaction SMILES: C(COC1C2CC(=CCCN3CCC(C4C=CC(Cl)=CC=4)(O)CC3)C3[C:15](OC=2C=CC=1)=[N:16][CH:17]=CC=3)(O)=O.[C:38]([C:41]([O:44][C:45]1[C:50]2[CH2:51][C:52](=[CH:60][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][C:66]([C:70]4[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=4)([OH:69])[CH2:65][CH2:64]3)[C:53]3[C:54]([O:59][C:49]=2[CH:48]=[CH:47][CH:46]=1)=[N:55][CH:56]=[CH:57][CH:58]=3)([CH3:43])[CH3:42])(O)=[O:39]>>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C:66]2([OH:69])[CH2:67][CH2:68][N:63]([CH2:62][CH2:61][CH:60]=[C:52]3[C:53]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:59][C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([O:44][C:41]([C:38]([N:16]([CH3:17])[CH3:15])=[O:39])([CH3:43])[CH3:42])[C:50]=4[CH2:51]3)[CH2:64][CH2:65]2)=[CH:71][CH:72]=1
Reactant: CC(C)(Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2)C(=O)O
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: CN(C)C(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 139.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23](OC)[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31]B(O)O.[C:35](=[O:38])(O)[O-].[Na+].[Cl-].[NH4+]>O1CCOCC1.O.ClCCl>[CH3:31][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:38][CH3:35])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: CB(O)O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (20 mg, 0.042 mmol), methyl-boronic acid (40 mg, 0.67 mmol), in 1,4-dioxane (2 mL) at 90° C. was added tetrakis-triphenylphosphine palladium (11 mg, 0.01 mmol) followed by the addition of a solution of sodium bicarbonate (40 mg, 0.48 mmol) in distilled water (0.5 mL). The reaction mixture turned red after 5 minutes. After 2 hours (tlc) the reaction mixture was brought to room temperature and was added saturated ammonium chloride (2 mL) and diluted with dichloromethane (20 mL). The organic layer was separated and washed with water, dried over magnesium sulfate and the solvent was removed by distillation under vacuum. The residue was purified by PTLC (eluent=Dichloromethane/Methanol, 1:1) to give the title compound (actate cleaved during reaction) as a fluffy white solid; (3 mg, 19%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1CCCC[N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=[C:38](CS(N)(=O)=O)[CH:39]=[CH:40][CH:41]=2)N=1.ClC1N=CN=C(N[C:55]2[CH:56]=C(CCS(N)(=O)=O)C=C[CH:60]=2)N=1>>[CH2:1]([O:2][CH2:3][C@H:4]1[CH2:56][CH2:55][CH2:60][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:11]=1)[C:41]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NS(=O)(=O)CCc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3COCc3ccccc3)n2)c1

Procedure:
B30 was prepared following the procedure reported for B4 using A1 and A4 and obtained as a white powder; yield: 270 mg (66%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.82-2.08 (m, 4H), 3.42-3.78 (m, 4H), 4.20 (2 s, 2H), 4.24-4.39 (m, 1H), 4.39-4.58 (m, 2H), 6.85 (bs, 2H), 6.93-7.02 (m, 1H), 7.18-7.39 (m, 6H), 7.67-7.77 (m, 1H), 7.73 and 7.88 (2bs, 1H), 8.21 (2 s, 1H), 9.67 (s, 1H). MS (ES) C22H26N6O3S requires: 454. found: 455 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[Cl:23][CH2:24][CH:25]=O.Cl.C([BH3-])#N.[Na+]>CO>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:25][CH2:24][Cl:23])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2)=[O:8]
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reaction time: 2.5 h

Procedure:
5-Amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (7 g, Example 29b) and chloroacetaldehyde (50% solution in water, 6.6 ml) were stirred in methanol (120 ml) under nitrogen for 10 min. A mixture of 6M hydrochloric acid (1.8 ml) and methanol (1.8 ml) was added, followed by sodium cyanoborohydride (1.48 g). The mixture was stirred for 2.5 h. The methanol was then removed under reduced pressure and the residue partitioned between saturated aqueous sodium hydrogencarbonate and dichloromethane The aqueous layer was extracted twice more with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the sub-title compound (8.2 g).
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:19])[CH2:9][CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:35](Cl)(=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1.O>[CH2:1]([O:7][C:8]([CH2:9][CH2:10][CH:11]([O:18][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:19])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CCC=CCCOC(=O)CCC(O)CCCCCC
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC=CCCOC(=O)CCC(CCCCCC)OC(=O)CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of 1.10 g of 4-hydroxy-decanoic acid hex-3-enyl ester, 0.64 g pyridine and 0.1 g dimethylaminopyridine in 5 ml tetrahydrofuran was slowly added a solution of 1.10 g myristoyl chloride in 5 ml tetrahydrofuran. The mixture was stirred for 16 hours at room temperature. Water was then added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 2N hydrochloric acid, water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel to give 1.81 g of a colorless liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])[CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl-:1].[O:11]=[C:3]([CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCC(CC)C(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)C(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 129.9 %

Procedure:
A solution of 1-chloro-3-ethyl-2-heptanone (88.4 g.) and triphenylphosphine (81 g.) in chloroform (100 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo to give crude 2-oxo-3-ethylheptyltriphenylphosphonium chloride (176.1 g.).