Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:33]>O1CCOCC1.[Cl-].[Na+].O>[NH2:33][C:13]1[N:14]=[C:15]([CH3:16])[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7](=[O:32])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]=2[N:12]=1
Reactant: [NH4+]
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1cc(-c1cnn(CCO)c1)c(=O)n2C1CCCC1
Temperature: 100 °C
Yield: 54 %

Procedure:
To the solution of 8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) in 5 ml 1,4-dioxane was babbled through ammonium gas for 10 minutes. The reaction tube was sealed and heated to 100° C. for 30 minutes. The reaction mixture was poured into brine and the precipitate was collected via filtration. The solid was then re-dissolved in 5 ml methanol and a few drop of concentrated HCl was added and the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (33 mg, 54% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:8]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O(CC)CC>[N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: Nc1ccc2sc3nccn3c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccc2c(c1)N1CCN=C1S2)C(=O)OCC
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of 5.5 parts of imidazo[2,1-b]benzothiazol-6-amine and 7.5 parts of diethyl 2-(ethoxymethylene)propanedioate is stirred for 30 minutes at 110° C. The solid product is suspended in 1,1'-oxybisethane. It is filtered off and dried, yielding 10 parts (95%) of diethyl 2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)aminomethylene]propanedioate; mp 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.Cl.C(OCC)(=[O:20])C>C1(C)C=CC=CC=1.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([CH3:12])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CC(C)=O)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 790 mg (2.90 mmol) of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (from Example 80, Step A) in 5.0 mL of toluene was combined with water (2.0 mL), iron powder (730 mg, 13.45 mmol), and ferric chloride (14.2 mg, 0.088 mmol) in a 25-mL three-neck round bottom flask fitted with a mechanical stirrer and reflux condenser. With vigorous agitation, the suspension was heated at 80° C., and 1.3 mL of conc. HCl was added over a period of 2 h via syringe. After the addition was completed, the heating and stirring were continued for an additional 30 min. After the reaction had cooled to RT, ethyl acetate (50 mL) was added to the solid was removed by filtration. The filtrate was washed with 20 mL of saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was filtered again and the filtrate was extracted with 2×40 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of brine. Drying over sodium sulfate and concentration afforded a red oil which was purified by flash column chromatography, eluting with 30% dichloromethane in hexane followed by dichloromethane, to give 411 mg of the title compound as a yellow syrup.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([O:32]CC1C=CC(OC)=CC=1)[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([OH:32])[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)O
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of (2S,6S,7S)-benzyl 2-((tert-butoxycarbonyl)amino)-7-((S)-1-((4-methoxybenzyl)oxy)-ethyl)-10-methyl-6-propoxyundecanoate (1.10 g, 1.75 mmol) in H2O (0.531 mL) and DCM (5.31 mL) was added DDQ (0.418 g, 1.84 mmol) at 0° C. The mixture was stirred vigorously at this temperature for 1 h and then 1N NaOH (1.84 mL, 1.84 mmol) and H2O (20 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (3×15 mL). The combined organic extracts were washed with brine (8 mL), dried over Na2SO4, filtered, and the filtrate was treated with Celite® (2 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (40 g SiO2, 0→60% EtOAc/hexanes) to afford the title compound (815 mg, 1.61 mmol, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 5.17 (app q, J=12.4 Hz, 2H), 5.07 (d, J=8.5 Hz, 1H), 4.44-4.39 (m, 1H), 4.39-4.30 (m, 1H), 3.87-3.75 (m, 1H), 3.54 (app dt, J=9.0, 6.6 Hz, 1H), 3.42-3.33 (m, 1H), 3.26 (app dt, J=8.9, 6.6 Hz, 1H), 1.87-1.76 (m, 1H), 1.72-1.37 (m, 17H), 1.35-1.07 (m, 7H), 1.04-0.93 (m, 1H), 0.93-0.84 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 172.66, 155.32, 135.39, 128.59, 128.42, 128.24, 82.50, 79.89, 71.42, 69.10, 66.99, 53.52, 45.46, 37.47, 32.82, 28.82, 28.31, 28.28, 25.27, 23.20, 22.68, 22.54, 22.44, 22.06, 10.66; ESIMS m/z 530 ([M+Na]+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O.B(Br)(Br)Br.[CH2:26](O)[CH3:27]>C(Cl)Cl>[CH2:26]([O:16][C:14]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:15])[CH3:27]
Reactant: CCO
Reactant: COc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: BrB(Br)Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(O)cc2)CCCC1
Temperature: -78 °C
Yield: 79 %

Procedure:
A solution of 1-(p-methoxyphenyl)-cyclopentanecarboxylic acid 093909 (5.0 g, 22.7 mmol) in ethanol (50 mL) was treated with conc. H2SO4 (4.40 g, 44.9 mmol) and heated to reflux under N2 for 12 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to 5.93 g crude ester (100%) that was utilized without purification. The ester (5.93 g, assume 22.7 mmol) was dissolved in dry CH2Cl2 (75 mL), cooled to −78° C. and then treated dropwise with BBr3 (11.4 g, 45.6 mmol). The reaction was warmed to 0° C. for 15 minutes and then quenched with methanol then water. The reaction mixture was extracted with CH2Cl2 and water, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 6:1 hexanes:EtOAc to afford 4.34 g (79%) 1-(4-hydroxy-phenyl)-cyclopentanecarboxylic acid ethyl ester. MS (ES+) Calc'd for C14H19O3 (M+1) 235. Found m/z 235 (100%). 1H NMR.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([OH:23])(=[S:22])[CH3:21].[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([NH:32][C:33]([C:35]2[N:36]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)=[O:34])=[C:27]([C:51](=[O:57])[NH:52][CH2:53][CH:54](O)[CH3:55])[CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([NH:32][C:33]([C:35]2[N:36]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=2)=[O:34])=[C:27]([CH:26]=1)[C:51]([NH:52][CH2:53][CH:54]([S:22][C:20](=[O:23])[CH3:21])[CH3:55])=[O:57]
Reactant: CC(O)=S
Reactant: Cc1cc(Cl)cc(C(=O)NCC(C)O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC(C)CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2.55 g (9.7 mmol) triphenylphosphine in 250 ml THF is added at a temperature of 0° C. 2.25 g (9.7 mmol) diterbutylazodicarboxylate in 25 ml THF. The solution is stirred for 1 hour at a temperature of 0° C. Then 0.35 ml (4.85 mmol) thioacetic acid is added and a white suspension is formed immediately. After that, a solution of 2.5 g (4.85 mmol) 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [4-chloro-2-(2-hydroxy-propylcarbamoyl)-6-methyl-phenyl]-amide in 30 ml THF is slowly added at a temperature of 0° C. The solution is stirred for 1 hour at a temperature of 0° C., and then 15 hours at 25° C., and then evaporated. The residue is submitted to flash-chromatography (ethyl acetate 1, hexane 2) to give 2.45 g (88%) white crystals (m.p. 137-139° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:15]([CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:37])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COCOc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(OCOC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 79.1 %

Procedure:
The portion of 120 mg of 60% sodium hydride were suspended in 10 ml of dimethylformamide, and cooled to 0° C., followed by dropwise addition of 1.22 g of N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide, and then followed by addition of 326 mg of ethyl chlorocarbonate. After stirring at room temperature for 19 hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methylene chloride was obtained 1.12 g of N-ethoxycarbonyl-N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: C([O:5][C:6](=[O:41])[NH:7]/[C:8](=[N:39]\O)/[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][C:25]([NH:28][C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)C(C)C>C1(C)C=CC=C(C)C=1.C1COCC1>[F:36][C:35]([F:37])([F:38])[C:32]1[N:31]=[CH:30][C:29]([NH:28][C:25]2[N:24]=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([CH:13]4[CH2:12][CH2:11][CH:10]([CH2:9][C:8]5[NH:7][C:6](=[O:41])[O:5][N:39]=5)[CH2:15][CH2:14]4)=[CH:21][CH:20]=3)=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CC(C)COC(=O)N/C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)=N\O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)c1
Product: O=c1[nH]c(CC2CCC(c3ccc(-c4ccc(Nc5ccc(C(F)(F)F)nc5)nn4)cc3)CC2)no1
Temperature: 180 °C

Procedure:
A solution of [1-[(Z)-hydroxyimino]-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-ethyl]-carbamic acid isobutyl ester (0.13 g, 0.23 mmol 1.0 equiv) was dissolved in a m-xylene/THF (4:1) mixture and then heated to 180° C. for 20 min. The cooled reaction was partitioned between EtOAc and water, and the organic layers were washed with brine and dried. Purification by silica gel chromatography (10-100% MeOH in DCM) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.10 (m, 2H) 1.34 (q, J=11.79 Hz, 2H) 1.59 (ddd, J=11.12, 7.58, 4.04 Hz, 1H) 1.70 (t, J=14.02 Hz, 4H) 2.29 (d, J=6.82 Hz, 2H) 2.38-2.46 (m, 1H) 7.23 (d, J=8.08 Hz, 2H) 7.18 (d, J=9.35 Hz, 1H) 7.72 (d, J=8.59 Hz, 1H) 7.84 (d, J=8.08 Hz, 2H) 7.94 (d, J=9.35 Hz, 1H) 8.56 (dd, J=8.59, 1.26 Hz, 1H) 8.81 (d, J=1.77 Hz, 1H) 9.90 (s, 1H) 12.03 (br. S., 1H); (M+H)+497.2.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1OB(O)O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:18][O:19][C:20]([C:22]1[CH2:26][O:25][CH2:24][C:23]=1OS(C(F)(F)F)(=O)=O)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH3:18][O:19][C:20]([C:22]1[CH2:26][O:25][CH2:24][C:23]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:21]
Reactant: CC(C)(C)C(=O)Nc1ccccc1OB(O)O
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COC1
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: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C1=C(c2ccccc2NC(=O)C(C)(C)C)COC1
Yield: 87 %

Procedure:
2-(Pivaloylamino)phenylboric acid (F. Guiller, F. Nivoliers, A. Godard, F. Marsais, G. Quéguiner, M. A. Siddiqui, V. Snieckus, J. Org. Chem. 1995, 60, 292) (0.66 g, 3.0 mmol), 3-(trifluoromethylsulfonyloxy)-2,5-dihydrofuran-4-carboxylic acid-methyl ester (0.69 g, 2.5 mmol), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) and a 2M aqueous Na2CO3 solution (1.26 ml, 2.52 mmol) are refluxed in DME (40 ml) for 2.5 hours. The batch is diluted with ethyl acetate, washed with water and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate-hexane yields 0.65 g (87%) of 4-(2-(pivaloylamino)phenyl)-2,5-dihydrofuran-3-carboxylic acid-methyl ester (flash point 105-6° C.). 0.59 g (1.94 mmol) of it is then refluxed in concentrated hydrochloric acid for 2 hours. The batch is poured onto ice and extracted with ethyl acetate and dichloromethane. After drying (Na2SO4) and concentration by evaporation, the residue is heated for two more hours with concentrated HCl and worked up as described: 0.22 g (58%) of product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([OH:29])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1.[CH3:44][Si](C=[N+]=[N-])(C)C>CO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([O:29][CH3:44])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid 8 (40 mg, 0.07 mmol) in methanol (2 mL) was added (trimethylsilyl)diazomethane (0.35 mL, 2.0 M in hexanes). The resulting mixture was further stirred for 30 minutes. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate 9 as an oil (40 mg, quant.). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.45-7.41 (m, 1H), 7.37-7.34 (m, 2), 7.29-7.21 (m, 5H), 7.18-7.10 (m, 2H), 4.63-4.53 (m, 1H), 4.21-4.18 (m, 1H), 3.86 (br, 3H), 3.44 (br, 1H), 3.24 (br, 3H), 3.08 (br, 1H), 2.53 (s, 3H), 2.36-2.34 (m, 3H), 1.91-1.71 (m, 11H), 1.59 (d, J=7.0 Hz, 2H). HRMS m/z (M+H)+ calcd 591.3335; obsd 591.3353.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29]([O:33][C:34]([NH:36][CH:37]([C:46](O)=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:46](=[O:47])[CH:37]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:35])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 88.6 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (575 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanine (417 mg) according to a similar manner to that of Example 5, mp. 125°-134° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:35]=[CH:34][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:33])[OH:32])=[CH:26][C:25]=3[O:36][CH3:37])[N:14]=2)=[CH:4][CH:3]=1.[CH3:38][C:39]1([CH3:55])[C:43]([CH3:45])([CH3:44])[O:42][B:41]([C:46]2[CH:47]=[N:48][N:49]([CH2:51][CH2:52][CH2:53]O)[CH:50]=2)[O:40]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:35]=[CH:34][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:32])[O:33][CH2:53][CH2:52][CH2:51][N:49]4[CH:50]=[C:46]([B:41]5[O:42][C:43]([CH3:45])([CH3:44])[C:39]([CH3:38])([CH3:55])[O:40]5)[CH:47]=[N:48]4)=[CH:26][C:25]=3[O:36][CH3:37])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Yield: 90.2 %

Procedure:
This material was prepared analogously to Example 44A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B, 0.220 g, 0.365 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 0.0918 g, 0.364 mmol) to afford the title compound as an off-white foam (275 mg, 90%). MS (ESI): m/z 837.21/839.20 [M+H]+. UPLC: tR=1.14 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(OCC)=[O:2].CCCCCCC.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[CH:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:2]
Reactant: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CCCCCC/C=C/C1C(CC=O)OC2CCCC21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1.00 g. (0.00308 mole) of 2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 5 ml. of heptane at -78° C. and under nitrogen is added dropwise 2.60 ml. of a solution of 25% diisobutylaluminum hydride in hexane. The resulting solution is stirred at -78° C. for 2.5 hours and then poured into cold dilute hydrochloric acid. The organic phase is washed with saturated brine, dried (Na2SO4), and evaporated to yield 0.863 g. of a colorless oil. IR 2695, 1723, 1045, 970 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[C:7]([CH3:16])[CH:6]=[CH:5]2.[Se](=O)=[O:18]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:16]=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 35 %

Procedure:
To 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 5.02 mmol) in dioxane/water (3.5 ml/0.3 mL) at ambient temperature was added selenium dioxide (0.668 g, 6.02 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-8-isopropoxyquinoline-2-carbaldehyde (410 mg, 35.0% yield) as a tan solid.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:13].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cnc2ccccn12
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cnc2ccccn12
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
22.1 g of 3-acetylimidazo[1,2-a]pyridine was dissolved in 220 ml of acetic acid. 35.1 ml of a 30% hydrogen bromide/acetic acid solution was added dropwise to the solution at 0° C. Then 28.6 g of bromine was added dropwise thereto at 40° C. The mixture was stirred at 40° C. for 2 h and crystals thus formed were filtered. The crystals were dissolved in 100 ml of water. The solution was made alkaline with an excess of an aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The organic layer was concentrated and the obtained brown solid was purified according to silica gel column chromatography (eluted with ethyl acetate) to obtain 13.5 g (yield: 40%) of 3-bromoacetylimidazo[1,2-a]pyridine (yield: 40%) in the form of yellow crystals. ii) A suspension comprising 1.91 g (6.0 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 3.0 g of potassium carbonate and 40 ml of dimethylformamide was stirred at 80° C. for 1 h. After cooling to room temperature, 1.99 g of 3-bromoacetylimidazo[1,2-a]pyridine prepared in the above step i) was added thereto and the mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a solid residue, which was then purified according to silica gel column chromatography (chloroform:methanol =96.4). The purified product was converted into its dihydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/acetone to obtain 1.75 g (yield: 58%) of the intended compound.