Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].COC1C=CC(C[N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][N:24]([C:28](=[O:37])[C@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH3+:30])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH:17]1[C:18]2[C:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:37])[C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH3+:30])[CH2:23][C:22]=3[CH:21]=[N:20][C:19]=2[NH:15][N:16]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H]([NH3+])c2ccccc2)CC4)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: [NH3+][C@H](C(=O)N1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C
Yield: 108.1 %

Procedure:
To (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate (0.109 g, 0.18 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added followed by removal of the solvent under reduced pressure. The mixture was evaporated to dryness in the Genevac and a dark brown solid was obtained. The crude product was purified using reverse phase HPLC to give the pure desired product, (S)-2-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate as a pale yellow solid (0.082 g, 84%). M.p.>100° C.; 1H NMR (400 MHz, DMSO-d6) δ12.75 (brs, 1H), 8.62 (brs, 2H), 8.39/8.13 (s, 1H, rotamers), 8.08/8.06 (s, 1H, rotamers), 7.56-7.35 (m, 5H), 5.74 (m, 1H), 4.91 (m, 2H), 3.73 (m, 2H), 3.08 (m, 2H); LCMS [M+H]: 308.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:47]([NH:49][CH2:50][CH2:51][OH:52])[CH3:48].ClCCl>ClC(Cl)C>[CH2:47]([N:49]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:39])=[O:40])[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])=[CH:27][CH:28]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)[CH2:50][CH2:51][OH:52])[CH3:48]
Reactant: CCNCCO
Reactant: Cn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc(NC(=O)N5CCCC5)cc4)ccnc3n2S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure described in Intermediate 101 using N-(4-{4-[2-(4-formylphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-1-pyrrolidinecarboxamide and 2-(ethylamino)ethanol in dichloroethane (instead of dichloromethane) provided the title compound. ESMS [M+H]+: 704.6.
Reaction SMILES: [O-2].[Y+3:2].[O-2].[O-2].[Y+3].[Y].[N+:7]([O-:10])([OH:9])=[O:8]>>[N+:7]([O-:10])([O-:9])=[O:8].[Y+3:2].[N+:7]([O-:10])([O-:9])=[O:8].[N+:7]([O-:10])([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Agent: [O-2]
Agent: [Y+3]
Agent: [Y]
Product: O=[N+]([O-])[O-]

Procedure:
In order to remove the excess yttrium oxide and phosphoric acid from the solids in the slurry, a small amount of an inorganic acid is added to the slurry. The acid releases the yttrium compound and phosphoric acid from the yttrium phosphate and allows them to react on their own until the phosphoric acid is consumed. The 1.5 molar percent excess of the yttrium compound reacts with the acid to form a soluble yttrium salt which dissolves in the aqueous phase of the slurry. When yttrium oxide is used as the yttrium compound and nitric acid is used as the inorganic acid, the reaction provides soluble yttrium nitrate which combines with the remaining phosphoric acid to produce yttrium phosphate solids and with minor amounts of yttrium nitrate in solution.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([CH3:25])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6].[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:27]=[CH:26][C:10]3[N:11]([CH3:25])[C:12]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:13][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30]1
Reactant: FC1(F)CCNCC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN3CCC(F)(F)CC3)ccc21
Yield: 44.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2 (4,4-difluoro-piperidin-1-yl)-ethyl]-amide (45 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-oxo-ethyl)-amide (80 mg), 4,4-difluoro-piperidine (36 mg), and Na(OAc)3BH (65 mg) in DCM (2 mL). LC/MS: m/z 504.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.97-8.88 (m, 1H), 8.14-8.12 (m, 1H), 7.97-7.96 (m, 1H), 7.88-7.80 (m, 1H), 7.56-7.52 (m, 2H), 7.43-7.40 (m, 1H), 4.08-4.05 (m, 1H), 3.74-3.69 (m, 7H), 3.57-3.47 (m, 1H), 3.46-3.17 (m, 3H), 2.46-2.43 (m, 3H), —NH proton signal was not observed.
Reaction SMILES: C(P([CH:7](C(C)C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([CH:32]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O.[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[C:7]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:18][C:20]1[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([CH:32]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:12]
Reactant: COc1ccc(C=O)cc1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C(C)C)P(=O)(CC)CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)OC(C)(C)C)c1)OC(C)C
Reaction time: 0.5 h
Yield: 162.1 %

Procedure:
1.6 g of ethyl 2-(diethylphosphoryl)-2-isopropylacetate was dissolved in 30 ml tetrahydrofuran, and 0.24 g of 60% sodium hydride was added thereto under ice-cooling. After stirring the reaction solution for 30 minutes under ice-cooling, 1.2 g of tert-butyl 5-formyl-2-methoxybenzoate was added, followed by stirring at room temperature for 3 hours. Aqueous ammonium chloride solution was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 1.5 g of tert-butyl 5-(3-ethoxy-2-isopropoxy-3-oxo-1-propenyl)-2-methoxybenzoate was obtained as an E-Z mixture.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][S:24]([CH3:23])(=[O:26])=[O:25])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)c2ccccc2c1N
Solvent: c1ccncc1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)c2ccccc2c1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
To 3.23 g (10 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl-1-naphthylamine in 25 ml pyridine add 1.25 g (11 mmole) methanesulfonyl chloride. After 2 hours, pour onto water and extract with Et2O. Wash with 1N HCl, and then extract with 1N NaOH. Acidify with concentrated HCl, extract with Et2O, dry and concentrate. Recrystallize from Et2O-hexane to obtain the product; m.p. 174° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1C=CC=CC=1.CO>[CH3:15][O:9][C:8](=[O:10])[C:7]1[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[NH2:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-nitro-anthranilic acid (2.200 g, 10.9 mmol, 1 eq) in benzene/methanol (4/1) (100 mL) was added TMSCHN2 (2M in hexanes) (12 mL, 24 mmol, 2.2 eq). The reaction was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 4-nitro-anthranilic acid methyl ester (1.841 g, 86%) as a bright yellow solid. 1H NMR (300 MHz, CDCl3); δ 8.00 (d, 1H), 7.50 (d, 1H), 7.40 (dd, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3[CH:16]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[O:13][C:12]2=[O:28])=[CH:7][CH:6]=1)[CH:2]=C.[CH3:29]S(O)(=O)=O>C(O)(=O)C>[C:24]([C:17]1[CH:18]=[C:19]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:14]2[O:13][C:12](=[O:28])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]4[O:4][CH:1]([CH3:2])[CH2:29][C:10]=4[CH:9]=3)[C:15]=2[CH:16]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: C=CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reactant: CS(=O)(=O)O
Solvent: CC(=O)O
Product: CC1Cc2cc(C3C(=O)Oc4c3cc(C(C)(C)C)cc4C(C)(C)C)ccc2O1
Yield: 28 %

Procedure:
3.80 g (10.0 mmol) of 3-(4-allyloxyphenyl)-5,7-di-tert-butyl-benzofuran-2-one are kept under nitrogen for about 4 hours at 220° C. After cooling, 10 ml of acetic acid and 0.3 ml of methanesulfonic acid are added and the reaction mixture is refluxed for 7 hours. After dilution with 100 ml of water, the product is extracted with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the eluant system dichloromethane/hexane=1:2 and crystallisation of the pure fractions from ligroin gives 1.07 g (28%)of 5,7-di-tert-butyl-3-(2-methyl-dihydrobenzofuran-5-yl)benzofuran-2-one, m.p. 136°-152° C. as a mixture of diastereoisomers (compound (101), Table 1).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CO.O1CCCC1>[CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:32][C:33]4[NH:37][C:36]5[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=5[N:34]=4)[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CO
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -19 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
The (4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methanol (520 mg, 1.96 mmol) obtained in the step (2d) was mixed with triethylamine (1.09 ml, 7.84 mmol) and tetrahydrofuran (10 ml) and the resultant mixture was cooled to −19° C. Methanesulfonyl chloride (228 μl, 2.94 mmol) was added to the mixture, which was stirred at −19° C. for 30 minutes. In the same conditions, 2-mercaptobenzimidazole (324 mg, 2.16 mmol) was added to the reaction mixture. After the reaction mixture was stirred at room temperature for 2 days, methanol and NH silica gel were added to the mixture, and the solvent was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (silica gel: 80 g, elution solvent: ethyl acetate/heptane=4/6 to 7/3→methanol/ethyl acetate=1/9) to obtain the title compound (629 mg, yield: 80.7%) as a colorless foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (151 mg, 0.45 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (135 mg, 1.35 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (80 mg, 42%) as a white solid: mp 190-193° C.; EI-HRMS m/e calcd for C19H21ClN6OS (M+) 416.1186, found 416.1183.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1>FC(F)(F)C(O)C(F)(F)F>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:9]2[C:8]3[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[NH:11][C:10]=2[CH3:14])=[CH:18][CH:17]=1
Reactant: Cc1cc2ccc(S(C)(=O)=O)cc2[nH]1
Reactant: Fc1ccc(S)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A solution of 6-methanesulfonyl-2-methyl-1H-indole (207 mg, 1 mmol) in 6 mL of hexafluoroisopropanol was treated with 4-fluorothiophenol (2 mmol) followed by addition of PIFA (1.5 mmol). The dark colored solution was stirred for 30 minutes followed by partitioning between EtOAc and water. Purification by TLC (2:1 hexane/EtOAc) afforded 145 mg of 3-(4-fluoro-phenylsulfanyl)-6-methanesulfonyl-2-methyl-1H-indole, 101, MS: 336 ([M+H]+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:27][C:28]([N:30]([CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)=[O:29]>O1CCCC1.[Cl-].[Na+].O>[O:19]=[C:14]1[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:27][C:28]([N:30]([CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)CBr)c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C1NCCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.75 h

Procedure:
A solution of potassium tert-butoxide (1.0 M in tetrahydrofuran, 0.70 mL, 0.70 mmol) was added dropwise via syringe to a suspension of the product of Example 68C (147 mg, 0.587 mmol) in anhydrous tetrahydrofuran (5 mL) at ambient temperature. The reaction mixture was stirred for 45 minutes, and then a solution of the product of Example 166B (273 mg, 0.587 mmol) in 3 mL tetrahydrofuran was added. The reaction was allowed to proceed for 1 hour at ambient temperature, then poured into brine. The product was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 25%-75% ethyl acetate/hexanes, 0-15 minutes, 30 mL/minute) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.69 (d, J=8.3, 2H), 7.35 (d, J=8.2, 2H), 7.32-7.15 (m, 10H), 4.86-4.72 (m, 1H), 4.24-4.05 (m, 2H), 3.67 (bs, 2H), 3.45 (t, J=6.3, 2H), 2.80 (t, J=12.6, 2H), 2.67-2.55 (m, 2H), 1.90-1.73 (m, 4H), 1.39 (s, 9H), 1.29-1.11 (m, 2H); MS (DCI+) m/z 636 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 1.0E1 mmol) and Morpholine (0.962 g, 11.0 mmol) were dissolved in a solution of Acetic acid (0.500 mL, 8.79 mmol) and Methylene chloride (50.0 mL, 7.80E2 mmol). After stirring at room temperature for 15 minutes, Sodium triacetoxyborohydride (4.2 g, 2.0E1 mmol) was added and the reaction was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and reduced. TLC (visualized with iodine) showed evidence of a new product. Crude 3-Morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (3.67 g) was used in the next synthetic step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.CN([CH:20]=[O:21])C>C1COCC1.Cl.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH:20]=[O:21]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)c1cc(Br)c(C=O)o1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of 69.65 g (0.246 mol) of methyl 4,5-dibromo-2-furoate in 700 mL of dry THF was cooled to −45° C. under argon. To this solution 141.5 mL (0.282 mol) of isopropyl magnesium chloride 2M (Aldrich) was slowly added over 45 min at −43/−48° C. and the mixture was stirred for an additional hour. The resulting suspension was treated dropwise with 56.8 mL (0.737 mol) of anhydrous DMF (Aldrich, H2O<0.005%) over 30 min at −45° C. and stirred for 15 min at the same temperature. The reaction mixture was slowly warmed to +20° C., stirred for 1 hour and then it was slowly poured in a mixture of 1.2 L of HCl 1 M and 1.0 L of MTBE. The aqueous layer was separated and extracted twice with 1.0 L and 0.5 L of MTBE. The combined organic extracts were concentrated to dryness affording 57.81 g of crude material, which was crystallized from 120 mL of hot toluene and 230 mL of n-heptane. The resulting slurry was cooled to +4° C., aged for 2 h and filtered to afford 46.55 g of beige solid.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11]O)[CH:2]=1.CN(C=O)C.C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH2:11]1[O:18][P:15]([OH:17])(=[O:16])[CH2:14][O:13][C@H:10]1[CH2:9][N:3]1[C:4](=[O:5])[N:6]=[C:7]([NH2:8])[CH:1]=[CH:2]1
Reactant: Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
cHPMPC was synthesized by adding to a stirred suspension of HPMPC (100 g, 0.358 mol) in DMF (2L) N, N'-dicyclohexyl-4-morpholine-carboxamidine (115 g, 0.393 mol). The reaction mixture was stirred for 12 hours at room temperature. This solution was added slowly to a hot pyridine solution (5 L, 60° C.) of DCC (185 g, 0.895 mol) through an addition funnel. The reaction mixture was stirred at 100° C. for 16 hours, cooled to room temperature and the solvents were removed under reduced pressure. The crude mixture was washed with diethyl ether (3 L), dissolved in water (2 L) and washed with CH2Cl2 (5×1 L). The aqueous layer was concentrated to 1 L volume and acidified to pH-3.5. Upon cooling cyclic-HPMPC crystallized (89 g, ~95% pure). The cHPMPC was recrystallized by dissolving in water at pH8 (with 1N NaOH) followed by acidification to pH 3.5 (with 1N HCl):
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1
Yield: 81.7 %

Procedure:
0.3 g (0.0015 mol) of 1-benzyl-4-hydroxypiperidine and 0.216 ml (0.00155 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.21 ml (0.0016 mol) of 4-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.404 g (82%) of 1-benzyl-piperidin-4-yl 4-chloro-benzoate was obtained as a colorless oil. MS: me/e (% basic peak)=329 (C19H20CINO2+, 7), 252 (7), 173 (32), 139 (15), 91 (91), 82 (100).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].CN1C2C(=CC=CC=2)C(C)=C1[CH:23]=[O:24]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:23]=[O:24])=[C:3]1[CH3:11]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: Cc1cc2ccccc2n1C
Product: Cc1c(C=O)c2ccccc2n1C

Procedure:
1,2-Dimethylindole-3-carboxaldehyde (mp 129° C.) was prepared from 1,2-dimethylindole following essentially the same procedure as that used for the preparation of 1,3-dimethylindole-2-carboxaldehyde referred to in (g) above.