Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: CP(=O)(O)CCCN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(C)(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylmethylphosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (119) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: OCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCCCN1CCOCC1
Yield: 102 %

Procedure:
A solution of 10.0 g (47.8 mmol) of 8-bromo-1-octanol, 10.41 g (120 mmol) of morpholine and tetrahydrofuran was heated to reflux for 3 hr. The cooled reaction mixture was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 10.50 g of 4-(8-hydroxyoctyl)morpholine.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:11][CH:10]([CH:12]([C:17]2[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1

Procedure:
Ethyl 3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzoate (7.6 g, 16.40 mmol) was hydrogenated in 150 mL of EtOH in the presence 3.4 g of Pd(OH)2 under 50 Psi pressure hydrogen for 24 h. Then it was filtered to remove the solid and washed with CH2Cl2. The combined organic layer was concentrated and washed with hexanes/ether to afford the title compound as an white solid. Mass Spectrum: m/e=298 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C@H:11]([NH:10][C:4](=[O:6])[C@@H:3]2[CH2:7][CH2:8][CH2:9][N:2]2[CH3:1])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a suspension of 1-methyl-L-proline (600 mg) and (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (758 mg) in anhydrous DMF (10 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) and 1-hydroxybenzotriazole (550 mg) were added. The mixture was stirred overnight at room temperature. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with an aqueous solution of sodium carbonate, 15% saline and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate, 5% methanol/ethyl acetate, 10% methanol/ethyl acetate), whereby 1.11 g of (3S)-1-(tert-butoxycarbonyl)-3-(1-methyl-L-prolylamino)pyrrolidine were obtained.
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10]C)=[O:9])[CH:4]=[CH:3]1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH2:19])[CH2:14]1.CO.[Li+].[OH-]>C1COCC1>[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6]2)[CH2:14]1
Reactant: COC(=O)c1ccc(=O)oc1
Reactant: CC1CCCC(N)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCCC(n2cc(C(=O)O)ccc2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of methyl 6-oxo-6H-pyran-3-carboxylate (620 mg, 4.0 mmol, Aldrich) and 3-methylcyclohexanamine (900 mg, 8.0 mmol, Pfaltz and Bauer) was heated in the Emry's optimizer microwave at 150° C. for 15 min. The resulting solution was transferred to a 50 mL round bottom flask with THF, then diluted with THF:MeOH to give approximately 40 mL of a 3:1 THF:MeOH solution. Add 1 M LiOH (6 mL, 6 mmol) and stir at RT overnight. The solution was concentrated in vacuo and the residue taken up in H2O. The aqueous solution was extracted with ether (30 mL). 2 N HCl was added to acidify the aqueous solution to pH 2. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc layers dried over MgSO4, and concentrated in vacuo to give 200 mg (21%) of the desired product as a light brown residue. MS m/z: 612.5(M+1).
Reaction SMILES: [F:1][C:2](F)([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[C:6](F)([F:8])[F:7].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F>>[F:16][C:2]1([F:1])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[C:6]1([F:8])[F:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: FC1(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F

Procedure:
Emulsions of dodecafluoropentane (boiling point 28-29° C.), a mixture of dodecafluoropentane and decafluorobutane with a boiling point of 20.0° C., and perfluorocyclopentane (boiling point of 22.5° C.) were formed and their echogenicity tested. The emulsions contained Fluorad 170 C as surfactant and were formed by applying acoustic energy from a waterbath sonicator. Echogenicity was tested by adding 0.2 mL of each emulsion to 1000 mL of water at 37° C. through a 1.2 micron filter and measuring the videodensity by the methods described in Example 1. The emulsion containing dodecafluoropentane produced a grayscale intensity six seconds following administration of 58.5 units (background of 2.9), the mixture of fluorocarbons produced an increase of 3.0 to 133.3 under the same conditions, and the perfluorocyclopentane produced the greatest increase, of from 3.6 to 158.9. Thus, the lower boiling fluorocarbons produced greater echogenicity than the higher boiling fluorocarbons.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccccc1
Yield: 84.2 %

Procedure:
To a mixture of piperonylamine (20.0 g, 0.133 mol), tetrahydrofuran (87.5 mL) and triethylamine (13.9 g, 0.137 mol) was added dropwise benzoyl chloride (18.6 g, 0.133 mol), at −10-+6° C., and during dropwise addition, tetrahydrofuran (total 123 mL) was appropriately added thereto to stir the content. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (10 mL). The reaction mixture was stirred at 2-11° C. for 15 hr under a nitrogen atmosphere. The consumption of the starting material was confirmed by TLC (eluent: hexane/ethyl acetate 1:1)). To the reaction mixture was added water (50 mL) at 11° C., and then added ethyl acetate (128 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (44 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (18 g). The large part of the solvent was evaporated under reduced pressure at 35° C. or lower (content 61 g), and ethyl acetate (61 mL) was added to the residue. The crystals were collected by filtration, washed with ethyl acetate (46 mL), and dried under reduced pressure at 50° C. or lower to give N-benzoylpiperonylamine (28.6 g, 84.7%) as white crystals.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(Cl)Cl>[C:39]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:27][CH3:28])[CH2:24][CH2:25]2)[CH2:9]1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:41])[CH3:40]
Reactant: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C(C)=O)C3CCCCC3)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(ethyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[S:11])=[CH:8][N:7]=1.Br[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>CCO>[CH2:18]([C:17]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:7][CH:8]=2)[S:11][CH:16]=1)[CH3:19]
Reactant: NC(=S)c1ccc(OCCCO)nc1
Reactant: CCC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1csc(-c2ccc(OCCCO)nc2)n1
Temperature: 70 °C
Yield: 91 %

Procedure:
To a solution of 6-(3-hydroxy-propoxy)-thionicotinamide (Example 72, 8.8 g, 41.46 mmol) in EtOH (205 mL) at rt was added 1-bromo-2-butanone. The reaction mixture was then heated at 70° C. for 3 h. Upon completion, triethylamine was added and the volatiles were removed under reduced pressure. The crude material was suspended in CH2Cl2 and purified by flash chromatography. The column was eluted with a mixture of EtOAc/hexanes (30 to 50% EtOAc) to give the title compound as a white solid (10.04 g, 91%) after concentration of the chromatography fractions. 1H NMR (400 MHz, acetone-d6) δ 8.70 (s, 1H), 8.19 (dd, 1H), 7.15 (s, 1H), 6.86 (d, 1H), 4.48 (t, 2H), 3.74-3.71 (m, 3H), 2.83 (q, 2H), 2.01-1.98 (m, 2H), 1.32 (t, 3H). LC/MS m/z 265.3 (M+H)+; RT 2.12 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.C1(C)C=CC=CC=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 490.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine (0.07 g, 0.29 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (0.22 g, 1.3 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was precipitated from methanol to give N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide as a white solid (0.6 g, 50% yield). 1H NMR (400 MHz, DMSO): 12.49 (s, 1H), 12.35 (s, 1H), 12.82 (s, 1H), 8.32 (s, 1H), 7.89 (dd, 1H), 7.53 (t, 1H), 7.42 (d, 2H), 7.34 (d, 4H), 7.29 (m, 1H), 7.19 (d, 1H), 6.64 (d, 1H), 3.82 (s, 2H); MS (ESI) for C21H16FN5O2S: 422 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:21][C:22]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:21][C:22]3[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=3)[N:4]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: COC(=O)c1cc(O)no1
Reactant: CCOC(=O)Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(C(=O)OC)on3)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A mixture of ethyl [4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl]acetate (2.00 g), methyl 3-hydroxyisoxazole-5-carboxylate (0.974 g), anhydrous potassium carbonate (0.941 g) and N,N-dimethylformamide (40 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through silica gel. The filtrate was concentrated to give methyl 3-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)isoxazole-5-carboxylate as colorless crystals (2.02 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-126° C.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].C1COCC1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2>CN(C=O)C.[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:1]#[C:2][CH3:3])=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Reactant: CC#C[Mg]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Zinc chloride (1.0 M in ether, 0.33 mL, 0.33 mmol) was added dropwise to a solution of 1-propynylmagnesium bromide in THF (0.5 M in THF, 0.66 mL, 0.33 mmol) at room temperature and the mixture was stirred under nitrogen for 10 min. N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (50 mg, 0.11 mmol) in DMF (2 mL) was added followed by bis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). The resulting mixture was stirred under nitrogen at room temperature for 2 h, and then was quenched with saturated ammonium chloride, extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamide (36 mg, 88%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.56 (d, J=7.0 Hz, 1H), 8.23 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 4.35-4.29 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.16-2.82 (m, 5H), 2.20-2.03 (m, 2H), 2.14 (s, 3H), 1.80-1.60 (m, 3H); MS (ESI+) m/z 386 (M+H); HPLC>99% (AUC), tR=13.24 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:57])[C@@H:22]([NH2:56])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[C:64](Cl)(=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)Cl>[C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:64](=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:21](=[O:57])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (14R,18R)-14-amino-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonic acid diethyl ester (1 eq, from example 18, step 6) in DCM (0.1 M) was cooled in an ice bath. Pyridine (1.2 eq) was added followed by palmitoyl chloride (1.1 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]2[C:6](=O)[O:7]C(=O)[NH:9][C:4]=2[CH:3]=1.C([O-])(=O)C.[NH4+:21]>C(O)(=O)C>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]=1[C:6]([NH2:21])=[O:7]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(=O)o1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
7-Chloro-1,4-dihydro-6-nitro-2H-3,1-benzoxazine-2,4-dione (6.5 g, 26.8 mmol) was suspended in glacial acetic acid (70 mL). Ammonium acetate (6.2 g, 80.6 mmol) was added, and the resulting mixture was heated to 100° C. with stirring for 3 hours. After cooling to room temperature, the brown solution was poured into distilled water (200 mL) to precipitate a yellow solid which was collected by filtration and washed well with water and ether. This material was first air dried, then dried overnight under high vacuum to provide 2-amino-4-chloro-5-nitrobenzamide (4.9 g, 23.0 mmol, 86%): 1H NMR (DMSO-d6): δ 6.92 (s, 1H), 7.49 (br s, 1H), 7.89 (br s, 2H), 8.22 (br s, 1H), 8.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)c(F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,4-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 45.6 mg (>100%) of the title compound were recovered.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22](OC(N1CCN(C(=O)C2C=CC(CN3CCOCC3)=CC=2)CC1)=O)([CH3:25])(C)[CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:25]1([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reactant: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
(4-Morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone. A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (1.163 g) in CH2Cl2 (10 mL) was treated with TFA (−4 mL). After 30 min, additional TFA (5 mL) was added, and the mixture was stirred for a further 2 h. The mixture was diluted with diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (0.255 g, 30%). MS (ESI): mass calcd. for C16H23N3O2, 289.18; m/z found, 290.4 [M+H]+. 1H NMR (CDCl3): 7.41-7.35 (m, 4H), 3.95-3.70 (m, 6H), 3.52 (s, 2H), 3.09-2.80 (m, 6H), 2.49-2.42 (m, 4H). Step D. A solution of (4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone (0.128 g) in methanol (7.5 mL) was treated with (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2 mL), and NaBH3CN (˜400 mg). The mixture was heated at 60° C. for 18 h, and then was cooled to rt and concentrated. The residue was diluted with 1 N NaOH and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (0.0548 g, 38%). MS (ESI): mass calcd. for C19H27N3O2, 329.21; m/z found, 330.4 [M+H]+. 1H NMR (CDCl3): 7.36 (s, 4H), 3.79-3.68 (m, 6H), 3.50 (s, 2H), 3.44-3.32 (m, 2H), 2.74-2.61 (m, 2H), 2.60-2.50 (s, 2H), 2.45-2.40 (m, 4H), 1.66-1.62 (m, 1H), 0.49-0.44 (m, 2H), 0.44-0.39 (m, 2H). Alternative Preparation of Example 1.