Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12]N=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-].[CH2:22](O)C>>[CH3:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:22]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1CSc1ccc([N+](=O)[O-])cn1
Reactant: CCO
Agent: [Ca+2]
Agent: [Cl-]
Product: Cc1ncccc1CSc1ccc(N)cc1
Temperature: 25 °C

Procedure:
To 2-methyl-3-[[(5-nitro-2-pyridinyl)sulfanyl]methyl]pyridine (4.0 g) was added 85% aqueous solution of ethanol (80 ml), calcium chloride (0.86 g) and reduced iron (4.3 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After allowing the mixture to be cooled to room temperature, and the solvent was removed under reduced pressure. The mixture was filtered with. Celite, and washed with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]aniline (3.2 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[NH:34][CH:35]=[C:36]([CH:38]=O)[N:37]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:36]4[N:37]=[C:33]([CH3:32])[NH:34][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]c(C)n4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-methyl-1H-imidazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COP([O-])OC
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Product: COc1ccc([C@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
The solution of ALB--CN in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 5 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 59 hours, 1N hydrochloric acid was added to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (R)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 25%. The chemical reaction in this Example is shown in chemical formula 46.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1)=[O:16])[CH:12]=[CH2:13].[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)[CH2:19]1)(=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1cncnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Under nitrogen atmosphere to a solution of potassium tert-butoxide (17.0 g) in N,N-dimethylformamide (77 ml) was slowly dropped thioacetic acid (12.1 g) at 0° to 10° C., and then the solution was stirred for 30 minutes at the same temperature. This solution was added to a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(pyrimidin-5-ylmethyl) pyrrolidine (25.8 g) in N,N-dimethylformamide (154 ml) at 15° to 25° C. under nitrogen atmosphere, and the reaction mixture was stirred for 2 hours at 80° to 90° C. After the reaction mixture was cooled and poured into ice-water (500 ml) and ethyl acetate (300 ml), the aqueous layer was adjusted to pH 8.2 with 1N-sodium hydroxide. The organic layer was separated and washed with water containing 10% sodium chloride (300 ml). This fraction and the fraction reextracted from the aqueous layer were combined, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil. The oil was dissolved in toluene (300 ml) and it was washed with water (150 ml), dried over magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (250 g) (solvent; hexane:ethyl acetate=3:1 to 1:6) to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-(pyrimidin-5-ylmethyl) pyrrolidine (17.7 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:16][CH:15]=1.[NH2:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:32])[NH:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])=[CH:18][CH:19]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-nitrophenyl 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate (200 mg, 0.42 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), a solution of diethyl aminomethylphosphonate (144 mg, 0.63 mmol, 1.50 equiv) in N,N-dimethylformamide (1 mL) and triethylamine (64 mg). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 mg (17%) of diethyl (3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)methylphosphonate as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1.I([O-])(=O)(=O)=[O:32].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:32]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(SC)c1
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)=O)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methylsulfanyl-pyridin-4-yl)-propyl]amide (0.10 mg, 0.24 mmol) in MeOH (5 mL) was added an aqueous solution of sodium periodate (51 mg, 0.24 mmol). After 1.5 hours, a solid precipitated and additional MeOH (3 mL) was added. After 5 days, mixture was concentrated and partitioned between water (5 mL) and EtOAc (50 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 mM 30×150 mm column) eluting with a gradient of 15-75% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile, made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.CN([CH:29]=[O:30])C>CO>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:30][CH3:29])[N:9]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2c(-c3cccc(Cl)n3)nn3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Add sodium hydride (20.7 mg, 60% dispersion in mineral oil, 0.52 mmol) to a solution of 2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (33.5 mg, 0.10 mmol) in DMF (2.5 mL) and methanol (2.5 mL) at room temperature. Stir the reaction mixture at room temperature for 4 hours and at 80° C. for 48 hours. Cool to room temperature and concentrate in vacuo. Add water (20 mL) and extract the aqueous solution with methylene chloride (3×20 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 31 mg (97%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])[C:35]=1[CH:36]=[O:37].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:52]([C:47]1[CH:48]=[C:49]2[C:44](=[C:45]([F:56])[CH:46]=1)[C:43](=[O:57])[N:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH:36]=[O:37])[N:51]=[CH:50]2)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 1 h
Yield: 60.5 %

Procedure:
88 mg (0.20 mmol) of 1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one and 81 mg (0.20 mmol) of 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzaldehyde were weighed into a 4 mL reaction vial fitted with a stir bar and septum cap. Added 2 mL of dioxane. Added 222 μL of an 0.88 mg/μL solution of cesium carbonate in water. Added 7.8 mg (0.0096 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane. The reaction was sparged with nitrogen for 5 min. Sealed the vial with a cap and stirred at 100° for 60 min. Poured the reaction mixture into 10 mL CH2Cl2 and 10 mL water. Separated phases and extracted the aqueous phase with 5 mL CH2Cl2. Combined the organic extracts, dried over Na2SO4 and removed the solvent on rotavap. Purified by silica gel flash chromatography using gradient elution with 100% hexane to 100% 5:6:1 hexane:CH2Cl2:2-PrOH. Recrystallized the product from 2-PrOH. Dried under high vacuum at 120° overnight to obtain 77 mg of the title compound as a pale yellow solid. MS (ESI) 637 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C:28](=O)[CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:28]2[CH2:27][C:26]3[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=3)[CH2:29]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1Cc2ccc(Cl)cc2C1
Product: CCCC(NC1Cc2ccc(Cl)cc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 5-Chloro-indan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.3, 39.8, 40.0, 40.4, 56.0, 59.1, 59.2, 61.4, 67.3, 104.8, 125.1, 125.2, 125.9, 126.0, 126.9, 126.9, 131.2, 137.3, 140.1, 143.2, 143.6, 172.0; MS m/z 458.4 (M+1).
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:37](=O)(OC)OC>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[CH3:37][P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 321.8 g (1.1 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added afterwards. After one hour of reaction and mixing, the reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 4 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 584.8 g of methyl triphenyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after recrystallization and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[O:17]C=C[N:20]=1)([O-])=O.Cl>CC(C)=O.O>[S:13]1[C:12]2[C:16](=[O:17])[NH:20][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:10][C:11]=2[CH:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccccc1Cc1ccsc1-c1ncco1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2Cc2ccsc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
A mixture of 5.0 g of the product of Example 5 in 100 ml of 3:1 acetone-water containing 30 ml of 1N HCl is refluxed for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in 100 ml of glacial acetic acid. The mixture is stirred at 70° C. while 10.0 g of zinc dust is slowly added. Stirring is continued for 6 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated in vacuo to a residue which is extracted with chloroform. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 2.9 g of the desired product as a brown solid, M+ =215.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24]O)[N:22]=1)=[CH:5]2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:50]I>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][I:50])[N:22]=1)=[CH:5]2
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Reaction time: 8 h
Yield: 39.9 %

Procedure:
The compound obtained in Example 13 (3.7 g, 10.2 mmol) was dissolved in tetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol), triphenylphosphine (4.0 g, 15.3 mmol) and iodine (3.9 g, 15.3 mmol) were added, and stirred for 8 h at 0° C.˜room temperature. After completion of the reaction, ethyl acetate (100 ml) was added, and the reaction mixture was washed with water (100 ml×2). The organic layer was concentrated and the residue was purified by column chromatography to give the title compound (2.0 g, 4.07 mmol, Yield 40%).
Reaction SMILES: [OH:1][CH:2]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([OH:33])[O:28][CH2:27]2)[C:3]([N:6]1[CH2:23][CH2:22][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[OH:1][CH:2]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[C:3]([N:6]1[CH2:7][CH2:8][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:22][CH2:23]1)([CH3:4])[CH3:5]
Reactant: CC1=C(N2CCC3(CCN(C(C)(C)C(O)c4ccc5c(c4C)COC5O)CC3)C2=O)COC1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C(C)(C)C(O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step J (340 mg, 0.723 mmol) in methylene chloride (30 mL) was added PCC (311 mg, 1.45 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 2 h. The reaction mixture was partitioned between methylene chloride and saturated bicarbonate, and the alkaline phase was extracted with methylene chloride (3×50 mL). The combined organic phase was dried over sodium sulfate, concentrated and the residue was purified on TLC using 10% methanol/methylene chloride as developing solvents to give the title compound. LC/MS: (M+1)+: 469.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=[O:7].C(O)(=O)C.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH:20]1([NH:12][C:4]2[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:22][CH2:21]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cc(F)c(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 4,5-difluoroanthranilic acid (1.13 g, 6.53 mmol) in anhydrous methanol (40 mL) is added molecular sieves (3 Å), acetic acid (3.70 mL, 65.3 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.25 mL, 26.11 mmol). After 30 minutes, sodium cyanoborohydride (2.08 g, 32.64 mmol) is added, and the reaction mixture is heated to reflux. After 16 hours, the reaction is cooled to room temperature, filtered, washed with methanol, and the combined filtrate concentrated under vacuum to afford a viscous oil. The resulting oil is dissolved in ethyl acetate and washed with 1.0 M hydrochloric acid, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated under vacuum to afford as a beige solid (1.32 g). MS CI: m/z 212 (M+).
Reaction SMILES: C(Br)CCCCCCCCCCCCC.[OH-].[K+].C(C(C(CO)O)O)C1C=CC=CC=1.[CH2:31]([O:47][CH2:48][CH:49]([CH2:67][OH:68])[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]CC)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(OCC(COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)OCCCCCCCCCCCCCC)CCCCCCCCCCCCCCC.Cl>C1(C)C=CC=CC=1>[CH2:31]([O:47][CH2:48][CH:49]([CH2:67][OH:68])[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCBr
Agent: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCCCCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-hexadecyl glycerol (105g, 0.33mol) and 93 g (0.33mol) tritylchloride were dissolved in 300 ml of pyridine. The mixture was heated at 100° C. for 16 hours. After cooling to room temperature 1500 ml of ethyl ether was added and the slurry washed 3 times with cold 0.5N H2SO4, 5% sodium bicarbonate and 2 times with water. The organic phase was dried over MgSO4, the ether removed on a rotary evaporator and the residue recrystallized from ethanol, yielding the intermediate 1-hexadecyl-3-trityl glycerol (129 g, 70%). The 2 position of this intermediate was alkylated with tetradecyl bromide in the same manner (powdered KOH in toluene) as described earlier for the dialkylation of benzyl glycerol in the preparation of 1,2-dihexadecyl glycerol. The resulting 1-hexadecyl-2-tetradecyl-3-trityl glycerol (128 g) was dissolved in 300 ml of petroleum ether. At room temperature 30 g of anhydrous hydrogen chloride was added. A precipitate formed within a short time. The slurry was stirred at room temperature for 4 hours and then filtered. The solids were recrystallized from acetone (10° C.) to give 45.6g of product, m.p. 42°-3° C.