Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1O.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1>CCOCC>[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)c(Br)c(O)c1Br
Agent: Br
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1nc(C)c(Br)c(Cl)c1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A 500-mL RB-flask was charged with solid 3,5-dibromo-2,6-dimethylpyridin-4-ol, hydrobromide (94 g, 260 mmol) and POCl3 (150 ml, 1609 mmol) was added. To this white slurry was added N,N-dimethylaniline (39.5 ml, 312 mmol) and the reaction mixture was heated to 130° C. (oil bath temp). After stirring for 2 h, the reaction mixture was cooled, concentrated and the brown residue taken up in toluene (100 mL) and concentrated to remove any unreacted POCl3. Then, the residue was treated with ice (250 g) for 30 min and carefully neutralized with powder Na2CO3, extracted with CH2Cl2 (3×250 mL). The combined organic layers dried (MgSO4/C), filtered, concentrated to give slurry which was dissolved in ether (500 mL), filtered through a plug of silica gel. The silica gel pad was washed with 1:1 Ether/Hex (1.5-lit). The filtrate was concentrated to give white slurry which was triturated with hexanes (200 mL) and left in the freezer (−10° C., 2 h). The liquid was decanted and solids were rinsed with cold hexanes (4×50 mL) and dried overnight under high vacuum (required to remove dimethylaniline) to afford 3,5-dibromo-4-chloro-2,6-dimethylpyridine (49.2 g, 164 mmol, 63.3% yield) as pale greenish-yellow solid. The decanted solvent was concentrated and purified by flash chromatography using 1-lit each hexanes, 0.5, 1, 2 and 5% EtOAc/Hex to afford additional 3,5-dibromo-4-chloro-2,6-dimethylpyridine (18.763 g, 62.7 mmol, 24.13% yield) as greenish-yellow solid. 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 6H). LCMS (M+H)=300.0.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:8][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:27]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:10][CH:11]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(-c3ccccc3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(-c2ccccc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-3-carboxamide hydrochloride (130 mg) in methanol (4 mL) were added benzaldehyde (40 μL) and sodium hydrogen carbonate (49.9 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (22.5 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (60.4 mg).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccccc1Oc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.448 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methylphenoxy)phenyl)pyridin-2-amine (392 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 5 hr. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (415.4 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6](F)[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C[C:26](CC(O)=O)(C(O)=O)[OH:27]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:27][CH3:26])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (Intermediate-2; step-2, 1.00 g, 3.31 mmol) in THF:MeOH:H2O (2:2:1; 5 mL) was added KOH (930 mg, 16.57 mmol). The reaction mass was heated in a sealed tube at 100° C. for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 700 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.65 (br s, 1H), 8.08 (t, 1H), 7.29-7.26 (d, J=8.4 Hz, 1H), 7.22-7.19 (d, J=8.7 Hz, 1H), 4.25 (d, J=5.7 Hz, 2H), 3.79 (s, 3H), 1.13 (s, 9H); MS (m/z): 300.05 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)=[O:10].C(OCC)C.[OH-].[Na+]>CO>[O:10]1[CH2:6][CH2:7][N:8]=[C:9]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(O)c1ccc(C2=NCCO2)cc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
2.2 ml of thionyl chloride was added to 2.23 g of methyl 4-(2-hydroxyethyl)aminocarbonylbenzoate. The mixture was stirred for 15 minutes. Thereto was added 10 ml of diethyl ether. The reaction mixture was added to 20 ml of a 5N aqueous sodium hydroxide solution being cooled with an ice-methanol cryogen. The mixture was stirred for a while. The resulting precipitate was collected by filtration and water-washed to obtain a white powder. The powder was dissolved in 20 ml of methanol. Thereto was added 4 ml of 5N sodium hydroxide. The mixture was stirred at 40° C. for 15 minutes and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made acidic with acetic acid. The resulting crystals were collected by filtration, washed with water and methanol in this order, and dried to obtain 1.6 g of 4-(2-oxazolin-2-yl)benzoic acid as a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:27]4\[NH:21][C:22](=[O:23])[NH:24][C:25]\4=[O:26])=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 35 %

Procedure:
To methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate (33 mg, 0.12 mmol) in 1.0 mL ethanol was added hydantoin (12 mg, 0.12 mmol) and piperidine (11 ul). The reaction was heated at 80° C. for two hours. The reaction was cooled to room temperature, the yellow precipitate was filtered, and washed with ethanol to yield 15 mg (40% yield) (Z)-methyl 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylcarbamate. LCMS (M+1=358)
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:18][C:19]1[CH:32]=[C:31]([NH:33][C:9](=[O:10])[C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: O=C(Cl)C#Cc1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.48 g (2.0 mmol) of biphenyl-4-ylpropynoic acid chloride (for preparation method see Bioorg. Med. Chem. 1996, 4, 851) is dissolved in 15 mL of toluene and 0.58 g (2.4 mmol) of [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine (educt IV.1) in 10 mL of toluene at ambient temperature is added dropwise. The mixture is stirred for 8 hours at ambient temperature, the solvent is eliminated, and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is purified through a silica gel column with dichloromethane/methanol/ammonia (9:1:0.01) as eluant. Yield: 0.28 g (31% of theory); m.p.: 105-108° C.; Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia=9:1:0.1); C27H27ClN2O2; EII mass spectrum: m/z=447/449 [M+H]+.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:11])[CH3:10].CI>C1COCC1>[C:9]([O:13][C:14](=[O:20])[CH:15]([CH3:2])[CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CC(=O)O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of LDA (6.3 mmol, 2M in hexane) in THF (5 mL) at −78° C. is added a solution of succinic acid mono-tert-butyl ester (523 mg, 3 mmol) in THF (2 mL) dropwise. After the addition, the mixture is warmed to −20° C. slowly and stirred at −20° C. for 30 minutes. The solution is re-cooled to −78° C. and MeI (511 mg, 3.6 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give 2-methyl-succinic acid 1-tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:24])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:26])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc3c(Br)c(O)cc(c23)C(=O)N1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Yield: 92.2 %

Procedure:
2-Benzyloxy-6-bromo-5-hydroxy-benzo[de]isoquinoline-1,3-dione (2.0 g, 5.0 mmol, from Example Y), potassium carbonate (2.75 g, 20.0 mmol), and dimethyl sulfate (2.7 g, 21.0 mmol) were reacted in acetone (300 mL) following the procedure as described in Example J to give 1.9 g of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:30][C:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:12](=[O:11])[CH2:16][N:15]1[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1(C)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)CC1(C)c1ccccc1
Temperature: 0 °C

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged anhydrous CH2Cl2 (5 mL). The flask was immersed in a cooling bath at −78° C. Oxalyl chloride (0.24 mL, 2.7 mmol) was added neat followed by DMSO (0.29 mL, 4.1 mmol) dropwise. The reaction was stirred 10 minutes at −78° C. prior to the addition of alcohol 20-5 (0.19 g, 0.7 mmol) in minimal CH2Cl2. The resulting solution was stirred an additional 1 hour at −78° C. prior to the addition of Et3N (0.76 mL, 5.4 mmol) neat and dropwise. The reaction warmed to 0° C. over 2 hour. Upon completion, the reaction solution was washed with 5% aq. NaHCO3, dried (MgSO4), filtered and concentrated. The residue was carried crude into the vinyl triflate formation: LRMS m/z (M-C(CH3)3+H) 220.1 found, 220.2 required.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[NH:11][C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16](OC)=[O:17])[N:15]=1>C1COCC1>[CH3:1][NH:2][C:16]([C:14]1[N:15]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:11][C:12](=[O:21])[C:13]=1[OH:20])=[O:17]
Reactant: CN
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
A sealed tube containing 2M solution of methylamine (2 ml, 4 mmol) in THF and methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.05 g, 163 μmol, Eq: 1.00) was heated at 150° C. in a microwave oven for 15 min, cooled and filtered. The solid was stirred in MeOH, in the presence of Amberlyst 15 IE resin, at 60° C. for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et2O to give the title compound as a white solid (0.015 g; 27%). LCMS: m/z=336 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([F:9])=[CH:7][NH:6][C:5](=[O:10])[N:4]=1.Cl[CH2:12][C:13]([OH:15])=[O:14]>[OH-].[K+]>[C:13]([CH2:12][N:6]1[CH:7]=[C:8]([F:9])[C:3]([S:2][CH3:1])=[N:4][C:5]1=[O:10])([OH:15])=[O:14]
Reactant: O=C(O)CCl
Reactant: CSc1nc(=O)[nH]cc1F
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(=O)n(CC(=O)O)cc1F
Yield: 36 %

Procedure:
4-Methylthio-5-fluoropyrimid-2-one (0.01 mol) was added to 2 M potassium hydroxide solution (10 ml) and dissolved. Chloroacetic acid (0.01 mol) was then added and the reaction mixture heated under reflux for 60 min when the pH was close to neutral. Some precipitate was removed by filtration from the cold reaction mixture and the filtrate brought to pH 2 with HCl. The precipitated product was recrystallised from aqueous methanol; yield 36%, m.p. 244°-245° C.
Reaction SMILES: N#N.Cl[C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=[C:6]2[CH:5]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CO.O1CCOCC1.O>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:4]2[CH:9]=[CH:8][N:7]3[C:10]([C:13]4[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=4)=[CH:11][N:12]=[C:6]3[CH:5]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: OCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CO)cc4)cnc3c2)cc1
Temperature: 65 °C
Yield: 100.8 %

Procedure:
Charge a 100 mL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, condenser, with [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-methanol (1.11 g, 4.3 mmol), 4-(methylsulfonyl)-phenyl boronic acid (1.27 g, 6.4 mmol), 2-Dicyclohexyl-phosphino-2′,6′-dimethoxy-1,1′-biphenyl (236 mg), Pd(OAc)2 (60 mg), K3PO4 (3.6 g, 16.9 mmol), dioxane: H2O 2:1 (50 mL), EtOH-(3A) (5 mL). Warm the reaction while purging with a N2 needle, then heat to 65° C. for 18 hours. Cool the reaction to room temperature and siphon off the bottom layer (8 mL). Evaporate the reaction under vacuum and dissolve the residue into warm MeOH and filter to remove Pd (0) solids. Rinse the solids with warm MeOH and combine all the MeOHd. (total of 1 L). Evaporate the dissolved crude product under vacuum with 20 g of SiO2 to dryness then chromatograph using SiO2 eluting with a gradient of 0% to 10% of 2 M NH3 in MeOH with the balance CH2Cl2. Dry the product in a vacuum oven at 40° C. for 24 hours to give a yellow solid 1.64 g (100. %) suspect trapped solvent. MS (ES), m/z 379 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[N+]=[N-].[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=CC=C[CH:29]=1.O>C1COCC1>[CH2:4]([NH2:1])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:33][C:28]#[CH:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCN
Reaction time: 12 h
Yield: 79.4 %

Procedure:
23-Azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (azido-PEG8-yne) (960 mg, 2.52 mmol, 1 equiv.), triphenylphosphine (992 mg, 3.78 mmol, 1.5 equiv.), and water (68 μL, 3.78 mmol, 1.5 equiv.) were dissolved in THF (10 mL) and stirred for 12 h. Reaction was concentrated and chromatographed (3 cm×20 cm Silica, CH2Cl2 then ramp to 80:20:1 CH2Cl2:MeOH:Et3N) and concentrated to yield 3,6,9,12,15,18,21,24-octaoxaheptacos-26-yn-1-amine (9) as a clear oil (815 mg, 91% yield). IR (thin film, NaCl) 3105 (br), 2914 (m), 1781 (m), 1638 (m), 1169 (s) cm−1. 1H-NMR (500 MHz, CDCl3) δ 4.17 (d, 2H, J=2.4), 3.66-3.57 (m, 28H), 3.54 (t, 2H, J=5.3 Hz), 2.88 (t, 2H, J=5.0 Hz), 2.41 (t, 1H, J=2.4 Hz), 2.18 (br s, 2H). 13C NMR (125 MHz, CDCl3) δ 79.52, 74.59, 72.54, 70.41, 70.38, 70.38, 70.35, 70.31, 70.20, 70.06, 68.90, 58.20, 41.44. HRMS (ES+) calc'd for C19H37NO8 (M+H) m/z 408.259194. Found 408.25712.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:30])([F:29])[O:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]2=[O:26])=[CH:16][CH:15]=1.[P:31](Cl)(=[O:46])([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>C1COCC1>[P:31]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([O:26][C:20]1[N:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:29])([F:11])[F:30])=[CH:28][CH:27]=2)[C:24](=[O:25])[CH2:23][CH2:22][CH:21]=1)=[O:46]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of 1 M LHMDS in THF (1.25 ml; 1.25 mmol; 1.2 equiv.) in anh. THF (2 ml) was treated dropwise with a solution of 1-(4-(trifluoromethoxy)benzyl)piperidine-2,6-dione (300 mg; 1.04 mmol; 1.0 equiv.) in anh. THF (2 ml), and the resulting mixture was stirred at rt, under nitrogen, for 1 h. The obtained mixture was cooled to −78° C., and treated with a solution of diphenyl phosphorochloridate (343 mg; 1.25 mmol; 1.2 equiv.) in anh. THF (1 ml). Stirring was continued at −78° C. for 10 min., and at rt for 1.5 h. A solution of 10% aq. NaOH (25 ml) was added, and the obtained mixture was extracted with Et2O (3×). The mixed organic layers were dried over anh. K2CO3, filtered, and concentrated to dryness under reduced pressure affording 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate as a yellow oil which was directly used for the next reaction. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 520.19 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C@@H:12]([F:13])[C@H:11]([O:14]CC3C=CC(C)=CC=3)[C@@H:10]([CH2:23][O:24]CC3C=CC(C)=CC=3)[S:9]2)[C:4](=[O:33])[N:3]=1.CO>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[S:9][C@H:10]([CH2:23][OH:24])[C@@H:11]([OH:14])[C@@H:12]2[F:13])[C:4](=[O:33])[N:3]=1
Reactant: Cc1ccc(COC[C@H]2SC(n3ccc(N)nc3=O)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 0 °C
Yield: 161.8 %

Procedure:
In a nitrogen atmosphere, 3.0 mL of a methylene chloride solution 1 mol/L boron trichloride was added to a solution of 70 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in 4.6 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0° C., and the mixture was then stirred for 30 minutes. Thereafter, 3.0 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was then collected by filtration, and it was then purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].CN(C)C=[O:40]>O=O>[C:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:40])[C:4]=1[CH3:12])([OH:36])=[O:35]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Reactant: CN(C)C=O
Agent: O=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
To a solution of 300 mg of 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (IV:n=21, R=H) in 20 ml of N,N-dimethylformamide is added 50 mg of bis(salicylidene)ethylenediiminocobalt(II) and the mixture is stirred in oxygen gas stream at room temperature for 24 hours. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and dried. The solvent is distilled off and the residue is dissolved in chloroform and column-chromatographed on silica gel, elution being carried out with chloroform. The eluate is recrystallized from ethanol to obtain 6-(21-carboxyheneicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I:n=21, R=H) as orange-yellow needles melting at 86° C.-87° C.