Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:23])[CH:13]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:6]=[CH:7][N:8]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:23])[CH:13]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(OC)ncnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3c(OC)ncnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
A solution of 4-methoxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [361 mg, Reference Example 4] in methanol (20 mL) was treated with potassium hydroxide (1.53 g). The reaction mixture was stirred for 16 hours at room temperature and refluxed 1 hour. The solution was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was separated, then dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diethyl ether to give 4-methoxy-6-(5-methoxy-1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (155 mg) as a solid m.p.=184° C. MS: 309 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C@H:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@@H:30]([OH:43])[CH2:29]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:14]([C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:15]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:17])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
(S)-2-((R)-4-(tert-Butoxycarbonyl)morpholin-3-yl)-2-(4-chlorophenyl)acetic acid (0.051 g, 0.143 mmol) was combined with (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0440 g, 0.143 mmol), and then slurried in methylene chloride (1.4 mL). The suspension was treated with diisopropylethylamine (0.0749 mL, 0.430 mmol) and then with HBTU (0.0544 g, 0.143 mmol). The mixture was then stirred at ambient temperature for 60 hours. The reaction was quenched with 10% Na2CO3 and separated. The reaction mixture was washed with methylene chloride (3×), and the combined organics were then dried with Na2SO4 and concentrated in vacuo. The resulting residue was subjected to chromatography on SiO2 (Biotage 12M) eluting with methylene chloride (96 mL) then 0% to 5% MeOH/methylene chloride (500 mL) and 5% MeOH/methylene chloride (96 mL). The desired material eluted cleanly in approximately 1% MeOH/methylene chloride to yield (R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate as an oil. (81.2 mg, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Sb](Cl)(Cl)(Cl)(Cl)Cl.[CH2:19]1[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1>C(Cl)Cl>[C:19]1([C:12]2[CH:11]=[CH:10][C:6]([C:7]([C:6]3[CH:10]=[CH:11][C:12]([C:19]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH:20]=4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc2c(c1)CC2
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1)c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
8.91 g (48.0 mmol) of 3-nitrobenzoyl chloride was placed in a 500 ml 3 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer and an addition funnel capped with a nitrogen inlet-adaptor. About 200 ml of methylene chloride was added and the resultant colorless solution was subsequently chilled to about -15° C. under nitrogen. A methylene chloride (20 ml) solution of antimony pentachloride (11.05 g, 48.25 mmol) was then added dropwise over a period of 20 minutes. The yellow and homogeneous reaction mixture was allowed to warm up to about 0° C., at which temperature it was continuously stirred for another 30 minutes. Then, it was chilled again to about -20° C. and a methylene chloride (30 ml) solution of benzocyclobutene (5.00 g, 48.0 mmol) was delivered via the addition funnel over a period of about 15 minutes. The reaction mixture slowly became dark and then bright yellow precipitates formed. At the end of the addition, the yellow reaction mixture was stirred at -20° C. for another hour and then allowed to warm up to room temperature on its own. Upon reaching room temperature, the reaction mixture was green and heterogeneous. It was stirred at room temperature overnight. The green reaction mixture was poured into a 2-liter beaker containing about 1000 g of ice cubes. The mixture was then stirred vigorously until all the ice melted. Two layers appeared; the methylene chloride layer was dark green and the aqueous layer was white and opaque. The methylene chloride solution was separated from the aqueous layer via a separatory funnel. The aqueous phase was subsequently extracted with two portions (30 ml) of methylene chloride. The combined extract was dried over anhydrous magnesium sulfate. After the removal of the drying agent by suction/filtration, the filtrate was concentrated to about 30 ml and passed through a small chromatography column containing about 50 g of silica gel saturated with hexane. The column was then eluted with 1:1 methylene chloride/hexane. Upon removal of the solvent from the first fractions, the desired product was isolated as a yellow solid. Yield: 11.0 g (90%). Anal Calc. for C15H11NO3 ;C, 71.13; H, 4.38; N, 5.53. Found: C, 70.67; H, 4.51; N, 5.52. IR(KBr pellet): ν(CO) at 1646 cm-1 vs; ν(NO2) at 1534 cm-1 and 1350 cm-1 vs. Proton NMR (CDCl3, δ in ppm): 3.30 (singlet, alicyclic protons, 4H); 7.17-7.32, 7.57-7.89, 8.14-8.65 (multiplet, aromatic protons, 7H).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.NC(=O)C[C@@H](NC(OCC1C=CC=CC=1)=O)C(O)=O.N1C=CC=CC=1.[NH2:47][CH2:48][C@@H:49]([NH:53][C:54]([O:56][C:57](=O)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C:50]([OH:52])=[O:51]>O.CN(C)C=O>[NH2:47][CH2:48][C@@H:49]([NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C:50]([OH:52])=[O:51]
Reactant: NC[C@@H](NC(=O)OC(=O)c1ccccc1)C(=O)O
Agent: NC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (6.45 g., 15.0 mmole) is dissolved in water-dimethylformamide 1:1 (80 ml.) and (R)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoic acid (2.4 g., 9.0 mmole) is added over a 10 minute period. The reaction is allowed to stir at room temperature for 30 minutes, until dissolution occurs. Pyridine (1.62 ml., 20 mmole) is added dropwise over a 5 minute period. The reaction is allowed to stir for 3 hours then stripped of solvent to yield a yellow precipitate. This semi-solid is triturated with a combination of isopropanol:ethyl ether. The precipitate is filtered and dried over phosphorus pentoxide to yield 1.35 g. of (R)-3-amino-2-[[(benzoyloxy)carbonyl]amino]propanoic acid as a white solid.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.CCOCC.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([Cl:6])[CH2:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared according to the method of Levantis and Silvius (1990). Oleyl chloride was prepared by slowly adding 3 ml (35 mmol) of oxalyl chloride to 1.0 g (3.5 mmol) oleic acid dissolved in 10 ml benzene without stirring at room temperature for 1 hour. After removal of solvent and excess oxalyl chloride under vacuum, the acid chloride was dissolved in 5 ml diethyl ether, and a further 5 ml of ether containing 0.20 g (1.7 mmol) of 3,N,-dimethylamino-1,2-propanediol and 0.15 g pyridine was added. The resulting mixture was stirred at room temperature for 30 minutes before quenching with 1 ml methanol. Solvents were removed under vacuum. The crude product was dissolved in 50 ml hexane and washed with 2×25 ml 0.1M sodium chloride. Drying over anhydrous sodium sulfate, and removal of hexane under vacuum gave a slightly yellow oil. Column chromatography on silica gel (70-230 mesh), wherein elution was with ethyl acetate, gave 0.92 g (84%) of pure product (TLC, Rf=0.5). 200 MHz 1H-NMR (CDCl3), δ ppm from TNS (J-coupling, integration): 5.3 (dd, 4H), 5.1 (m, 1H), 4.0 (dd, 1 h), 2.4 (dd, 2H), 2.2 (s, 6H), 2.0-0.8 (m, 62H). This procedure was also used to prepare the deuterated analog rac-1-N,N-dimethylamino-2,3-bis(9,10-dideuteriooleoyl)propane (AL-1-d4) and ±-1,2-didecanoyl-1-N,N,-dimethyl-aminopropane (AL-6).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[CH3:25].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCOc2ccc3ccccc3c2)ccc1C(=O)C(=O)O
Yield: 90.1 %

Procedure:
A solution of 2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.52 g of purified 2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (4:1) hydrate as a colorless solid, mp 129°-131° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[C:11]=1[F:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:18](=[NH:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:18](=[N:31][C:12]1[C:11]([F:17])=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[CH:14][N:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxymethyl)-2-chloro-3-fluoropyridine (30 mg, 108 μmol), benzophenone imine (14 μL, 84 μmol), tris(dibenzylideneacetone)dipalladium(0) (7.7 mg, 8.4 μmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (15.7 mg, 25.3 μmol) and sodium tert-butoxide (10.4 mg, 108 μmol) in toluene (0.5 mL) was stirred at 60° C. overnight. Ethyl acetate was then added to the reaction solution, and the solution was washed with sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (27 mg, 60%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:43]([CH2:54][O:55][C:56](=[O:63])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:42][C@H:33]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:32]2[O:64][C:65](=[O:72])[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C@H:6]1[O:73][C:74](=[O:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)C=C>CO.ClCCCl.[Pd](Cl)Cl>[C:74]([O:73][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@H:44]([O:45][C:46](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]([CH2:54][O:55][C:56](=[O:63])[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:42][C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:32]1[O:64][C:65](=[O:72])[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)(=[O:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of the allyl ether 49 (688 mg, 0.627 mmol) in MeOH (6 mL) and 1,2-dichloroethane (6 mL) (0.05 M) was treated with solid palladium chloride (25 mg). The mixture was stirred at 70° C. (external oil bath) for 2 h. TLC indicated complete conversion. The mixture was evaporated onto silica and purified by column chromatography (silica 2.7×17 cm, gradient elution with hexane-EtOAc 200:20, 200:40, 200:50, 210:70, 200:100) to give the alcohol 50 as a colourless gum (0.539 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.18-8.03 (m, 8H, Ph), 7.85-7.81 (m, 4H, Ph), 7.68-7.25 (m, 23H, Ph), 5.97 (dd or t, 1H, JH3(I)H4(I)=9.8, JH4(I)-H5(I)=9.8, H4I), 5.68 (dd, 1H, J JH1(I)-H2(I)=2.0, JH2(I)-H3(I)=2.9, H2I), 5.60 (dd or t, 1H, J JH3(II)-H4(II)=9.8, J JH4(II)-H5(II)=9.8, H4II), 5.28 (br s, 1H, H1II), 5.15 (d, 1H, J JH1(II)-H2(II)=2.0, H1I), 5.05 (dd, 1H, JH1(II)-H2(II)=2.0, JH2(II)-H3(II)=2.9, H2II), 4.77 (d, 1H, Jgem=11.7, CH2), 4.65-4.56 (m, 4H, CH2, H6Ieq, H3I and H6II), 4.44 (dd, 1H, Jgem=12.7, JH5(I)-H6(I)ax=4.9, H6Iax), 4.34 (m, 1H, H5II), 4.32 (dd, 1H, Jgem=10.7, JH5(II)-H6(II)=2.9, H6II), 4.28 (ddd, 1H, JH5(I)-H6(I)ax=4.9, JH5(I)-H6(I)eq=2.9, H5I), 4.17 (dd, 1H, H3II).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CCN(CC)CC.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:37][CH:38]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)[C:39]1[CH:44]=[CH:43][C:42]([PH:45](=[O:47])[OH:46])=[CH:41][CH:40]=1>C(#N)C>[OH:1][C:2]1[C:7]([C:8]([NH:37][CH:38]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:39]2[CH:44]=[CH:43][C:42]([PH:45](=[O:46])[OH:47])=[CH:41][CH:40]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: COc1ccc(C(N)c2ccc([PH](=O)O)cc2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc([PH](=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid (1-1-h, 1.1 g, 5.1 mmol) in acetonitrile (20 ml) was added Et3N (1.02 g, 10.2 mmol). The mixture was aged for 15 min at room temperature. To the mixture was added CDI (800 mg, 5.1 mmol) and the resulting mixture was heated to 70° C. for 3 h. To the hot homogeneous solution was then added in one portion 4-(amino(4-methoxyphenyl)methyl)phenylphosphinic acid hydrochloride (1-1-e, 1.4 g, 5.1 mmol). Heating was continued for 2 h at 70° C. Then it was concentrated under vacuum and the residue was purified on prep-HPLC to provide the 1-1-6 (160 mg, 6%). 1H NMR (CD3OD, 300 MHz,): δ 13.35 (br, 1H), 8.80 (m, 1H), 8.62 (m, 2H), 8.45 (m, 1H), 7.23 (m, 7H), 7.79 (m, 2H), 6.52 (s, 1H), 6.25 (m, 1H), 3.70 (m, 3H).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:41]([OH:43])=[O:42])[CH2:20][S:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH2:4]C1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].[C:44]1([CH3:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:29]([O:43][C:41](=[O:42])[C@H:19]([CH2:20][S:21][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:18][C:1]([O:3][CH2:4][C:48]1[C:49]2[CH2:26][C:25]3[C:50](=[CH:27][CH:28]=[CH:23][CH:24]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1)=[O:2])([CH3:34])([CH3:30])[CH3:22]
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1cccc2c1Cc1ccccc1-2
Temperature: 80 °C

Procedure:
A suspension of Fmoc-S-trityl-L-cysteine (2.9 g, 5 mmol) in dry toluene (10 mL) was heated to 80° C. To this suspension was added over 20 min., di-tert-butyl-dimethylformamide acetal (4.8 mL, 20 mmol). The solution was cooled, washed with water, saturated sodium bicarbonate (2×10 mL), and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (15/85), to give 2.2 g of N-Fluorenylmethoxycarbonyl-S-trityl-L-Cysteine-t-butyl ester.
Reaction SMILES: C[O:2][C:3](=[O:22])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=2)/[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Br
Temperature: 47.5 °C
Yield: 98718.4 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-bromo-4-(methanesulfonyl)-phenyl]-acrylic acid methyl ester (357 mg, 0.92 mmol) in ethanol (6 mL) was treated with a 1N aqueous sodium hydroxide solution (2 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[3-bromo-4-(methanesulfonyl)-phenyl]-acrylic acid (339 g, 98%) as an amorphous solid: EI-HRMS m/e calcd for C15H17BrO4S (M+) 372.0031, found 372.0028.
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1.O>CN(C)C=O.ClCCl.CCCCCC>[O:1]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(O)CC(=O)OCC
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(=O)OCC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 96.3 %

Procedure:
To a solution of 1.22 g (5.97 mmol) of diethyl 3-hydroxyglutarate in dry dimethylformamide (30 ml) were added 1.95 g (7.09 mmol) of tert-butyldiphenylsilyl chloride and 1.41 g (20.7 mmol) of imidazole in an atmosphere of argon, and the mixture was allowed to react at room temperature for 10 hours. To the solution was added water followed by extraction with benzene. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. From the eluate with dichloromethane-hexane (1:1) was afforded 2.54 g (5.75 mmol) of diethyl 3-(tert-butyldiphenylsiloxy)glutarate.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([NH2:20])=[O:19].ClC(Cl)(Cl)C(O)=O>CN(C=O)C.C(OCC)(=O)C>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([NH2:20])=[O:19]
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: NC(=O)NO
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 20 h

Procedure:
15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say 2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and left for 20 hours at 0° C. in a refrigerator. The resultant crystal sludge was diluted with 70 ml of ethyl acetate and after 2 hours was drawn off by suction, washed, dried and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9](O)O)[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1([NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:22])[CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[NH:23][C:12]3[C:21]4[C:16]([CH:15]=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=4[NH:22]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Nc1cccc2cccc(N)c12
Solvent: Cc1ccccc1
Product: Fc1ccc(B2Nc3cccc4cccc(c34)N2)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 3-chloro-4-fluorobenzene boronic acid (4 g, 22.8 mmol) and naphthalene-1,8-diamine (3.62 g, 22.9 mol) in anhydrous toluene (80 mL) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The residue was trituated with hexane to afford the title compound as a grey solid in 88% yield, 6 g.