Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:23]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:5][CH2:6]C(OCC1C=CC=CC=1)C1C=CC(F)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[C:58]([O:61][CH2:62][CH3:63])(=O)[CH3:59]>O1CCCC1>[CH2:62]([O:61][CH:58]([C:59]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:5][CH:4]1[CH:23]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:37]=2)[N:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:3]1=[O:2])[C:63]1[CH:6]=[CH:5][CH:4]=[CH:23][CH:32]=1
Reactant: COC(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(CCC(OCc2ccccc2)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Temperature: -22.5 °C
Reaction time: 0.5 h

Procedure:
10 gms of 5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoic acid methyl ester was dissolved in 500 ml of tetrahydrofuran and cool the reaction mass to −20 to −25° C. To the reaction mass 16 ml of 1M Lithium bis(trimethylsilyl)amide was added under nitrogen atmosphere and stirred for about 30 minutes. To the reaction mass 100 ml of 2 N hydrochloride solution was added at 20-25° C. Stirred the reaction mass by adding 150 ml of ethyl acetate and separated the organic layer. Washed the organic layer with water and dried over sodium sulphate. Distilled the solvent completely under reduced pressure at 50-55° C. to get 8.0 gms of 3-[3-Benzyloxy-3-(4-fluoro-phenyl)-propyl]-4-(4-benzyloxy-phenyl)-1-(4-fluoro-phenyl)-azetidin-2-one.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li+].[OH-]>C1COCC1>[CH2:16]([C:6]1[N:5]([CH2:4][C:3]([OH:23])=[O:2])[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of methyl(2-benzyl-5-phenyl-1H-pyrrol-1-yl)acetate (203 mg, 0.66 mmol) in THF (1 ml) was added aqueous 1N LiOH (1 ml) at room temperature. After 3 h stirring at room temperature, the reaction was quenched with H2O (10 ml). The aqueous was extracted with Et2O (2×10 ml). The aqueous was acidified with 1N HCl to pH˜3, extracted with EtOAc (3×15 ml). The combined organic extracts were washed with H2O (15 ml), brine (15 ml), dried (Na2SO4) and concentrated. The crude material was purified by chromatography (EtOAc/MeOH: 95/5) to provid the titled compound (185 mg, 96%) as a solid: mp 137-139° C.; MS (+) ES, 292 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 150–152° C.; 1H NMR (300 MHz, CDCl3): δ 7.09 (s, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 4.95–4.90 (m, 1 H), 4.35 (t, J=8.1 Hz, 2 H), 3.89 (s, 3 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.36 (s, 3 H), 3.09 (t, J=8.4 Hz, 2 H), 1.96–1.77 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O3BrClF (M+H)+: 460.0439; found m/z 460.0460.
Reaction SMILES: [CH:1](=[N:8][N:9]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25]C)=O)[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C>[OH:25][C:23]1[C:19]2[S:20][CH:21]=[CH:22][C:18]=2[N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:17])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)N(N=Cc1ccccc1)c1ccsc1C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2sccc2n(N=Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of the product of Example 268B (37.8 g, 0.101 mol) in ethanol (0.5 L) under nitrogen was reacted with sodium ethoxide in ethanol (21% by weight, 32.8 g, 0.104 mol) at room temperature. The mixture was slowly warmed to 50° C. and stirred for 1 hour at 40-50° C., cooled to 25° C., partitioned between ethyl acetate and water, and acidified to pH 4 with 1 M hydrochloric acid. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (12.0 g, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 1.47 (t, J=7.17 Hz, 3 H) 4.52 (q, J=7.23 Hz, 2 H) 7.33 (d, J=5.15 Hz, 1 H) 7.50 (m, 3 H) 7.75 (d, J=5.52 Hz, 1 H) 7.88 (dd, J=7.72, 1.84 Hz, 2 H) 9.44 (s, 1 H) 14.16 (s, 1 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Al+3].[Cl-].[Cl-].[Cl-].[Si]([C:29]#[N:30])(C)(C)C>ClCCCl>[N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[C:29]#[N:30])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: C[Si](C)(C)C#N
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Yield: 34 %

Procedure:
Following the general procedure for cyano formation outlined in Example 1, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.3065 g, 1.003 mmol), AlCl3 (0.661 g, 4.99 mmol) and TMSCN (0.66 mL, 4.95 mmol) in 1,2-dichloroethane (17.0 mL) were reacted to give the desired product (0.1073 g, 34.1%). EI-MS m/z 315 (M+) Rt (1.65 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][C:39]1([NH2:43])[CH2:42][O:41][CH2:40]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:43][C:39]4([CH3:38])[CH2:42][O:41][CH2:40]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(N)COC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(NC(=O)c2ccc(OCc3c(-c4ccc(F)cc4)noc3CO)nc2)COC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) in DMF (3.3 mL) was added 1,1′-carbonyl-diimidazole (58.2 mg, 0.35 mmol). The reaction mixture was stirred for 1 h at 60° C. 3-Methyl-3-oxetanamine (27.8 mg, 0.32 mmol) was then added at room temperature and the mixture was stirred overnight. Extraction with water/ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (10 mg, 8%) as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.BrC([C:14]1[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=1[C:16](C1C=CC=CC=1)=[O:17])Br.S(=O)(=O)(O)O>>[C:1]([C:14]1[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=1[CH:16]=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1C(Br)Br
Agent: BrBr
Agent: O=S(=O)(O)O
Product: O=Cc1ccccc1C(=O)c1ccccc1

Procedure:
The benzaldehyde of formula VII may be prepared from the corresponding methyl-substituted benzophenone. The methyl substituent is first subjected to side-chain bromination, e.g. by treatment with bromine and the resulting dibromomethyl benzophenone hydrolysed with strong mineral acid, e.g. sulphuric acid to give the corresponding benzoyl-benzaldehyde. The aldehyde group can then be protected, e.g. as an acetal or ketal and the unprotected carbonyl group linking the two aromatic rings then reacted with methyl magnesium iodide under the conditions of the Grignard synthesis followed by dehydration or reacted with a Wittig reagent to convert that carbonyl group into a corresponding 1-phenylvinyl benzaldehyde in which the aldehyde group is protected. The protecting group can then be removed to give the 1-phenylvinyl benzaldehyde which can then be reacted with methyl magnesium iodide, hydrogen cyanide or ethynyl magnesium bromide to give the correspondingly α-substituted 1-phenylvinyl benzyl alcohol. Protection of the aldehyde group is not necessary when, for example, an α-methyl-benzyl alcohol product is required. In such a case, a benzoyl-benzaldehyde can be reacted with 2 equivalents of, for example, methyl magnesium iodide in accordance with the reaction: ##STR13## The Grignard technique can also be used directly on α-substituted benzoyl-benzoyl alcohols, e.g. in accordance with the reaction: ##STR14##
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:14])(=[O:13])[C:5]=2[S:4][C:3]=1[C:15]([OH:17])=[O:16].C(Cl)(=O)C(Cl)=O.[CH2:24]([N:26]1[C:30](O)=[CH:29][CH:28]=[N:27]1)[CH3:25].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:13])(=[O:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][C:30]1[N:26]([CH2:24][CH3:25])[N:27]=[CH:28][CH:29]=1)=[O:16]
Reactant: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2(=O)=O
Reactant: CCn1nccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nccc1OC(=O)c1sc2c(c1C)C(C)(C)CCS2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2.0 g (0.0073 mol) of the title compound of Step D of Example 1 was added to 50 mL of methylene chloride. 1.27 mL (0.0146 mol) of oxalyl chloride (purchased from Janssen) was added followed by 2 drops of N,N-dimethylformamide. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.90 g (0.0080 mol) of 1-ethyl-1H-pyrazol-5-ol was added to the mixture followed by 2.8 mL (0.0020 mol) of triethylamine and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness. The residue was stirred in 100 mL of water and the water was decanted. The residue was washed with hexane (2×100 mL) and then chromatographed on silica gel eluting with 4:6 ethyl acetate/hexane to yield 1.57 g of the title compound of Step A as a solid melting at 119°-120° C. 1H NMR (CDCl3): δ 1.4 (t, 3H), 1.5 (s, 6H), 2.5 (m, 2H), 2.8 (s, 3H), 3.4 (m, 2H), 4.1 (q, 2H), 6.2 (d, 1H), 7.5 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[C:13]([CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1)([OH:15])=[O:14]
Reactant: C1CNCCNCCN1
Reactant: O=C(O)CCCl
Product: O=C(O)CCN1CCN(CCC(=O)O)CCN(CCC(=O)O)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 3-chloropropionic acid and base.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([O:23]C)=[O:22])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C1C=CC=CC=1)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@H:6]([C:7]([OH:9])=[O:8])[C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[CH:13]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Agent: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(C(=O)O)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-6-(tert-Butoxy(carboxy)methyl)-5-(4-chlorophenyl)-7-methylquinoline-2-carboxylic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-methylquinolin-6-yl)acetic acid of Example 12, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD). δ8.15-8.05 (m, 2H), 7.93 (d, 1H), 7.70-7.60 (m, 3H), 7.40-7.35 (m, 1H), 5.24 (s, 1H), 2.70 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23ClNO5: 428.9. Found: 428.1, 430.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].B(O[O-])=[O:15].[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: Cc1cc(C=O)c(Cl)cc1[N+](=O)[O-]
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Yield: 77.1 %

Procedure:
A solution of 2-chloro-5-methyl-4-nitrobenzaldehyde (1.72 g, 8.6 mmol) in acetic acid (20 ml) at 80° C. was treated with sodium perborate (2.64 g, 17.2 mmol). After 0.5 h a further portion of sodium perborate (1.32 g, 8.6 mmol) was added. After 0.25 h the reaction mixture was added to ethyl acetate--half saturated brine, and the organic extract dried (Na2SO4) and evaporated, affording the title product as a white solid (1.43 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]3([OH:18])[CH2:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[S:13][C:12]([C:14]3([OH:18])[CH2:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:3]=[C:2]([NH:1][C:20]2[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=2)[CH:7]=1
Reactant: Nc1cc(Cl)cc(-c2cnc(C3(O)CCC3)s2)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OC1(c2ncc(-c3cc(Cl)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Yield: 55.8 %

Procedure:
The product of Step 3 (460 mg, 1.720 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (314 mg, 1.638 mmol), Xantphos (284 mg, 0.492 mmol), palladium (II) acetate (73.6 mg, 0.328 mmol), cesium carbonate (1.068 g, 3.28 mmol) and dioxane (12.3 mL) were heated at 90° C. for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. Filtration and solvent evaporation gave a residue which was further purified by column chromatography on silica gel, eluting with 40% ethyl acetate in hexane to afford 1-[5-(3-chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol as a brown solid (390 mg, 55.8%). 1H NMR (500 MHz, CDCl3): δ 8.71 (d, J=4.7 Hz, 1H); 7.92 (s, 1H); 7.85 (s, 1H); 7.78 (s, 1H); 7.69 (s, 1H); 7.25 (s, 1H); 7.13 (d, J=4.8 Hz, 1H); 3.81 (s, 1H); 2.73 (s, 2H); 2.58-2.47 (m, 2H); 2.13-1.97 (m, 2H) MS APCI: [M+H]+ m/z 427.1. rhSYK activity=++
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=2)=[O:19])[CH2:3][CH2:2]1.[CH2:31]=O.[BH4-].[Na+].Cl>O.CO>[CH3:31][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[N:22]=2)=[O:19])[CH2:5][CH2:6]1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Yield: 96.8 %

Procedure:
To 0.12 g of 1-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinolin-4-yl]-3-(6-trifluoromethyl-pyridin-2-yl)-urea (0.290 mmol) were added subsequently 2 ml of methanol, 0.366 ml of formaldehyde (4.64 mmol) and a solution of 0.055 g of sodium borohydride (1.451 mmol) in 0.8 ml of water. The reaction was slightly exotherm. A small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium bororhydride. After neutralization with sodium bicarbonate, methanol was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with ethylacetate, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 120 mg of the desired product were obtained as an off white powder (yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([CH3:12])[CH:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: Cc1ccc(N)cc1C
Solvent: C1COCCO1
Product: Cc1ccc(NS(=O)(=O)c2cccnc2Cl)cc1C
Yield: 62.6 %

Procedure:
The title compound (966 mg, 3.26 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.11 g, 5.21 mmol) and 3,4-dimethylaniline (698 mg, 5.73 mmol) in 1,4-dioxane (30 mL) using the methods of (IntC1).
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([CH2:22][O:23][P:24]([O:27][CH2:28][CH2:29][N+:30]([CH3:33])([CH3:32])[CH3:31])([OH:26])=[O:25])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl.CO>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:18][CH2:19][C@@H:20]([O:21][C:34]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:41])[CH2:22][O:23][P:24]([O:27][CH2:28][CH2:29][N+:30]([CH3:32])([CH3:31])[CH3:33])([O-:26])=[O:25])=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(=O)(O)OCC[N+](C)(C)C
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCC(=O)O
Yield: 42 %

Procedure:
PGPC (FIG. 1A, 1) was synthesized according to a modified version of the procedure by Watson et al. (J. Biol. Chem. 272, 13597-13607, 1997) and Subbanagounder et al. (Free Radic. Biol. Med. 28, 1751-1761, 2000). A solution of dry 1-palmitoyl-sn-glycero-3-phosphocholine (62 mg, 125 μmol), dry glutaric anhydride (70 mg, 613 μmol, 5 eq) and DMAP (p-(N,N′-dimethylamino)pyridine, 75 mg, 614 μmol, 5 eq) in 6 ml of anhydrous dichloromethane was magnetically stirred over night at 35° C. The reaction was monitored by TLC with CHCl3/MeOH/25% NH3 (65:35:5, v/v/v) as a developing system, and quenched by addition of 3 ml of MeOH. The resulting mixture was washed once with 1.8 ml of MeOH/H2O (1:1, v/v). After evaporation of the organic phase, excess DMAP was removed by trituration with 4 ml of diethylether. Removal of the supernatant afforded 32 mg of PGPC (42%, Rf=0.05).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:18]=[CH:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:18]=[C:17]([Br:21])[C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(=O)[nH]c2=O)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(=O)[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 4 (0.6 g, 2.13 mmol) and N-bromosuccinimide (0.456 g, 2.56 mmol) was added DMF (15 mL) and stirred at ambient temperature for 3-4 h. The solution was partitioned between ethyl acetate (50 mL) and 10% Na2S2O3 (40 mL). Organic layer was separated, washed with brine (3×50 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (70% ethyl acetate-dichloromethane) to give pure 5.
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-])=[O:24])[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:12]=3[C:11]=2[O:33][CH3:34])=CC=1)([O-])=O.[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:43])[C:41]=1[NH2:42].[H-].[Na+].Cl>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:43])[C:41]=1[NH:42][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:12]=2[C:11]([O:33][CH3:34])=[CH:10][CH:22]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3ccccc3n(Cc3ccccc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3ccccc3n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-nitrophenyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate (229 mg, 0.506 mmoles) and 3,5-dichloro-4-aminopyridine (82.53 mg, 0.506 mmoles) in dry DMF (10 ml), under N2 atmosphere, 60% sodium hydride (44.19 mg, 1.012 mmoles) was added at 25° C. and the reaction mixture was stirred overnight. The reaction mixture was poured into ice-cold water and neutralized with 1N HCl. The compound was extracted with chloroform (2×15ml), combined the organic layers and washed with water (3×15 ml) and with brine (15 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 200 mg of the crude compound which was purified by column chromatography to yield 139 mg of the title compound as light brown colored solid, m.p: 215-217° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(C)=O)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{2-[(acetyl-ethyl-amino)-methyl]-4-amino-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and trimethylacetyl chloride.