Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C@@H:11]([CH3:32])[C:12]([NH:14][CH:15]1[C:21](=[O:22])[N:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:13]>>[CH3:23][N:20]1[C:21](=[O:22])[CH:15]([NH:14][C:12]([C@@H:11]([O:10][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:32])=[O:13])[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]1=2
Reactant: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Reactant: O=C=Nc1ccccc1
Product: C[C@H](OC(=O)Nc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=430.3 (M+H+), was prepared in analogy to example 1 from phenylisocyanate and (S)-2-hydroxy-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19].C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Trifluoroacetic anhydride (0.5 ml.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 180 mg.) in dry tetrafuran (10 ml.) and stirred at room temperature for 10 minutes. Triethylamine (0.2 ml.) was added to the resultant solution and stirred at room temperature for 10 minutes. Ethyl acetate was added to the solution and adjusted to pH 2.0 with 6N hydrochloric acid. The solution was washed with water and a sodium chloride saturated aqueous solution successively and dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 171.5 mg.).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC=C([Cl:41])C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:41][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Clc1cccc(CCBr)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cccc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3-chloro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]1(CC(O)=O)C2C(=CC=CC=2)C=C[CH:2]=1.C1[CH:16]=[C:17]([CH2:20][NH:21][C:22]2N=[CH:29][N:28]=[C:24]3N=CN[C:23]=23)OC=1.[CH2:31](O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[C-]#[Si+]>>[N:28]1[CH:24]=[C:23]([CH:22]2[CH2:16][CH2:17][CH2:20][N:21]2[CH3:31])[CH:2]=[CH:1][CH:29]=1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: c1coc(CNc2ncnc3nc[nH]c23)c1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [C-]#[Si+]
Product: CN1CCCC1c1cccnc1
Yield: 2.8 %

Procedure:
Nicotiana tabacum cv. Xanthi (tobacco) leaf cells (about 300-400 mg. fresh weight per flask) were grown in the dark in suspension in a growth medium, as described by Murashige and Skook (Physiol. Plantarum 1962 15: 473), containing 1 mg./l. 1-naphthaleneacetic acid, 0.1 mg./l. kinetin and 3% sucrose in 125 ml. Erlenmeyer flasks on a rotary shaker (120 rpm, 25° C.). The volume of growth medium per flask was 30 ml., which contained about 10-20 mg. fine mesh carborundum. Comparative runs were carried out with and without addition to the medium of modified protein in the form of oxidized BSA (20 μg./ml.). After 4 weeks, the cells were harvested, weighted, frozen and lyophilized. The dried cells were extracted with methanol in a Soxhlet extractor and the extract was evaporated to dryness at 40° C. with a Buchi Rotoevaporator. The residue was dissolved in 0.5N HCl and extracted with ether. The aqueous layer was brought to pH 9.5 with NaOH, extracted twice with ether and the combined two ether extracts were dried with K2CO3, prior to adding HCl and then evaporating to dryness. The residue was dissolved in 0.5N HCl and aliquots were applied to TLC plates of silica gel G (Merck). The plates were developed in 85:14:1 chloroform-ethanol-ammonia, dried in a stream of N2, and alkaloids were visualized by Dragendorff's reagent. Quantitatively the alkaloids were determined by GLC analysis. In absence of elicitor there were obtained 2.8×10-3 % (dry weight) nicotine, compared with 2.2% (dry weight) in presence of elicitor, the latter representing a 7.8×103 fold enhancement of yield. The dry weight of cells at the end of the run was 3.2 g. per flask.
Reaction SMILES: [BH4-].[Na+].[CH:3]([Si:6]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([CH3:5])[CH3:4]>O1CCCC1.O>[CH:18]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:21]([CH3:23])[CH3:22])[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=1)([CH3:19])[CH3:20]
Reactant: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OCCc1cccc(CO)c1)(C(C)C)C(C)C
Yield: 99 %

Procedure:
Sodium borohydride (0.062 g, 1.63 mmol) was added to a mixture of 14 (0.500 g, 1.63 mmol) in tetrahydrofuran (4 mL) and water (0.25 mL). The reaction mixture was heated to reflux temperature for 2 h. After cooling, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was dried under high vacuum to afford the desired compound as colorless oil. Yield: 99%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:20])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Reaction time: 15 h
Yield: 47.6 %

Procedure:
To a suspension of (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A20) (10.0 g, 32.6 mmol), tetrakis(triphenylphosphine)palladium (3.76 g, 3.26 mmol) and potassium carbonate (13.5 g, 97.7 mmol) in dioxane/water (9:1; 100 ml) was added at RT trimethylboroxine (4.53 ml, 32.6 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 19:1) to yield a light yellow solid (4.45 g, 48%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH3:17])=[C:11]([N+:18]([O-])=O)[CH:10]=1)=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:18][C:11]1[CH:10]=[C:9]([NH:8][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH:14]=[CH:13][C:12]=1[NH:15][CH2:16][CH3:17])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, br s), 7.44–7.51 (3H, m), 7.23–7.34 (5H, m), 7.16 (1H, t), 7.08 (1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74 (3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588(MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
(6-Bromopyridin-2-yl)acetonitrile (Example 235, Step 1) (500 mg, 2.54 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LHMDS (1.0 M in THF, 3.05 ml, 3.05 mmol) was added dropwise, and the solution was maintained at −78° C. for 20 minutes. A solution of (2-bromoethoxy)-tert-butyldimethylsilane (600 μL, 2.79 mmol) in THF (5.0 mL) was added dropwise over 5 minutes. The resulting mixture was maintained at −78° C. for 2 hours and warmed to room temperature overnight. The solution was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Silica gel chromatography (0-15% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[S:10][C:11]([CH2:20][CH2:21][CH3:22])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:8]>O>[C:14]1([C:12]2[CH:13]=[C:9]([C:7](=[O:8])[CH3:1])[S:10][C:11]=2[CH2:20][CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCc1sc(C(=O)N(C)OC)cc1-c1ccccc1
Reactant: C[Mg]Br
Solvent: O
Product: CCCc1sc(C(C)=O)cc1-c1ccccc1
Reaction time: 2 h

Procedure:
At 2° C. methylmagnesium bromide (1 mL, 1.7 M in THF) is added to a solution of 4-phenyl-5-propyl-thiophene-2-carboxylic acid methoxy-methyl-amide (900 mg, 3.11 mmol). The mixture stirred for 1 h before another portion (0.2 mL) of the Grignard reagent is added. Stirring is continued for 2 h. The mixture is diluted with water, extracted with EA and the organic extracts are dried over MgSO4 and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 5:4 to give 1-(4-phenyl-5-propyl-thiophen-2-yl)-ethanone (456 mg) as a yellow oil; LC-MS: tR=1.06 min, [M+1]+=245.14, 1H NMR (CDCl3): δ 7.59 (s, 1H), 7.47-7.32 (m, 5H), 2.87-2.81 (m, 2H), 2.54 (s, 3H), 1.76-1.63 (m, 2H), 0.95 (t, J=/.6 Hz, 3H).
Reaction SMILES: CC1CSC(C(OC)=O)C1=O.[CH3:12][C:13]([CH3:27])([CH2:21][C:22]([O:24]CC)=[O:23])[S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(C)([O-])C.[K+]>>[CH3:12][C:13]1([CH3:27])[S:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22](=[O:23])[CH2:21]1.[CH3:12][CH:13]1[S:14][CH:15]([C:16]([O-:18])=[O:17])[C:22](=[O:24])[CH2:21]1
Reactant: CCOC(=O)CSC(C)(C)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: COC(=O)C1SCC(C)C1=O
Agent: [K+]
Product: CC1CC(=O)C(C(=O)[O-])S1
Product: CCOC(=O)C1SC(C)(C)CC1=O

Procedure:
The keto esters, alkyl 4-oxo-2,3,4,5-tetrahydrothiophene-3-carboxylate and alkyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate may be prepared by the procedure of Woodward and Eastman, J. Am. Chem. Soc. 68, 2229 (1946); alkyl 4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate by the method of G. M. Bennett and L. V. D. Scorah, J. Chem. Soc., 194, (1927); and alkyl 3-oxo-2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate by the procedure of Leonard and Figueras, J. Chem. Soc., 74, 917 (1952). Methyl 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylate is disclosed in Chemical Abstracts, 63, 5491 (1965). Ethyl 5,5-dimethyl-3-oxo-tetrahydrothiophene-2-carboxylate is prepared by reacting diethyl 4,4-dimethyl-3-thiahexanedioate with potassium tertiary butoxide. 5-methyl-3-oxo-tetrahydrothiophene-2-carboxylate is formed by reacting diethyl 4-methyl-3-thiahexanedioate with potassium tertiary butoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH:14]=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH2:22].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:22][CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CN
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Dissolve 50 g (0.18 mol) of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propionaldehyde in 625 mL of methanol. Cool the resulting solution to 0° C. Then add 62.5 mL (0.81 mol; 4.5 equivalents) of 40% aqueous methylamine solution. Stir for one hour at 0° C., and then add 7.5 g (0.2 mol; 1.1 equivalents) of NaBH4. Stir for 30 minutes at 0° C. and then stir for 12 hours at ambient temperature. Evaporate off the methanol. The residue is taken up in aqueous hydrochloric acid solution (1N), washed with ethyl acetate and then the aqueous phase is brought to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic, phase is washed with water, dried over MgSO4, filtered and then evaporated to dryness to obtain 52 g of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([CH2:32][CH2:33][CH3:34])=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[O:19]2)=[CH:14][CH:13]=1)=[O:10]>C1C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:35])[C:17]([CH2:32][CH2:33][CH3:34])=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=4)[O:19]3)=[CH:14][CH:13]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CCl)ccc2c1=O
Solvent: c1ccccc1
Product: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CN3CCOCC3)ccc2c1=O
Reaction time: 4 h

Procedure:
The mixture consisting of 9.2 of this derivative, 700 cc of benzene, 20 cc of morpholine is heated to reflux of the benzene with stirring for 4 hours, then cooled. The benzene phase is washed with water several times, dried on sodium sulfate and evaporated. The residue is recrystallized in ethyl alcohol. Yield 60%. MP=196° C. NMR in CDCl3 : δ=0.9 ppm, 3H, triplet, CH3 (propyl), δ=1.2-1.9 ppm, 2H, poorly resolved multiplet, CH2CH2CH3 ; δ=2.3-2.9 ppm, 6H, complex multiplet, CH2CH2CH3 +2CH2N (morpholine); δ=3.2 ppm, 2H, singlet, COCH2N; δ=4.0 ppm, 3H, singlet, CH3, ester; δ=7.0-8.3 ppm, 7H, complex multiplet, aromatic protons; δ=9.4 ppm, 1H, broad peak, NH, (interchangeable with D2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[CH3:40])[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[CH3:40])[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2ccc(OC)cc2C)nc1C(=O)Cl
Product: CCOc1cn(-c2ccc(OC)cc2C)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5×4 was prepared from A2 and 4-ethoxy-1-(4-methoxy-2-methylphenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.36 (t, J=7.0 Hz, 3H), 2.20 (s, 3H), 3.80 (s, 3H), 3.94 (s, 6H), 4.05 (q, J=7.0 Hz, 2H), 6.46 (d, J=5.2 Hz, 1H), 6.90 (dd, J=2.9 Hz, J=8.8 Hz, 1H), 6.98 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.95 (s, 1H), 8.03 (dd, J=2.4 Hz, J=13.3 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H), 10.10 (s, 1H). MS (ES) C31H29FN4O6 requires: 572. Found: 573 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:11]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:11]([CH2:20][C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(O)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(5-(4-bromophenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)acetate (2.0 g, 5.013 mmol) in THF/H2O (v/v=1/1, 20 mL) was added LiOH H2O (632 mg, 15.038 mmol). The solution was stirred at room temperature for 3 h. THF was evaporated in vacuo and the resultant aqueous solution was acidified with 10% HCl to pH=3.0. The resultant precipitate was isolated by filtration, rinsed with water (50 mL) and dried in vacuo to afford 4C, R2=4-bromophenyl (1.380 g, yield 74%) as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:13][C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]2)=[N:10][C:11]#[N:12])[CH:5]=[N:6][CH:7]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:13][C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]2)=[N:10][C:11]#[N:12])[CH:5]=[N:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: N#CN=C(Nc1cncc(N)c1)NC1(c2ccccc2)CCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(NC(=NC#N)NC2(c3ccccc3)CCC2)c1
Temperature: 0 °C
Yield: 8.3 %

Procedure:
A stirred solution of the product from Example 3 (0.87 g, 0.0028 mol) in pyridine (10 ml), was cooled under nitrogen in an ice bath and treated with acetyl chloride (0.22 ml, 0.0031 mol). The mixture was kept in the ice bath for 1 hour and at ambient temperature for 20 hours. It was then concentrated in vacuo. The residue was mixed with saturated NaHCO3 and extracted with CHcl3. The extract was concentrated in vacuo and the residue was chromatographed on silica gel with 5% MeOH-0.25% NH4OH--CHcl3. The product was crystallized from MeOH-EtOAc to give 0.343 g, mp 208°-209° C. and 0.0813 g, mp 207°-208° C. of the titled product.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][OH:23])[O:20][CH3:21])[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].ClC(Cl)(Cl)C(=N)O[CH:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32]>>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:22][O:23][C@@H:28]1[O:53][C@H:52]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@@H:43]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:29]1[O:30][C:31](=[O:33])[CH3:32])[O:20][CH3:21])[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]
Reactant: CC(=O)O[C@H]1C(OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OC
Product: CCCCCCCCCCCCCCCCOC[C@H](CO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O)OC
Yield: 76 %

Procedure:
1-O-Hexadecyl-2-O-methyl-sn-glycerol (433.3 mg, 1.3 mmol) prepared as described above, was glucosylated with 2-O-acetyl-3,4,6-tri-O-benzyl-α,β-D-glucopyranosyl trichloroacetimidate (930 mg, 1.4 mmol) to give 1-O-Hexadecyl-2-O-methyl-3-O-(2'-O-acetyl-3',4',6'-tri-O-benzyl-β-D-glucopyranosyl)-sn-glycerol in 76% yield (805 mg). [α]D -8.5 deg. 1H-NMR: δ 7.32-7.15 (m, 15H, 3PhCH2) 4.99 (dd, 1H, J1',2a' =2.5 Hz, J1',2a' ~1.0 Hz, H-1'), 3.93 (m, 1H, H-5'), 3.44 (s, 3H, OCH3), 2.15 (ddd, 1H, J2e',3' =4.7 Hz, J2e',2a' =11.5 Hz, H-2e'), 1.7 (ddd, 1H, H-2a', 1.25 (s, 26H, CH2), 0.87 (t, 3H, CH3). 13C-NMR: δ 98.05 (C-1'), 79.33, (C-5'), 62.07 (C-6'), 57.94 (OCH3), 37.36 (C-2'), 31.90, 29.64, 29.48, 29.31, 26.06, 22.67 (CH2), 14.06 (CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:28]([NH:35][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCc2ccccc2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 2-chloro-6-methoxyisonicotinic acid (4.90 g, 26.00 mmol, prepared according to Okajima S., Yakugaku Zasshi, (1953), 73, 845-847) and 4-methylmorpholine (3.3 mL, 30.00 mmol) in tetrahydrofuran (100 mL) was added isobutyl chloroformate (3.8 mL, 28.00 mmol) at 0° C. The resulting solution was stirred at ambient temperature for 1 hour, followed by the addition of benzylamine (4.2 mL, 38.00 mmol). The reaction mixture was stirred at ambient temperature for 20 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL). The organic solution was dried over anhydrous sulphate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexanes to give N-benzyl-2-chloro-6-methoxyisonicotinamide (6.20 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 7.18 (s, 1H), 6.94 (s, 1H), 6.43 (br s, 1H), 4.58 (d, J=5.7 Hz, 2H), 3.94 (s, 3H); MS (ES+) m/z 277.4 (M+1).