Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S@:5](=[O:29])[C@@H:6]2[C@H:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[Cl-].[NH4+].[Mg]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]=[C:3]1[C@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[N:7]2[C:16](=[O:28])[C@@H:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:6]2[S@@:5](=[O:29])[CH2:4]1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C[S@](=O)[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C1C[S@](=O)[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a stirred solution of 480 mg (1 mmole) of tert-butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-phenylacetamido-3-cephem-4-carboxylate in 12.5 ml of dimethylformamide was added 2.5 ml of water, 1 g of ammonium chloride and 500 mg of magnesium powder at 0° C. After stirring for 2 hours at 0° C. 100 ml of ethyl acetate was added. After filtration the diluted reaction mixture was subsequently washed with water, 1 N hydrochloric acid, brine, and dried with magnesium sulfate. After treating the dried solution with diethylether and n-hexane the title product was filtered off, washed with n-hexane and dried, yielding 382 mg of tert-butyl (1S,4R,6R,7R)-3-methylene-1-oxo-7phenylacetamido-cepham-4-carboxylate
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:52]([O:56][C:57](=[O:66])[NH:58][C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1)([CH3:55])([CH3:54])[CH3:53]>CS(C)=O.O>[C:52]([O:56][C:57]([NH:58][C:59]1[CH:60]=[CH:61][C:62]([NH:65][C:13]([C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[O:15])=[CH:63][CH:64]=1)=[O:66])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of Carbobenzyloxy-L-proline (0.20 g, 0.80 mmol) and HATU (0.32 g, 0.84 mmol) in DMSO (6 mL) was added diisopropylethylamine (0.42 mL, 2.41 mmol) followed by tert-buty-4-aminophenylcarbamate (0.175 g, 0.82 mmol). The solution was stirred at ambient temperature for two hours, then diluted with water and the solid product was filtered off and purified by combi-flash 12 g column, eluting with 0-20% ethyl acetate in dichloromethane to give a solid (0.245 g, 70%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:11][CH2:12][C:13]1[C:14]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:15][C:16]2[N:20]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[C@H:24]([CH:25]([CH3:27])[CH3:26])[C:19]3=[N:18][C:17]=2[CH:35]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([O:11][CH2:12][C:13]1[C:14]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:15][C:16]2[N:20]3[CH2:21][CH2:22][NH:23][C@H:24]([CH:25]([CH3:26])[CH3:27])[C:19]3=[N:18][C:17]=2[CH:35]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
TFA (1 mL) was added dropwise to a solution containing (R)-tert-butyl 8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (210 mg, 0.452 mmol) in DCM (5 mL) at rt. The mixture was stirred at rt for 2 h. TLC showed compound 3 was consumed completely. The solvents were removed under reduced pressure at 30° C. and then DCM (10 mL) was added. The mixture was neutralized by sat. NaHCO3 solution to pH=8. The mixture was extracted with DCM (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (R)-(1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (160 mg, 97.1% yield) as a white solid, which was used directly for the next step without further purification.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]I)[CH3:19]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.[OH-].[Na+]>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5])[CH3:19]
Reactant: CCOC(CI)OCC
Reactant: N#CCC(O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(COC(CC#N)(c1ccccc1)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of 11.15 g of 3-hydroxy-3,3-diphenylpropionitrile, 13.4 g of iodo acetaldehyde diethylacetal, and 0.9 g of tetra-n-butylammonium hydrogen sulfate in 40 ml of methylene chloride, 10 ml of 50% aqueous sodium hydroxide are added and the mixture is well stirred at room temperature for 24 hours. It is washed with water, dried and evaporated, to give the 2-(2-cyano-1,1-diphenylethoxy)-acetaldehyde diethylacetal as an oil which is sufficiently pure to be used without purification.
Reaction SMILES: [OH-].[K+].COC([C:7]1([O:29][CH3:30])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[C:9]([C:15]([C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[O:16])=[C:8]1[OH:28])=O>O1CCOCC1.O>[OH:28][C:8]1[CH:7]([O:29][CH3:30])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[C:9]=1[C:15]([C:17]1[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC1CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 3 h

Procedure:
0.586 g of potassium hydroxide is added to 1.4 g of 2-hydroxy-1-methoxy-5-methyl-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-4-oxo-cyclohex-2-enecarboxylic acid methyl ester in dioxane/water (5:3) and the batch is stirred for 3 hours. The batch is then acidified (pH 3) and extracted with fresh ethyl acetate. The crude product is purified by chromatography analogously to Example P7. 3-Hydroxy-4-methoxy-6-methyl-2-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-cyclohex-2-enone is obtained in the form of a viscous oil (as a mixture of 3 tautomeric forms, according to 1H-NMR).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(OC)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:33])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][OH:32])=[CH:29][CH:30]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (50 mg, 0.11 mmol), 1 mL TFA and 2 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 8.24 (s, 1H), 7.93 (t, 1H), 7.88 (s, 1H), 7.28-7.30 (s, 2H), 7.21-7.23 (s, 2H), 6.15 (s, 1H), 5.78 (bs, 2H), 5.30 (s, 2H), 5.18 (t, 1H), 4.47 (d, 2H), 4.27 (d, 2H), 2.30 (s, 3H), 2.17 (s, 3H); LCMS (method A) RtA=0.128 min; [M+H]+=366.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:8])[CH2:7][CH2:6][CH2:5]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][CH2:3][C:4]2([OH:8])[CH2:7][CH2:6][CH2:5]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an atmosphere of nitrogen, potassium tert-butoxide was added under ice-cooling to a mixture of cyclobutanone, ethyl chloroacetate and THF, spending 40 minutes, followed by stirring at 0° C. for 2 hours, raising the temperature to room temperature, and stirring at room temperature for 1 day, thereby obtaining ethyl 1-oxaspiro[2,3]hexane-2-carboxylate. A diethyl ether solution of the resulting ethyl 1-oxaspiro[2,3]hexane-2-carboxylate was added to a THF suspension of lithium aluminum hydride under ice-cooling in an atmosphere of nitrogen, followed by stirring at room temperature for 7 hours to obtain 1-(2-hydroxyethyl)cyclobutanol. A mixture of the resulting 1-(2-hydroxyethyl)cyclobutanol, 4-methylbenzenesulfonyl chloride, triethylamine and THF was stirred at room temperature for 16 hours to obtain 2-(1-hydroxycyclobutyl)ethyl 4-methylbenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[OH:26][CH2:27][C:28](CO)([CH2:31][OH:32])[CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:28]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][OH:26])=[O:7]
Reactant: OCC(CO)(CO)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OCC(CO)(CO)CO)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 10 h

Procedure:
Under reduced pressure of 60-70 mmHg and nitrogen gas stream, 250 g (0.71 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise at 78-83° C. to a solution of 157 g (1.15 mol) of pentaerythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL). After the reaction mixture was stirred at the same temperature for 10 hours, formic acid was added at 75° C. to adjust the pH to 4. After the resulting solution was subjected to vacuum concentration, the residue was diluted with t-butylmethylether (1.5 L), and the resulting insoluble matter was separated by filtration. The filtrate was washed with 10% sodium bicarbonate aqueous solution twice, and decolorized with activated carbon (8 g). After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate mixture) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.104 g, 0.421 mmol), (2R)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.024 g, 0.421 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.028 g, 0.421 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.110 g).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38]C(C5C=CC=CC=5)C5C=CC=CC=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:95])/[C:55](/[C:89]2[N:90]=[C:91]([NH2:94])[S:92][CH:93]=2)=[N:56]\[O:57][CH:58]([C:73]([O:75]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:74])[C:59]2[CH:64]=[CH:63][C:62]([O:65][C:66](=[O:68])[CH3:67])=[C:61]([O:69][C:70](=[O:72])[CH3:71])[CH:60]=2)[C:19]3=[O:96])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:94][C:91]1[S:92][CH:93]=[C:89](/[C:55](=[N:56]/[O:57][CH:58]([C:73]([OH:75])=[O:74])[C:59]2[CH:64]=[CH:63][C:62]([O:65][C:66](=[O:68])[CH3:67])=[C:61]([O:69][C:70](=[O:72])[CH3:71])[CH:60]=2)/[C:54]([NH:53][C@@H:20]2[C:19](=[O:96])[N:18]3[C@@H:21]2[S:22][CH2:23][C:24]([CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([OH:38])=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:95])[N:90]=1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: COc1ccccc1
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(C)nc5nc(C(=O)O)nn45)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
To a solution of the product obtained in Step 2 (0.87 g) in dichloroethane (1.6 ml) were added anisole (0.8 ml) and trifluoroacetic acid (2.4 ml) under ice cooling, and the resulting solution was stirred at room temperature for two hours. After removing the solvent by decantation, the residue was washed with dichloroethane and crystallized with ether, giving 0.6 g of the objective compound (as trifluoroacetic acid salt).
Reaction SMILES: CS(O)(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([OH:26])=[O:25])([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:11][CH2:10]2.[CH2:27](O)[CH3:28]>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:11][CH2:10]2
Reactant: CCO
Reactant: O=C(O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
Methane sulfonic acid (12 mL) was added to a solution of 1E (8 g, 26.5 mmol) in ethanol (50 mL), and the mixture was stirred at room temperature for 12 h. Ethanol was removed from reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate and washed with brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 20% ethyl acetate in hexanes to give the title compound (6 g, 56%) as a syrup. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=9.2 Hz, 1H), 6.75 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.1 (q, J=6.8 Hz, 2H), 3.0-2.8 (m, 4H), 2.62-2.5 (m, 2H), 2.4 (m, 1H), 2.3 (m, 1H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 331 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C@@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[CH2:17]([N:19](CC)CC)[CH3:18].ClC(OCC(C)C)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH2:17]([NH:19][C:14](=[O:16])[C@H:5]([CH2:4][S:3][CH2:1][CH3:2])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CSCC)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To 14.92 g (100 mmole) of S-methyl-L-cysteine were added 55 ml of water and 21 ml (110 mmole) of triethylamine and the mixture was dissolved in 55 ml of dimethylformamide at room temperature. Thereafter, 26.4 g (110 mmole) of t-butyl-S-4,6-dimethylpyrimidin-2-ylthiol carbanate was added and the mixture was stirred for about 10 hours at room temperature. After addition of 150 ml of water, the mixture was extracted with 2×200 ml of ethyl acetate. The aqueous layer was ice-cooled, adjusted to pH 2 with addition of 6 N hydrochloric acid and extracted with 1×150 ml and 2×80 ml of ethyl acetate. The organic layers were washed with 3×100 ml of 5% hydrochloric acid and 2×100 ml of aqueous saturated sodium chloride and then dried over magnesium sulfate. The solution was concentrated in vacuo to give 24.5 g (98% yield) of S-ethyl-N-butyloxycarbonyl-L-cysteine as an oil. ##STR10## To a solution of 6.23 g (25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine dissolved in 60 ml of tetrahydrofuran was added 3.48 ml (25 mmole) of triethylamine. To the resulting mixture cooled to -15° C. was added dropwise 3.28 ml (25 mmole) of isobutyl chloroformate and the mixture was stirred at that temperature for 20 minutes. After cooling to -40° C., 3.2 g of aqueous 70% ethylamine solution (50 mmole) was added in a portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the organic layer was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and dried over anhydrous magnesium sulfate. The solution was then concentrated in vacuo, resulting in precipitation of crystals, which were recrystallized from ethyl acetate-n-hexane to give 4.93 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide, 71% yield, m.p. 109°-110° C. ##STR11## To 40 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate was added dropwise a solution of 2.00 g (7.25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide in 50 ml of ethyl acetate over 20 minutes. After stirring for 2.5 hours at room temperature, the mixture was concentrated in vacuo and the residual oil was treated with ethyl ether to give 1.31 g (85% yield) of S-ethyl-L-cysteine ethylamide hydrochloride as powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH:25]=[C:20]3[N:19]=2)[CH:11]=1>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:17][C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:1](=[O:3])[CH3:2])=[CH:28][CH:27]=4)[CH:25]=[C:20]3[N:19]=2)[CH:11]=1
Reactant: COc1ccnc(CCc2nc3cc(-c4ccc(N)cc4)cnc3[nH]2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccnc(CCc2nc3cc(-c4ccc(NC(C)=O)cc4)cnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.025 ml of acetic acid anhydride are added to 0.086 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-(4-aminophenyl)-3H-imidazo[4,5-b]pyridine (example 27) in 2 ml of dichloromethane and the mixture is stirred at ambient temperature for three hours. The solvent is evaporated in vacuo and the residue is is chromatographed on a silica gel column (dichloromethane/methanol 18:1+2% aqueous ammonia solution (25% strength)). Concentration of the chromatographically pure fractions and drying gives 0.085 g of the title compound as a solid of m.p. 220–221° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 388.4 and 797.0 Da.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][C@H:10]1[O:11][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 80 %

Procedure:
Since both the α and β isomers yielded the same β-bromide (compound 9), it was decided to skip the column purification and instead use the mixture as such. In this case, 2,3,4-tri-O-benzyl-L-fucopyranose (compound 6) (25 g, 55 mmol) was treated with p-nitrobenzoyl chloride (compound 7) as described above and the crude material (33.0 g) was dissolved in CH2Cl2 (100 mL) and simply filtered through a short column of silica gel. This removed the color and other polar material. This procedure furnished the anomeric mixture of esters (compound 8) as a gummy material (25.7 g, yield 80%).