Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].O>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)CCc1ccc(N)nc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-(6-aminopyridin-3-yl)propanoate (500 mg, 2.78 mmol) in pyridine (5 mL) was added 2-nitrobenzenesulfonyl chloride (924 mg, 4.17 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (365 mg, yield 36%) as yellow crystals.
Reaction SMILES: C(N[C@H](C([NH:14][C@H:15]([C:19]([N:21]([C:39](=[O:48])[CH2:40][CH2:41][CH:42]([NH2:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]([C:25]([CH:27]([CH:31]([OH:38])[CH:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[C:28]([OH:30])=[O:29])=[O:26])[CH2:23][OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=O)C(C)C)(=O)CC(C)C.P([O-])([O-])([O-])=O>>[NH2:14][C@H:15]([C:19]([N:21]([C:39](=[O:48])[CH2:40][CH2:41][CH:42]([NH2:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:22]([C:25]([CH:27]([CH:31]([OH:38])[CH:32]([NH2:37])[CH2:33][CH:34]([CH3:35])[CH3:36])[C:28]([OH:30])=[O:29])=[O:26])[CH2:23][OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CC(=O)N[C@H](C(=O)N[C@H](C(=O)N(C(=O)CCC(N)CC(C)C)[C@@H](CO)C(=O)C(C(=O)O)C(O)C(N)CC(C)C)C(C)C)C(C)C
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CC(N)CCC(=O)N(C(=O)[C@@H](N)C(C)C)[C@@H](CO)C(=O)C(C(=O)O)C(O)C(N)CC(C)C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A reaction mixture containing 100 mg of isovaleryl-L-valyl-L-valyl-4-amino-3-hydroxy-6-methylheptanoyl-L-alanyl-4-amino-3-hydroxy-6-methylheptanoic acid, 250 units of purified enzyme prepared by the procedure described in Experiment 17 and 0.05M phosphate buffer, pH 7.2, in a total volume of 100 ml was incubated at 37° C for 20 hours. By a procedure similar to that described in Example 1, 61.8 mg of crystalline Val--X--Ala--X was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[CH2:15]([OH:17])[CH3:16]>O1CCOCC1>[ClH:14].[CH2:15]([O:17][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)=[NH:2])[CH3:16]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5.16 g (29 mmol) of ethyl 4-cyanobenzoate was stirred in 50 ml of 4N solution of hydrogen chloride in dioxane. 5 ml of ethanol was added to the resultant mixture, and they were stirred at room temperature for 4 days. The solvent was evaporated, and the residue was washed with ethyl acetate and dried to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[H-].[Na+].CI.[C:15](OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:15])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1cc(Cl)nc(Cl)c1
Reaction time: 2 h

Procedure:
0.18 g of 2,6-dichloro-4-pyridinemethanol were dissolved into 5 ml of tetrahydrofuran (hereinafter referred to as “THF”), the solution was cooled by ice, and thereafter 0.04 g of sodium hydride (oil base, 60%) were added. To this, a solution of 0.15 g of methyl iodide dissolved in 2 ml of THF was added dropwise, and stirring was conducted for 2 hours at room temperature. Ethyl acetate was added to the reacted solution, and after the organic phase was washed by water, the organic phase was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 0.06 g of 2,6-dichloro-4-methoxymethylpyridine (Compound No. 1).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[C:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:15]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 96.9 %

Procedure:
[(R)-1-((R)-2-Hydroxy-propionyl)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (500 mg) was prepared by following General Procedure F starting from (R)-2-hydroxy-propionic acid (200 mg), (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (372 mg), HBTU (800 mg), and DIEA (400 uL) in DMF (4 mL).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)O

Procedure:
To a solution tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (110 mg, 0.27 mmol) in DCM (3.0 mL) and TFA (3.0 mL) was stirred at room temperature for overnight. Solvent was removed under reduced pressure to give 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetic acid. A solution of 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino) acetic acid, [NEt4]2[ReBr3(CO)3] (270 mg, 0.35 mmol) and K2CO3 (78 mg) in MeOH (6.0 mL) was stirred at 90° C. for 4 hrs at a pressure tube. The reaction mixture was purified by Amberchrom (CG-161) eluting with MeOH/H2O to give [Re(CO)3][2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)-amino)acetic acid] (105 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.79 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=0.8 Hz, 1H), 7.25 (s, 2H), 7.15 (d, J=1.2 Hz, 1H), 4.76 (d, J=16.4 Hz, 1H), 4.58 (d, J=16.0 Hz, 1H), 4.03 (d, J=16.8 Hz, 1H), 3.67 (d, J=16.8 Hz, 1H), 3.65-3.49 (m, 2H), 3.17-3.09 (m, 2H); MS (ESI), 623 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34]>CN(C=O)C>[C:19]1([C:8](=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:34]=[CH:33]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:3][CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A yellow solution of 16, Et3N, ethyl acrylate and dichlorobis(triphenylphosphine) palladium(II) in DMF (25 mL, anhydrous, Aldrich) was stirred overnight under N2 at 110° C. After 16 h the reaction was allowed to cool to RT, filtered, and the filtrate diluted with ether (100 mL) and water (100 mL). The ether layer was rinsed with water (2×75 mL) and brine (1×74 mL) then dried (MgSO4) and concentrated to 5.75 g of a yellow solid. The crude product was purified first by column chromatography on 250 g silica gel with 2% EtOAc/hexanes to yield 6.22 g of an impure white solid. Crystallization from hexanes (˜100 mL) afforded 2.39 g (55%) of the title compound 17 as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J=8.0 Hz, 2H), 7.59 (d, J=16.1 Hz, 1H), 7.15-7.30 (m, 7H), 6.56 (d, J=16.1 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 1.91 (s, 2H), 1.88 (s, 2H), 1.21-1.25 (m, 5H), 0.88 (s, 6H), 0.87 (s, 6H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].O=[C:17]1[CH2:22][CH2:21][C:20]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)([C:23]#[N:24])[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[S:27]1[CH:28]=[CH:29][C:25]([C:20]2([C:23]#[N:24])[CH2:21][CH2:22][C:17]3([O:15][CH2:12][CH2:13][O:14]3)[CH2:18][CH2:19]2)=[CH:26]1
Reactant: OCCO
Reactant: N#CC1(c2ccsc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CC1(c2ccsc2)CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Catalytic quantities of para-toluene sulfonic acid and ethyleneglycol (13.3 g: 0.21 mole) were added to 4-oxo-1-thiophen-3-yl-cyclohexanecarbonitrile (22 g; 0.107 mole) dissolved in toluene (500 ml). The reaction mixture was stirred for about 2 hours under reflux. On completion of the reaction (reaction monitored by thin layer chromatography), the toluene phase was separated, washed with sodium hydrogen carbonate solution (200 ml), dried (sodium sulfate) and concentrated under vacuum. 25 g 8-thiophen-3-yl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (95%; colorless solid) were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([C:6](=[O:36])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=1)[CH2:3][CH:4]=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]([CH3:37])([CH2:3][CH2:4][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:6]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[CH:8]=1)=[O:36]
Reactant: C1COCCN1
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CC=O)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CCN2CCOCC2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Reaction time: 15 h
Yield: 13.1 %

Procedure:
A mixture of crude 3,3-dimethyl-4-oxo-4-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyraldehyde (0.161 g, 0.305 mmol), morpholine (0.029 mL, 0.34 mmol), and sodium triacetoxyborohydride (0.129 g, 0.610 mmol) in 3 mL of 1,2-dichloroethane was stirred for 15 h. A sat. aq. NaHCO3 solution (10 mL) was added, and the mixture stirred for 10 min. The layers were separated, and the aqueous layer was extracted with two 20 mL portions of ethyl acetate. The three combined organic layers were dried over MgSO4, filtered, and concentrated to a residue. Column chromatography (0→10% MeOH/CH2Cl2) afforded 0.024 g (13%) of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one as a brown oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CCCC)[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[H-].[Na+].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:32]=1>O1CCCC1>[C:39]([N:38]([CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)NCc1cccnc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)N(Cc2cccnc2)C(C)=O)cc1C(C)(C)C
Yield: 176.3 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 0.90 g of product from Example 33, 0.316 g of washed 50% sodium hydride, 2.57 g of product from Example 14 and 25 ml of dry tetrahydrofuran. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 1.81 g of the desired product as a yellow oil which crystallizes on standing.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Nc1cccnc1)c1ccc(F)cc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N(CCCCCl)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.1 %

Procedure:
To a stirred solution of 21.6 parts of 4-fluoro-N-(3-pyridinyl)benzamide in 235 parts of N,N-dimethylformamide were added portionwise 5.76 parts of a sodium hydride dispersion 50% at <25° C. under nitrogen atmosphere. After stirring for 1.5 hours at room temperature, the mixture was cooled to 0° C. and 27.8 parts of 1-bromo-4-chlorobutane were added. The reaction mixture was stirred for 3 hours at 60° C. After cooling, the whole was poured into 1000 parts of ice water and the product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7.4 parts (24.1%) of N-(4-chlorobutyl)-4-fluoro-N-(3-pyridinyl)benzamide as a residue (int. 67).
Reaction SMILES: [H-].[Na+].[C:3]([C:6](=[C:11]([NH:17][CH2:18][CH:19]=[CH2:20])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4].[CH3:21]I>>[C:3]([C:6](=[C:11]([NH:17][CH2:18][CH:19]=[CH2:20])[CH:12]([CH3:21])[C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4]
Reactant: C=CCNC(CC(=O)OC)=C(C(C)=O)C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: C=CCNC(=C(C(C)=O)C(=O)OC)C(C)C(=O)OC

Procedure:
In the same manner as in Reference Example 4-2-(1) but using 60 % sodium hydride (0.8 g; 20 mmole), dimethyl 2-acetyl-3-allylamino-2-pentenedioate (2.55 g; 10 mmole) and methyl iodide (2.84 g; 20 mmole), there was produced dimethyl 2-acetyl-3-allylamino-4-methyl-2-pentenedioate.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5].C(=O)(O)[O-].[Na+].[CH3:13][C:14]([CH3:16])=O>Cl(O)(=O)(=O)=O.O>[C:14](=[C:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5])([CH3:16])[CH3:13]
Reactant: OCC[C@@H](O)CO
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(C)=C(O)[C@H](O)CCO
Reaction time: 0.17 h
Yield: 31 %

Procedure:
(R)-(+)-1,2,4-Butanetriol (0.7 g, 6.6 mmol), prepared as described in step a) above, was stirred for 1.5 h in acetone (50 ml) containing 3 drops of conc. perchloric acid, a satured solution of sodium bicarbonate in water (5 ml) was added and the stirring was continued for additional 10 min. The precipitate was filtered off and the filtrate evaporated under reduced pressure (2.7 kPa, 30° C.). The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate (5 ml) and brine (5 ml), and dried over magnesium sulphate. Evaporation of the solvent and distillation gave the title compound as a colourless oil (0.3 g, 2.05 mmol, 31%): b.p. 104°-106° C. at~2.7 kPa. nD20 =1.4390.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1.[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH2:14]([O:8][C:7]1[CH:6]=[C:5]([CH:11]=[CH:10][CH:9]=1)[O:4][CH2:3][CH2:2][OH:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCOc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCOc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of O-(2-Hydroxyethyl)resorcinol (4 g) and sodium hydroxide (1.04 g) dissolved in methanol (60 mL) was added benzyl bromide (4.44 g), and the resulting reaction mixture was stirred overnight. After this time, approximately 30 mL of the methanol was removed in vacuo, and the mixture was diluted with methylene chloride (100 mL). The organics were washed with water and aqueous 1N NaOH, dried, and concentrated to provide 2-(3-benzyloxyphenoxy)ethanol (5.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([C:31](=[O:35])[C@H:32]([OH:34])[CH3:33])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C@H:32]([CH3:33])[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1)=[O:35]
Reactant: C[C@@H](O)C(=O)N1CC[C@@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 28.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (50 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl) 2-hydroxy-propan-1-one (100 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 498.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[C:14]([O:34]C(=O)C)=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[C:14]([OH:34])=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2O)=C(C)C1=O
Yield: 67.2 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-morpholinoaniline (0.075 g, 0.145 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.048 g, 0.0975 mmol, 74%).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[CH:37]C(Cl)=O)=[CH:32][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:25])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)[CH:37]=[CH:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:41])[F:42])=[CH:35][CH:34]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cccc(Cc2nc(NC(=O)OC(C)(C)C)co2)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Cc2nc(N(C=Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)co2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-benzyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (15 mg, 0.05 mmol) in THF (1.0 mL) was added to a suspension of NaH (5 mg, 0.12 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 3-(4-trifluoromethyl-phenyl)-acryloyl chloride in THF (1.0 mL). The resulting suspension was stirred for 5 min at 0° C. followed by 30 min at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.17 min, [M+H]+=515.82.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7][C:8]([O:10]C(C)(C)C)=O)[CH:2]=[CH2:3].C1C(=O)N(OC([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=2[N+:43]([O-:45])=[O:44])=O)C(=O)C1.C(N(CC)CC)C>Cl.O1CCOCC1>[CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7][C:8](=[O:10])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:35]=1[N+:43]([O-:45])=[O:44])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(CCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@H](CO)NC(=O)CCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-serine allyl ester (0.175 g, 0.731 mmol) in 4 M hydrogen chloride/dioxane (2 mL) was stirred at ambient temperature for 40 minutes. The reaction mixture was concentrated on a rotary evaporator and the crude HCl salt was taken up in anhydrous tetrahydrofuran (3 mL). To this solution was added N-succinimidyl 6-(2,4-dinitroanilino)hexanoate (0.288 g, 0.791 mmol) and triethylamine (102 mL, 0.731 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic phase was washed with saturated NaHCO3 and saturated NaCl. It was dried over MgSO4, filtered, and concentrated under reduced pressure to yield the crude product (0.293 g) as a yellow oil. Purification using a Thomson Instruments Single Step 12 g silica gel cartridge eluting with 50% hexanes/50% ethyl acetate followed by ethyl acetate gave the product (0.222 g, 72%) as a yellow oil. 1H NMR (DMSO-d6) δ 1.32 (2H, m), 1.52-1.64 (4H, m), 2.15 (2H, t, J=7.0 Hz), 3.44 (2H, m), 3.59 (1H, m), 3.66 (1H, m), 4.33 (1H, m), 4.55 (2H, m), 5.02 (1H, t, J=5.5 Hz), 5.17 (1H, m), 5.28 (1H, m), 5.83 (1H, m), 7.21 (1H, d, J=9.5 Hz), 8.12 (1H, d, J=7.9 Hz), 8.23 (1H, dd, J=2.5 Hz, J=9.4 Hz), 8.85 (2H, m).