Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[C:29](O)=[O:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN(C1C=CN=CC=1)C>[CH2:23]([N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:11]([C:29]([NH:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:30])[CH2:12]1)=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NCCN1CCOCC1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)NCCN2CCOCC2)C1
Yield: 46.5 %

Procedure:
According to the procedure of Example 1, Step E above, 47 mg (0.09 mmole) of 1-(N,N-diphenylcarbamoyl)-4-(N,N-di-n-pentylcarbamoyl)piperazine-2-carboxylic acid, 3 mg (0.02 mmole) of DMAP, 25 mg (0.13 mmole) of EDAC, and 24 mg (0.18 mmole) of 4-(2-aminoethyl)morpholine after purification by flash chromatography on 16 g of silica gel with 100:3CH2Cl2 :MeOH provided 26 mg (46%) of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][Cl:34])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CO)cs2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH2Cl2 (10 mL) was added MsCl (285 L, 1.3 eq.) dropwise. The resulting mixture was stirred overnight. The reaction solution was then concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as an oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])[CH3:2].[OH-].[Na+]>CO.O>[C:9]([C:5]1[N:6]=[CH:7][S:8][C:4]=1[S:3][CH2:1][CH3:2])([OH:11])=[O:10]
Reactant: CCSc1scnc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCSc1scnc1C(=O)O
Yield: 84.1 %

Procedure:
6 g of methyl 5-ethylthio-1,3-thiazole-4-carboxylate were dissolved in 100 ml of methanol and heated with 1.2 g of NaOH in 10 ml of water under reflux for about 1 h. After the solvent had been removed in a rotary evaporator, the solids were removed by filtration, and the filtrate was acidified with 2N HCl solution. After drying, 4.7 g of the title compound, of melting point 158°-9° C., were obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:17])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[N+:19]([O-:9])[CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)N1C(=O)c2cccnc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)N1C(=O)c2ccc[n+]([O-])c2C1=O
Reaction time: 2 h

Procedure:
79.7 g of 55% strength 3-chloroperbenzoic acid are added to 22 g of N-isopropylpyridine-2,3-dicarboximide in 100 ml of methylene chloride in the course of 2 hours while refluxing and stirring, and stirring is continued for a further 2 hours. The reaction mixture is extracted three times with 10% strength sodium carbonate solution and then with water and saturated sodium chloride solution, dried, and evaporated down under reduced pressure. The residue is stirred with methyl tert-butyl ether, 11.2 g of the title compound of melting point 138°-142° C. being obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](C(C)C)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=[O:39])[C:28]=2[CH:27]=1)=O>>[CH:10]([O:9][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:35](=[O:37])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)([CH3:16])[CH3:11]
Reactant: CC(C)c1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CC(C)Oc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-isopropylphenyl)-5-phenylbenzoxazole (188 mg, 0.55 mmol) and 1,2,4-benzenetricarboxylic anhydride (106 mg, 0.55 mmol) the title compound was obtained (102 mg, 36%). 1H NMR (DMSO) δ 8.42(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H), 7.85(d, 1H), 7.71(m, 3H), 7.50(m, 3H), 7.39(t, 1H), 4.87(m, 1H), 1.41(d, 6H). MS 519 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=2)[O:12]1.C(N(C(C)C)CC)(C)C.Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)(C)C>[CH2:23]([C:20]1[O:19][C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[O:12]2)=[N:22][CH:21]=1)[CH3:24]
Reactant: CCc1cnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 355.6 %

Procedure:
To a solution of (2R,3R,4S,5S)-2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol (0.19 g), in isopropanol (15 ml) was added diisopropylethylamine (0.3 ml) and 4-aminotetrahydropyran hydrochloride (0.135 g). After stirring at reflux for 16 h, further diisopropylethylamine (0.2 ml) and 4-aminotetrahydropyran hydrochloride (60 mg) were added. Stirring was continued at reflux for a further 20 h before the mixture was cooled and concentrated in vacuo to give a yellow gum (0.8 g). Purification by chromatography on silica gel (Merck 7734) with dichloromethane:ethanol:ammonia (250:8:1)-(100:8:1), gave the title compound, as a white foam (0.182 g).
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.OO.S(=O)(=O)(O)[OH:21]>C(O)(C)(C)C>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:21])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])[CH3:17]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CCC1(C(C)=O)CCCCC1=O
Agent: OO
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC1(C(=O)O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 2-acetyl-2-[2-(ethoxycarbonyl)ethyl]-cyclohexanone (see Preparation 4) (40 g, 0.16 mol) in tert-butanol (85 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (21.7 ml, 0.19 mol) and concentrated sulfuric acid (0.25 ml, 98% w/w) at room temperature. The mixture was further stirred for 24 hours, partitioned between dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The dichloromethane layer was washed with 5% aqueous sodium sulphite solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil, (34.35 g). Purification of this material by chromatography on silica by eluting with ethyl acetate/hexane (1:2 changing to 1:1), followed by neat ethyl acetate in the latter stages, gave, after combination and evaporation of appropriate fractions, the title compound as a yellow oil, (22.96 g, 67%). RF. 0.28 (silica, ethyl acetate/hexane, 1:1). 1H-NMR (300 MHz, CDCl3): =1.31 (t, 3H), 1.47-1.62 (m, 2H), 1.62-1.82 (m, 4H), 1.92-2.08 (m, 2H), 2.10-2.27 (m, 2H), 2.32-2.46 (m, 2H), 4.19 (q, 2H) ppm. 13C-NMR (75.5 MHz, CDCl3) 14.26, 25.15, 31.21, 33.56, 36.15, 53.21, 60.49, 173.38, 183.52 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 5-fluoroisatin (5 g, 30.2 mmol) in DMF (60 mL) was cooled in an ice/water bath and treated with sodium hydride (1.44 g, 60.6 mmol) portionwise. The reaction was stirred for 15 minutes after the addition of the last portion and then treated with p-methoxybenzyl chloride (5.32 g, 45.3 mmol) and allowed to stir for 1 hour. The reaction was then quenched by slow addition of excess methanol. After bubbling had stopped, the reaction was poured into water (100 mL) and extracted twice with ethyl acetate. The organics were combined, dried over MgSO4 and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 7.1 g (82%) of 5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione; 1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 4.86 (s, 2H), 6.75 (dd, 1H, J1=3.6, J2=8.6), 6.84-6.90 (m, 2H), 7.19 (ddd, 1H, J1=J2=8.6, J3=3.6), 7.22-7.27 (m, 1H), 7.26-7.31 (m, 2H); HPLC-MS calcd. for C16H12FNO3 (M+H+) 286.1, found 286.3. Step B: A solution of 5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9 mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed overnight, diluted with water and extracted twice with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 6.1 g (90%) of 5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; 1H NMR (CDCl3, 400 MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J1=4.2, J2=8.6), 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS calcd. for C16H14FNO2 (M+H+) 272.1, found 272.3.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16][CH3:17])[N:9]3[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=23)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:37])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:17])=[O:37])[N:9]3[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=23)=[CH:28][CH:29]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(SC)cccc12
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the sulfide of Step 12 (270 mg, 0.6 mmol) in 30 ml of CH2Cl2/MeOH (10:1) mixture at 0° C. was added MMPP (312 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 70% EtOAc in Hexanes to provide 210 mg as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:19](=O)[CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=[O:17])[C:9]=3[N:8]=2)[CH2:6][CH2:5][N:4]([CH2:19][CH2:20][CH3:21])[CH2:3]1
Reactant: CC1(c2nc3c(C(N)=O)cccc3[nH]2)CCNC1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC(C)(c2nc3c(C(N)=O)cccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A solution of the free base of Example 10E (70 mg, 0.3 mmol) in methanol (5 mL) was treated with propionaldehyde (25 mg, 0.4 mmol) at room temperature overnight. Sodium triacetoxyborohydride (254 mg, 1.2 mmol) was then added and the solution was stirred at rt for 3 h. After concentration under vacuum, the residue was separated by HPLC (Zorbax C-8, 0.1% TFA/CH3CN/H2O) to give 55 mg of desired product. Yield: 35%. MS (APCI) m/z 287 (M+H)+; 1H NMR (500 MHz, CD3O): δ 0.89 (t, J=7.33 Hz, 2 H), 1.60 (s, 3 H), 1.63-1.77 (m, 2 H), 2.12-2.40 (m, 1 H), 2.59-2.73 (m, 1 H), 3.03-3.40 (m, 5 H), 3.69 (s, 1 H), 3.96-4.50 (m, 1 H), 7.21 (t, 1 H), 7.56 (s, 1 H), 7.76 (s, 1 H); Anal. Calcd for C16H22N4O.2.0 TFA: C, 46.70; H, 4.70; N, 10.89. Found: C, 46.89; H, 4.68; N, 10.98.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[N:2]1.[C:11]([O:15][C:16]([CH2:18][O:19][NH2:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1.O>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([OH:9])=[O:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C(=O)c1cnsn1
Reactant: CC(C)(C)OC(=O)CON
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cnsn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (1,2,5-thiadiazol-3-yl)glyoxylic acid (6 g) in tetrahydrofuran (30 ml) and water (30 ml) was added tert-butoxycarbonylmethoxyamine (8.37 g) at room temperature. The mixture was adjusted to pH 4.5-5.0 with 4 N aqueous sodium hydroxide and stirred at ambient temperature for 4 hours. The mixture was adjusted to pH 7.5 with 4 N aqueous sodium hydroxide and washed with ethyl acetate (100 ml×2). The aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml×2). The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated in vacuo to give 2-(tert-butoxycarbonylmethoxyimino)-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn and anti mixture) (10.02 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)=[O:17])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1COCCN1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
3-[4-(4-Fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.98 g, 7.04 mmol) was stirred in DCM (30 mL) at 0° C. TFA (6 mL) dissolved in DCM (24 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between DCM (30 mL) and aqueous NaHCO3 (5 g in 30 mL). The aqueous layer was extracted with DCM (3×30 mL), dried (MgSO4) and the solvent removed in vacuo to give morpholin-3-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.18 g, 96%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[N:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:22]([N:10]1[CH2:11][CH2:12][C:13]2[N:14]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc2c(s1)CNCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2c(s1)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate obtained in step V of example 1 was deprotected to get the 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester. To a solution of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester (1 eq) and triethyl amine (1 eq) in chloroform, acetic anhydride was added and the reaction mixture was stirred for 1 h at room temperature. Reaction mixture was then diluted with chloroform and washed with water. Organic layer was then separated, dried and concentrated under reduced pressure to afford the desired ethyl 5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@H:9]([OH:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 82.3 %

Procedure:
A solution of (1S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1) (50 mg, 0.145 mmol) in HOAc (4 mL) and H2O (1 mL) was hydrogenated in the presence of Pd/C (11 mg, 10% Pd/C) at 23° C. for 23 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (6.75 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (5 mL) and propylene oxide (2 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3S,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-2) (24 mg, 86%) as a white solid. 1H-NMR (250 MHz, D2O) □2.05 (1H, d,J=15 Hz), 2.10-2.20 (2H, m), 2.12 (1H, m), 2.61 (1H, m), 4.20 (1H, d, J=7.2 Hz); MS[ISP] 202 (M+H+); mp 208° C. (dec.); □D20 +27.52° (c=1.03, H2O).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:30][Mg]Br>C(OCC)(=O)C.CCCCCC>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:30])[CH3:2]
Reactant: CC(=O)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Reactant: C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)(C)O)cc1)CO2
Yield: 42 %

Procedure:
Using N-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 176 and methylmagnesium bromide, the title compound was synthesized in the same manner as in Example 22. Yield: 42%. Melting point: 132-134° C. (ethyl acetate-hexane).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34].C(N(CC)CC)C>ClCCl>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (0.30 g) was added to a solution of benzyl 4-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.60 g) obtained in Example 39a) and triethylamine (0.28 mL) in dichloromethane (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from hexane/ethyl acetate=1/1 to hexane/ethyl acetate=1/4) to obtain the title compound (0.78 g, 99%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (5.00 g, 27.47 mmol) in DMSO (30 mL) were added BOP (18.21 g, 41.21 mmol), NH4Cl (4.41 g, 82.41 mmol) and DIPEA (10.63 g, 82.41 mmol) and the reaction mixture was stirred at rt for 14 h and it was quenched with ice-water and the precipitate obtained was filtered, washed with Et2O and dried to afford 4.90 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.48 (br s, 2H), 8.19-8.17 (m, 2H), 7.96-7.94 (d, J=7.2 Hz, 1H), 7.62 (br s, 1H), 6.71-6.65 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O.S(Cl)(Cl)=O>ClCCl>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[C:13](=[O:15])[CH:12]([CH:16]([CH3:18])[CH3:17])[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COc1ccc(SC(C(=O)O)C(C)C)c(Cl)c1Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1Cl)SC(C(C)C)C2=O
Temperature: 25 °C
Yield: 45 %

Procedure:
To 6.0 g of α-(2,3-dichloro-4-methoxyphenylthio)isovaleric acid in 27 ml of dry dichloromethane is added 5.5 ml of thionyl chloride. The reaction is heated under reflux for 1 hour and excess reagent is removed under aspirator pressure. The residue is diluted with 70 ml of dichloromethane and the resulting slurry is added over less than one minute to a slurry of 2.79 g of aluminum chloride in 8 ml of dichloromethane at -60°. The cooling bath is removed and the reaction allowed to warm to room temperature over one hour. Stirring is continued for an additional hour and reaction is quenched with 250 ml of water. The mixture is extracted with three 125 ml portions of ether and the combined ether extracts are washed with two 150 ml portions and one 60 ml portion of saturated sodium bicarbonate solution, water and brine and dried over anhydrous magnesium sulfate to give 2.54 g of oily 6,7-dichloro-5-methoxy-2-isopropylbenzo[b]thiophen-3(2H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18]>>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17](=[O:19])[CH3:18]
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969) and acetyl chloride