Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:57])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (285 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 127 mg) was added at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethanol-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (Compound 80) (220.9 mg) as pale yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:36]1[S:37][C:38]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([C:46]([F:49])([F:48])[F:47])[C:39]=2[N:40]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.O>[F:45][C:44]1[C:38]2[S:37][C:36]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)=[N:40][C:39]=2[C:41]([C:46]([F:49])([F:47])[F:48])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Fc1ccc(C(F)(F)F)c2nc(Cl)sc12
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (60 mg, 0.127 mmol, 1 eq), 2-chloro-7-fluoro-4-trifluoromethyl-1,3-benzothiazole (42 mg, 0.153 mmol, 1.2 eq), and potassium carbonate (43 mg, 0.317 mmol, 2.5 eq) in 20% aq. dioxane (15 mL) was bubbledN2 gas for 15 min. Catalyst PdCl2dppf (5 mol %) was added to the stirred solution and N2 gas bubbling continued for another 10 min. The reaction mixture was then heated at 80° C. for 2 h. Cooling of the reaction mixture and evaporation of dioxane under reduced pressure yielded a brown residue. It was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a yellowish-green solid. It was purified by column chromatography (50% ethyl acetate in hexane) to afford the BOC-protected title compound as yellowish-green solid; MS(ES+): m/z=563 [MH+]. To a solution of this Boc derivative (40 mg, 0.07 mmol) at 0-5° C. in dry DCM (10 ml) was added 4M HCl in dioxane (0.2 ml) dropwise and stirred the reaction mixture overnight at rt. Removed solvent under reduced pressure to afford the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.06-8.96 (brm, 1H), 8.85-8.73 (brm, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.17 (very brs, 1H), 8.09 (s, 1H), 8.03 (dd, J=5.2, 8.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 4.56-4.46 (mc, 1H), 3.41 (brd, J=12.4 Hz, 2H), 3.12 (brq, J=11.4 Hz, 2H), 2.31-2.11 (m, 4H). MS(ES+): m/z=463.05 (100) [MH+], 380.02 (80) [MH+-piperidine]. HPLC: tR=2.29 min (polar—5 min, ZQ2).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][O:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][O:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(I)cc2F)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCC(O)CO)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide (488 mg, 0.89 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 310 mg, 48% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.40 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 527.8, [M+Na].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]2OCC[O:12]2)=[CH:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cc2ccc(C3OCCO3)s2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 2-(5-(3-chloro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 43 (1.6 g, 5.7 mmol) in methanol (20 mL) was added citric acid aqueous solution (20 mL), and the solution was stirred at room temperature for 20 minutes. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (1.2 g, 5.08 mmol, 89.2%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:60]=[CH:59][C:52]([CH2:53][NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])=[CH:51][CH:50]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:46][CH2:47][CH2:48][C:49]3[CH:60]=[CH:59][C:52]([CH2:53][NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])=[CH:51][CH:50]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: CC(C)CNCc1ccc(CCN)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(CNCC(C)C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (46 mg, 0.27 mmol), DIPEA (0.134 mL, 0.76 mmol) and N-[4-(2-aminoethyl)benzyl]-2-methylpropan-1-amine (40 mg, 0.14 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@@H:12](O)[C:11](=[CH2:15])[C@@H:10]1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:25][C:26]1[N:34]=[C:33]([NH2:35])[N:32]=[C:31]2[C:27]=1[NH:28][CH:29]=[N:30]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:30]2[CH:29]=[N:28][C:27]3[C:31]2=[N:32][C:33]([NH2:35])=[N:34][C:26]=3[Cl:25])[C:11](=[CH2:15])[C@@H:10]1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C=C1[C@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: -23 °C
Reaction time: 3.5 h
Yield: 58.2 %

Procedure:
370 mg (1.0 mmol) (1R,3R,4S)-4-(tert-butyldimethylsilyloxy)-3-[(tert-butyldimethylsilyloxy)methyl]-2-methylene-cyclopentanol (Compound 4a, R1═R2=t-BuMe2Si), 338 mg (2.0 mmol) 6-chloro-2-aminopurine (Compound 23) and 524 mg Ph3P (2.0 mmol) were placed into 20 ml round bottom flask, to which 5 ml anhydrous THF was then added. The mixture was cooled to −23° C., to which a solution of 350 mg DEAD (1.0 mmol)/5 ml THF was added dropwise. After addition was completed, the reaction mixture was stirred at −23° C. for 3.5 hours, warmed to room temperature and stirred at room temperature overnight. Subsequently THF was evaporated off under reduced pressure. 10 ml t-BuOMe was added to the residue. The mixture was stirred for 5 minutes, to which 15 ml n-hexane was added. The mixture was maintained standing for 5 hours, and filtered to remove insoluble substance. The filtrate was purified with column chromatography, eluting with petroleum ether/EtOAc (3/1 (v/v)), to afford 305 mg (59%) of title compound as light yellow oil.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=2)=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=1
Reactant: COc1ccc(COc2coc(C)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(=O)c(O)co1
Reaction time: 3 h

Procedure:
5-p-Methoxybenzyloxy-2-methyl-4-pyrone, 10 g, was dissolved in 10 ml of anisole and 15 ml of trifluoroacetic acid was dropwise added to the solution under ice cooling. After stirring at the same temperature for 3 hours, the mixture was concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (200 g) to give 2.4 g of the title compound.
Reaction SMILES: N(C(OC(C)C)=O)=NC(O[CH:6](C)[CH3:7])=O.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[O:25]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:15])[N:17]1[N:26]([CH2:6][CH3:7])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl 1,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0° C. and the reaction solution was stirred at room temperature for 1 h (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes) to provide tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90% yield) as a white solid which was used as it in the next step
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12]O)[C:3]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:3]2[O:14][CH2:12][CH2:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)c(O)c(CCO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)c2c(c1)CCO2
Reaction time: 3 h
Yield: 68.8 %

Procedure:
2-Bromo-6-(2-hydroxyethyl)-4-nitrophenol (3.12 g) was dissolved in tetrahydrofuran (20 ml) and was added dropwise to a cooled (0° C.) solution of triphenylphosphine (4.03 g) and diethylazodicarboxylate (2.43 ml) in tetrahydrofuran (30 ml). The mixture was stirred for 3 h and the solvent was removed in vacuo. The residue was purified on silica using 15% ethyl acetate in hexane as eluent to afford the title compound as a white crystalline solid (2 g). 1H NMR (250 MHz, CDCl3) δ 3.43 (2H, t, J=8.7 Hz), 4.85 (2H, t, J=9 Hz), 8.03-8.05 (1H, m), 8.20-8.29 (1H, m).
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:27]1[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][C:26]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCCCc1csc2ccc(NN)cc12
Agent: Cl
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4

Procedure:
The compound is formed analogously to that described in Example 5, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 23 g of 1-benzyl-4-piperidone. Melting point: 127°-128° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][O:35][C:31]1[N:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:21][CH2:22]3)=[CH:24][CH:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)n1
Yield: 95.9 %

Procedure:
A solution of the compound (426 mg, 0.79 mmol) obtained in Example 40-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (320 mg, 95%) as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[Cl:29])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[ClH:29].[Cl:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN(CC(C)C)c2ccc(F)cc2Cl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CN(CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
The above ester (13.1 g, 31 mmol) was dissolved in ethanol (50 ml), 2N sodium hydroxide (50 ml) was added and the mixture was heated at reflux for 1 h. After cooling to ambient temperature pH was adjusted to 0 with concentrated hydrochloric acid. The resulting mixture was washed with dichloromethane (2×100 ml) and pH in the aqueous phase was adjusted to 2.5 with 1N sodium hydroxide. The mixture was extracted with dichloromethane (100 ml) and the solvent was evaporated from the organic phase in vacuo. To the residue was added acetone (50 ml) and diethylether (50 ml) and the mixture was left for crystallisation. This afforded 5.8 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23]>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Product: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
In a batch procedure (300 l), Mal-Tyr-OEt (0.25M) and Arg-OEt (0.25M) are reacted with α-chymotrypsin (0.025 mg/ml) at pH 9.5 and 25° C. After 2 hours, filtration of the precipitate and washing with water result in 26.0 kg of Mal-Tyr-Arg-OEt (75% of theoretical yield) with an HPLC purity greater than 97%.
Reaction SMILES: N#N.C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23]C)[C:20]([O:25]C)=[C:19]([O:27]C)[CH:18]=2)[CH2:9][CH2:8]1)=[O:6].B(Br)(Br)Br.O>C(Cl)Cl.CO>[OH:23][C:21]1[CH:22]=[C:17]([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)=[O:29])[CH:18]=[C:19]([OH:27])[C:20]=1[OH:25]
Reactant: COC(=O)C1CCC(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(CCc1cc(O)c(O)c(O)c1)N[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 10.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve cis-{4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid methyl ester (75) (82 mg, 0.21 mmol) in anhydrous DCM (2.0 mL), cool the solution to −78° C. and add dropwise BBr3 (205 μL, 2.17 mmol). Stir the reaction mixture for 20 min at −78° C. and after slowly warming up for additional 2 h at rt Add dropwise water, followed by DCM and MeOH and remove solvent. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain cis-4-[3-(3,4,5-Trihydroxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid (76) (7 mg, 10%) as a colorless sticky solid. 1H NMR (400 MHz, CD3OD): 1.47-1.60 (m, 2H); 1.62-1.73 (m, 4H); 1.91-2.02 (m, 2H); 2.42 (t, 2H, J=7.6 Hz); 2.47-2.54 (m, 1H); 2.71 (t, 2H, J=7.3 Hz); 3.75-3.84 (m, 1H); 6.23 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[C:8]2[C:7]1=[O:23].I[CH3:26]>C1COCC1>[CH3:26][O:3][CH:4]([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[C:8]2[C:7]1=[O:23]
Reactant: CI
Reactant: CC(O)CN1CCn2nc(COc3ccccc3)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (8.6 mg, 0.21 mmol) was added to a solution of (rac)-5-(2-hydroxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (54 mg, 0.18 mmol) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and then iodomethane (0.02 mL, 0.36 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with a saturated solution of NH4Cl and extracted with AcOEt, dried with (Na2SO4), filtered and the solvent evaporated in vacuo to yield a yellow oil which was purified by flash column chromatography (silica; AcOEt in heptane from 0:100 to 0:100) to yield a colourless oil which was triturated with DIPE to yield (rac)-5-(2-methoxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (28 mg, 49% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (d, J=6.4 Hz, 3H), 3.27 (dd, J=14.0, 7.9 Hz, 1H), 3.33 (s, 3H), 3.60-3.69 (m, 1H), 3.79-3.85 (m, 1H), 3.85-3.90 (m, 1H), 3.93-4.02 (m, 1H), 4.36 (t, J=6.2 Hz, 2H), 5.09 (s, 2H), 6.93 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=8.1 Hz, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](Cl)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 115 °C
Yield: 46.6 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (12 g, 34 mmol) in DMSO (50 mL) was added morpholine (3.6 g, 41 mmol) followed by N,N-diisopropylethylamine (8.9 g, 69 mmol). The mixture was heated at 110-120° C. for 4 hours, then cooled to ambient temperature, quenched with water (50 mL) and extracted with ethyl acetate (3x100 mL). The combined organics were washed with brine (2×30 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6.3 g (46% yield) of N-(5-chloropyridin-2-yl)-2-nitro-3-(morpholin-4-yl)-5-chlorobenzamide; NMR (CDCl3) 8.2 (m, 1), 7.7 (m, 1), 7.2-7.4 (m, 3), 3.8 (m, 4), 3.0 (m, 4) ppm.
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:9]([OH:10])[C@H:8]([OH:11])[C@@H:7]([CH2:12][OH:13])[O:6][C@@H:3]1[O:4]C.C[O-].[Na+]>CO>[Cl:1][C@@H:2]([C@H:9]([C@@H:8]([C@@H:7]([CH2:12][OH:13])[OH:6])[OH:11])[OH:10])[CH:3]=[O:4]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C[C@@H](Cl)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3.5 h
Yield: 90 %

Procedure:
The methyl 2-chloro-2-deoxy-mannopyranoside (6) was dissolved in the minimum of methanol and the pH adjusted to 10 by addition of 1 molar sodium methoxide. The solution was kept for 2-5 hours at room temperature and evaported to give the 2-chloro-2-deoxy mannose in about 90% yield.