Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([SH:23])([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])([OH:3])=[O:2]>C(O)C(C)C>[CH3:1][CH:4]([O:2][C:1]([CH2:4][CH2:5][C:6]([SH:23])([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])=[O:3])[CH2:5][CH3:6]
Reactant: COc1cc2c(cc1OC)C(C(S)(C#N)CCC(=O)O)=NCC2
Solvent: CC(C)CO
Product: CCC(C)OC(=O)CCC(S)(C#N)C1=NCCc2cc(OC)c(OC)cc21

Procedure:
Following the procedure described in Example 19 but starting from 1.67 g. of α-(2-carboxyethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-isoquinolyl-acetonitrile and 5 ml. of isobutanol 1.4 g. of α-[2-(2-butoxycarbonyl)-ethyl]-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 120° C. after recrystallization from absolute ethanol.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11](SC3SC=CC=3)=[C:12]([CH:14]=[O:15])[S:13][C:7]=2[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5]1=[O:26]>CO.O>[OH:15][CH2:14][C:12]1[S:13][C:7]2[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:5](=[O:26])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=2[C:11]=1[CH2:14][C:12]1[S:13][CH:7]=[CH:8][CH:11]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C=O)sc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cc3cccs3)c(CO)sc21
Reaction time: 24 h
Yield: 104.4 %

Procedure:
Sodium borohydride (0.06 g) was added to 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-6-carboxaldehyde (0.25 g) in methanol (25 ml) and the mixture was stirred for 24 hours. The reaction was diluted with water (30 ml) and was then extracted with ethyl acetate (3×50 ml). The organic phases were washed with brine and dried over magnesium sulfate, filtered and evaporated to leave a green oil. Purification by chromatography (1:4 ethyl acetate:isohexane) gave the subtitle compound as a yellow foam (0.125 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[C:15]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:24])[N:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[N:36]=[C:37](Cl)[C:38]2[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[C:39]=2[N:40]=1>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]([C:10](=[O:11])[NH:12][C:13]1[CH:18]=[C:17]([C:37]2[C:38]3[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[C:39]=3[N:40]=[CH:35][N:36]=2)[CH:16]=[C:15]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:24])[N:14]=1)[CH3:32])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1cc(B(O)O)cc(NC(=O)c2ccc(Cl)cn2)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1nn(C)c2c(Cl)nc(Cl)nc12
Product: Cc1nn(C)c2c(-c3cc(NC(=O)c4ccc(Cl)cn4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12

Procedure:
K63a is prepared analogously from D1 utilizing 5,7-dichloro-1,3-dimethyl-1H-pyrazolo-[4,3-d]pyrimidine:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10].Cl.Cl.[CH3:35][O:36][C:37](=[O:45])[CH:38]([NH2:44])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37](=[O:45])[C@@H:38]([NH:44][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][C:12]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:10])[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Reactant: COC(=O)C(N)CCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (32.0 g, 72.2 mmol) and 2-amino-4-dimethylaminobutyric acid methyl ester dihydrochloride (19.35 g, 83.0 mmol) in dichloromethane was added triethylamine (35 mL, 253 mmol) and the mixture stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (400 mL). The solution was washed with saturated NH4Cl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude product.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:23]Br>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:10]([Br:23])=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: COc1c(F)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1c(F)cnc2c1c(Br)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68b, (0.79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([F:19])[CH:5]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[F:19])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid methyl ester from Example E3.5 (640 mg, 2.25 mmol) in dioxan (40 ml) was added 1N NaOH (4.5 ml, 4.5 mmol). The mixture was stirred for 18 h, diluted with EtOAc, washed with 1N KHSO4, water and brine and concentrated in vacuo to give a white solid identified as the title compound (608 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[C:17]1([N:23]2[C:27](B(O)O)=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([N:7]2[C:6]3[CH:16]=[C:2]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Reactant: OB(O)c1ccnn1-c1ccccc1
Product: c1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white solid (36 mg, 29%), MS (ISP) m/z=337.3 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and commercially available 1-phenyl-1H-pyrazol-5-ylboronic acid [CAS No. 1238702-56-1] (89.5 mg, 476 μmol).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:5][C@H:4]([C:6]2[N:10]3[CH:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]3=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[N:7]=2)[CH2:3]1.NC1C2N(C([C@H]3C[C@H](COS(C4C=CC(C)=CC=4)(=O)=O)C3)=NC=2C2C=CC(OC3C=CC=CC=3)=CC=2)C=CN=1>>[CH3:1][C@H:2]1[CH2:5][C@H:4]([C:6]2[N:10]3[CH:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]3=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[N:7]=2)[CH2:3]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Product: C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1

Procedure:
Prepared according to the procedure described above for cis-3-(3-methylcyclobutyl)-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using trans-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:25])[C:20](=[O:21])[CH2:12][C:11](=[O:13])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:14])([F:15])[F:3])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Yield: 79.7 %

Procedure:
Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of 1-(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reaction was allowed to come to room temperature and then heated to 45° C. for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1×100 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxylamine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1). Step 2. Preparation of [5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol (Compound 13B)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16][CH:17]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(OC(=O)c3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>C(Cl)Cl>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:3]=[C:2]([CH3:1])[CH3:12])[N:5]=3)=[O:11])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)=Cn1ccc(C(=O)O)n1
Solvent: ClCCl
Product: CC(C)=Cn1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 75.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1-(2-methylprop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.151 mmol, 191 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.959 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture was diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried, filtered and evaporated. The crude product was purified flash chromatography. 297 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 1.80 (d, 3H), 1.85 (d, 3H), 4.25-4.52 (m, 3H), 6.66 (d, 1H), 6.77-6.81 (m, 1H), 6.95 (d, 1H), 7.83 (t, 2H), 7.94-7.97 (m, 2H), 8.06-8.10 (m, 1H), 8.18 (d, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)(Cl)(Cl)Cl>C1COCC1>[C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:6]1[N:36]=[N+:37]=[N-:38])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1,3,4,6-Tetra-O-acetyl-2-O-trifluormethanesulfonyl-β-D-mannopyranose (6) (53 mg, 0.11 mmol) was dissolved at 25° C. in 3 mL of THF. Trimethylsilyl azide (19 μL, 0.15 mmol) was added via syringe followed by TBAF (150 μL, 0.15 mmol). The solution was stirred at 25° C. for 22 h. The reaction mixture was filtered through a plug of silica gel and concentrated in vacuo to give a yellow oil which was chromatographed (2:1, hexane/EtOAc) to afford 30 mg (73%) of β-anomer as a colorless oil. IR (CCl4) 2113, 1762; 1H NMR (CDCl3) 5.56 (d, J=8.8), 5.10 (t, J=9.5), 5.05 (t, J=9.5), 4.31 (dd, J=4.8, 12.5), 4.09 (dd, J=12.5), 3.79 (ddd, J=9.5, 4.8, 2.0), 3.65 (dd, J=9.5, 8.8), 2.18 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H). The spectra for the anomeric mixture has been previously reported (Vasella, A. et al., Helv. Chim. Acta 74:2073-2077 (1991)).
Reaction SMILES: Cl.C(OCC)(=O)C.C(Cl)[Cl:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][N:42](C(OC(C)(C)C)=O)[CH3:43])[O:13]1>CCOCC>[ClH:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][NH:42][CH3:43])[O:13]1
Reactant: CN(CC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1)C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNCC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (5 ml, 20 mmol) was added at 0° C. to a methylene chloride solution (10 ml) that contained the N-tert-butoxycarbonyl-N-methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester (1.15 g, 2.0 mmol) obtained in step A. The obtained mixture was stirred at a room temperature for 5 hours. Thereafter, ether was added to the reaction mixture, so that powders were completely precipitated and collected by filtration. The filtrate was washed with ether and hexane, and was then dried under reduced pressure, so as to obtain methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester hydrochloride (967 mg, 95%) in the form of white powders.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[CH3:31][O:32][C:33](=[O:47])[C@@H:34]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[NH2:35]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:47])[C@H:34]([NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=1)[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1
Reactant: COC(=O)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (5.32 g; 21.2 mmol) was dissolved in N,N-dimethylformamide (20 ml). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.06 g, 21.2 mmol) was added and the mixture was stirred for 20 min. A solution of (R)-3-(2-naphthyl)alanine methyl ester (4.85 g, 21.2 mmol) in N,N-dimethylformamide (20 ml) and triethylamine (4.4 ml) was added and stirring was continued for 18 h. The mixture was diluted with ethyl acetate (400 ml) and the organic phase was washed with water (200 ml), 10% aqueous sodium hydrogensulfate (50 ml), 5% aqueous sodium hydrogencarbonate (100 ml) and water (100 ml). The phases were separated and the organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 8.9 g of (R)-2-(3-(tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(OC(C)(C)C)=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[O:32]=[C:33]1[NH:37][C:36](=[O:38])[CH:35]([CH2:39][C:40]2[CH:50]=[CH:49][C:43]([O:44][CH2:45][C:46](O)=[O:47])=[CH:42][CH:41]=2)[S:34]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:46](=[O:47])[CH2:45][O:44][C:43]3[CH:42]=[CH:41][C:40]([CH2:39][CH:35]4[S:34][C:33](=[O:32])[NH:37][C:36]4=[O:38])=[CH:50][CH:49]=3)=[C:3]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(N)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 57.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate (500 mg), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (366 mg), diethyl cyanophosphonate (212 mg), triethylamine (132 mg) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired compound (395 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.CN(C)C1CCNCC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH:15]([N:8]([CH3:6])[CH3:9])[CH2:10][CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Agent: CN(C)C1CCNCC1
Product: CN(C)C1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using dimethylpiperidin-4-ylamine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as an orange solid (244 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH2:63])([CH3:54])[CH3:53]>CN(C)C=O>[C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH:63][C:5](=[O:7])[C:4]1[C:8]([S:16][CH3:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[O:2][CH3:1])([CH3:54])([CH3:51])[CH3:53]
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 1.1 g, 4.1 mmol) was dissolved in 40 mL dimethylformamide. N,N-Diisopropyl ethyl amine (763 mg, 5.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.57 g, 4.1 mmol) were added. After 5 minutes of stirring at room temperature [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) (993 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane ethyl acetate 100:0→1:1) yielded the title compound as a white solid (1.8 g, 100%), MS: m/e=449.2 [(M+H)+].
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].CC(O)=O>CO.O>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:8])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 1.3 h
Yield: 87.7 %

Procedure:
To a stirred solution of qinghaosu (I) (240 g, 0.85 mol) in 12 l MeOH was added NaBH4 (240 g, 6.34 mol) over a period of 2 h keeping the reaction mixture at 0°-5° C. After an additional stirring for 1.30 h under the same conditions, the mixture was neutralized with 375 ml AcOH maintaining the temperature in the range of 0°-5° C. and subsequently diluted with 24 l water. After stirring for 1 h at 0°-1° C., the white precipitate formed was collected and washed with 700 ml water-MeOH (2:1, 0°-5° C.) The filtrate was stirred for 14 h at 0° C. The small amount of material precipitated was collected and washed with H2O--MeOH (2:1, 2×30 ml). The wet crops were combined and dissolved in 7 l CH2Cl2. After drying on magnesium sulphate (120 g) and evaporation of the solvent, 212 g (88%) of (II) was obtained: mp 149°-153° C.