Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].CN1CCOCC1>C1COCC1.CCOC(C)=O>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) in THF (2 ml) was treated with methyl bromoacetate (55 μl, 0.57 mmol) and NMM (63 μl, 0.57 mmol) and stirred at room temperature, under a nitrogen atmosphere for 3 days. The reaction mixture was diluted with EtOAc and washed with H2O followed by brine, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (5:95) gradually changing to (50:50) to afford the title compound as a colourless oil (170 mg, 70%).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.O1CCOCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1NC(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (768 mg) in tetrahydrofuran (8 ml) was added 4N hydrogen chloride solution in 1,4-dioxane (8 ml) at 0° C., and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue was diluted with chloroform and water. The mixture was basified with aqueous solution of sodium hydroxide (1N) and the organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give methyl 4′-[2-(benzylamino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (600 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[O:26]1[CH2:29][C:28](=[O:30])[CH2:27]1>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([C:28]3([OH:30])[CH2:29][O:26][CH2:27]3)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccn(COCC[Si](C)(C)C)n1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C2(O)COC2)n(COCC[Si](C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Into a 5 L 4-necked round-bottom flask under nitrogen was placed 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (132.0 g, 452.89 mmol, 1.00 equiv.) in THF (2 L), followed by the addition of butyl lithium (208 mL, 2.4 M, 1.10 equiv) dropwise with stirring at −78° C. over 15 min. The resulting solution was stirred at −50° C. for 40 min. To this was added a solution of oxetan-3-one (40.0 g, 555.07 mmol, 1.20 equiv) in THF (500 mL), dropwise with stirring at −78° C. over 30 min. The resulting solution was stirred at −78° C. for 30 min then quenched by the addition of 2 L of satd. aq. NH4Cl. The mixture was concentrated in vacuo and extracted with 3×1 L of EtOAc. The combined organic layers were washed with 2×1 L of water and 1×500 mL of brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:20-1:5) to afford 3-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl]oxetan-3-ol (142.0 g, 82% yield) as a light yellow oil.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CC(C)(N)CN>O.C(O)(C)(C)C>[C:8]([O:7][C:1]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCCNC1
Agent: CC(C)(N)CN
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Reaction time: 16 h

Procedure:
Di-t-butyl carbonate (11.9 g.) was added to a solution of 3-hydroxypiperidine (5.0 g.) in water (10 ml.) and t-butanol (5 ml.) at ambient temperature, and the mixture was stirred for 16 hr. at ambient temperature. 1,1-Dimethylethylenediamine (1.5 ml.) was added and the mixture was stirred at ambient temperature for 1 hr. The solution was poured into water (150 ml.) and extracted with diethyl ether (3×50 ml.). The diethyl ether extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (50 ml.), and then dried (MgSO4). The solvent was evaporated to give 1-t-butoxycarbonyl-3-hydroxypiperidine, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([Br:33])[S:14](=O)[C:13]=2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(Cl)(Cl)Cl.ClCCl.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([Br:33])[S:14][C:13]=2[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1C(Br)=C(Oc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc21
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-1-oxo-1H-1λ4-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (22.36 g, 40.3 mmol) in methanol (160 mL) and chloroform (80 mL). Add a 30% solution of titanium trichloride in aqueous HCl (31.4 mL, 80.6 mmol) and stir at ambient temperature for 2 hours. Quench reaction mixture with saturated aqueous sodium bicarbonate (500 mL) and dilute with dichloromethane (500 mL). Separate layers and wash the organic layer with saturated aqueous sodium bicarbonate (500 mL), water (500 mL), and brine (500 mL). Dry with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol (containing 10% NH4OH) in dichloromethane (0 to 2%) to give 19.2 g of the title compound (88%).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](Cl)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 3.0 g of product from Example 87 is added 50 ml of methylene chloride, 0.829 g of 2-(aminomethyl)pyridine and 2.31 g of pyridine. The reaction is stirred at 0° C. for 3 hours; followed by 20 hours at room temperature. The mixture is poured into chloroform and saturated sodium bicarbonate. The aqueous layer is extracted with chloroform and the combined chloroform layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 75% ethyl acetate/hexane) to give 2.90 g of the desired product as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[O:22][CH2:21]1.O>CO>[OH:22][CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: C1CO1
Solvent: O
Solvent: CO
Product: OCCN1CCOC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
The mixture of 6.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine, 1.2 g of ethylene oxide, 0.5 ml of water and 20 ml of methanol is stirred at 40°-45° for 4 hours and at 50° for 2 1/2 hours. It is cooled, the precipitate formed, filtered off and recrystallized from benzene-hexane, to yield the 4-(2-hydroxyethyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 122°-123° (its hydrochloride melts at 190°-192° ).
Reaction SMILES: C1(S(CC2C(C(O)=O)=C(OCCNC(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:36]1([S:42]([CH2:45][C:46]2[C:51]([C:52]([O:54]C)=[O:53])=[C:50]([O:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:49]([C:68]3[CH:72]=[CH:71][O:70][CH:69]=3)=[CH:48][CH:47]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([S:42]([CH2:45][C:46]2[C:51]([C:52]([OH:54])=[O:53])=[C:50]([O:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])[C:49]([C:68]3[CH:72]=[CH:71][O:70][CH:69]=3)=[CH:48][CH:47]=2)(=[O:44])=[O:43])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Product: CC(C)(C)OC(=O)NCCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 6-(benzenesulphonylmethyl)-2-(3-t-butoxycarbonylaminopropoxy)-3-(furan-3-yl)benzoate (Intermediate 109).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(dimethylamino)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 76) (200 mg, 0.51 mmol) and N-methylmorpholine (112 μl, 1.00 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (79 μl, 0.69 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (85 μl, 0.61 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2×25 ml) and brine (25 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a foam (180 mg).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:43])[CH2:40][C:41]#[N:42])[CH2:35][CH2:34]1.C(O)(=O)C.N1CCCCC1>C(O)C>[N:36]1([C:39]([C:40](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:10]4=[N:11][CH:12]=3)=[CH:18][CH:19]=2)[C:41]#[N:42])=[O:43])[CH2:37][CH2:38][O:33][CH2:34][CH2:35]1
Reactant: N#CCC(=O)N1CCOCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Yield: 55.6 %

Procedure:
To a 50 ml three necked round bottom flask 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.00055 mole) and 3-morpholino-3-oxopropanenitrile (0.34 g, 0.0022 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (1.0 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 4 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified using column purification by eluting the compound with 40-50% ethyl acetate in hexanes to yield 0.18 g of 2-(morpholine-4-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile which was converted to the title compound using the procedure described in Example 1, Step 2 above.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[N:34][C:29]=2[CH:28]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N(Cc2nc3cc(F)ccc3[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 25.7 %

Procedure:
A mixture of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.50 g, 1.47 mmol) and 4-fluorobenzene-1,2-diamine (0.15 g, 1.18 mmol) in anhydrous toluene (20.0 mL) was refluxed overnight under N2. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give the title compound (0.13 g, 22%): mp 138-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.47-7.39 (m, 1H), 7.32-7.22 (m, 2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H), 5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 179.2, 161.3, 158.1, 156.2, 149.2, 149.1, 142.5, 141.2, 131.5, 129.5, 124.4, 124.0, 118.0, 111.6, 111.2, 109.9, 103.1, 101.7, 93.5, 80.5, 58.5, 38.9; MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[OH:32][CH2:33][CH:34]1[CH2:42][CH:41]2C(CNC2)[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])([OH:43])[CH2:35]1.C(N(C(C)C)CC)(C)C>ClCCl>[OH:32][CH2:33][CH:34]1[CH2:42][CH:41]2[CH:11]([CH2:12][N:8]([C:1](=[O:2])[CH:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:27]=3)[CH2:9]2)[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])([OH:43])[CH2:35]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CC2CNCC2C(O)(c2ccccc2F)C1
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C(OCc1ccccc1)c1ccccc1)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
0.54 g of carbonyldiimidazole is added to a solution of 0.8 g of 2-benzyloxyphenylacetic acid in 10 cm3 of dichloromethane, cooled to 0° C. The mixture is stirred at this temperature for 2 hours and then 0.8 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol hydrochloride and 1.04 cm3 of diisopropylethylamine are added. The reaction mixture is stirred at room temperature for 18 hours, and then the organic phase is washed with 10 cm3 of water, then with 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with ethyl acetate and collecting fractions of 25 cm3. Fractions 18 to 50 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.72 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-(benzyloxyphenylacetyl)perhydroisoindol-4-ol is obtained in the form of a thick white foam.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:17])[C:5]=2[NH:4][N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])[CH2:31][CH2:30]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:17])[C:5]=2[N:4]([C:18](=[O:21])[CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=3[CH3:44])[CH2:31][CH2:30]2)[N:3]=1
Reactant: Cc1cc(C)c(CN2CCN(C(=O)CCCl)CC2)c(C)c1
Reactant: Nc1n[nH]c2c1CCN(c1ccccc1)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)c(CN2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(c3ccccc3)CC4)CC2)c(C)c1

Procedure:
A target compound (92.7 mg, 0.185 mmol, 35.3%) was yielded in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-phenyl-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (120 mg, 0.525 mmol) with potassium carbonate (108.7 mg, 0.787 mmol) and 3-chloro-1-{4-(2,4,6-trimethylbenzyl)piperazin-1-yl}propan-1-one (178.2 mg, 0.577 mmol).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[CH3:11][N:12]([C+:14]([N:16]([CH3:18])[CH3:17])Cl)[CH3:13]>O>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[CH3:11][N:12]([CH3:13])[C:14]([N:16]([CH3:18])[CH3:17])=[N+:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: CCNCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CC[N+](CC)=C(N(C)C)N(C)C

Procedure:
3.42 g (46.8 mmol) of diethylamine are added with stirring and ice-cooling to 5.00 g (21.3 mmol) of bis(dimethylamino)chlorocarbenium perchlorate. The reaction mixture is subsequently stirred for 1 hour at room temperature and subsequently added to 20 ml of water. The organic phase is separated off and washed with 20 ml of water. The liquid is subsequently dried at 50° C. under reduced pressure (7.0 Pa), giving 5.17 g of N,N,N′,N′-tetramethyl-N″,N″-diethylguanidinium perchlorate, corresponding to a yield of 89.6%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:5][N:6]=1
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Sc2cnc(N)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 2-amino-5-(4-aminophenylthio)thiazole, (4.0 g) in a mixture of acetic acid (40 ml) and acetic anhydride (2.2 g) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-acetylaminophenylthio)thiazole (2.1 g, yield: 44.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CN(C1C=CN=CC=1)C.O>[Cl:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:12][C:10]2[S:11][C:7]3[C:6]([C:13]4[N:14]=[C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[S:16][CH:17]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.165 g of 4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-ylamine (0.00047 Mol) were dissolved in dioxane (5 ml) and combined with 0.1 ml of triethylamine (0.0007 Mol), 0.006 g DMAP (0.000047 Mol) and a solution of 0.116 g of 4-(chlormethyl)benzoylchlorid (0.00062 Mol) in dioxane (1 ml). The reaction mixture was stirred for 6 hrs. at 70° C. After cooling down to room temperature, water (10 ml) and sat. NaHCO3 (10 ml) were added. A precipitation formed. It was filtered, washed with water and tried. This crude product was subjected to column chromatography (silicagel, CH2Cl2/MeOH 19:1). The title compound was obtained as a light yellow solid (65%); F.p.: 166-168° C.