Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:16])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
A suspension of 60% NaH (635.7 mg, 15.89 mmol) in THF (10 ml) was cooled to 0° C. To the mixture was added a solution of 2-t-butoxycarbonylamino-2-methyl-1-propanol (1.5398 g, 8.14 mmol) in THF (5 ml) dropwise, and stirred for 1.5 hours. To the mixture was added a solution of methyl iodide (0.50 ml, 8.03 mmol) in THF (5 ml) dropwise at 0° C., and stirred for 2.5 hours. The reaction mixture was added to water and extracted three times with ethyl acetate. The extract was dried over MgSO4, concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/1-0/1) to give the title compound (422 mg; 26%).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2occ(C(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
Methyl 3-isopropyl-1-benzofuran-5-carboxylate (1.20 g, 5.51 mmol) is dissolved in MeOH (20 ml) and water (4 ml), treated drop-wise with 2N NaOH (3.3 ml, 6.6 mmol) and stirred at RT for 2 days, then at 40° C. for 4 h. The volatiles are removed in vacuo, the residue is dissolved in water (10 ml) and the pH is adjusted to 3 with concentrated HCl. The resulting precipitate is isolated via filtration and dried overnight to afford 1.08 g (97%) of 3-isopropyl-1-benzofuran-5-carboxylic acid as a white solid. MS (ESI−) for C12H12O3 m/z: 203.0 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CCCCC2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclohexylmethyl-piperazine, yield 76%. White crystals, m.p. 265-266° C.; IR (KBr): ν 1732 (C═O) cm−1.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(-n2cnc3c([N+](=O)[O-])cccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(-n2cnc3c(N)cccc32)cc1
Reaction time: 26 h
Yield: 42.3 %

Procedure:
To a stirred solution of 4-(4-nitro-1H-benzimidazol-1-yl)benzonitrile (1.2 g, 4.54 mmol) in ethanol (100 mL) at rt was added Pd/C 10% (96 mg) in one portion and the mixture was stirred under a hydrogen atmosphere at normal pressure for 26 h. The suspension was filtered, and the solution was evaporated. Purification of the residue by flash chromatography yielded 4-(4-amino-1H-benzimidazol-1-yl)benzonitrile (0.45 g, 42.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cccc(S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(S(C)(=O)=O)c1
Yield: 63 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-5-methyl-4-(3-(methylsulfonyl)phenyl)pyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 63% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 3.09 (s, 3H), 2.43 (bs, 8H), 2.26 (s, 6H). MS (ESI): 452.3 [M+H]+, 226.8 [M+2H]2+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC3CCCCO3)cc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2Cl)CC1
Yield: 72 %

Procedure:
A mixture of tert-butyl 4-[2-chloro-4-(tetrahydropyran-2-yloxy)phenyl]piperazine-1-carboxylate (4.73 g, 11.9 mmol) prepared in Reference Example 193 and a catalytic amount of pyridinium p-toluene sulfonate in ethanol (50 ml) was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride and saturated sodium hydrogencarbonate aqueous solution were added to the residue, which was stirred for a while. The resulting precipitates were collected by filtration, and dried in vacuo to afford tert-butyl 4-(2-chloro-4-hydroxyphenyl)piperazine-1-carboxylate (2.68 g, yield 72%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester, 11, (1.0 g, 2.81 mmol) is dissolved in THF (30 mL) and the solution cooled to −78° C. A 5.0 M solution of borane-dimethyl sulfide complex in ether (1.2 mL, 5.61 mmol) is added dropwise. After 1 hour at −78° C., the reaction is quenched by slow addition of NH4Cl (sat. aq.) (10 mL). The cooling bath is then removed, and the mixture allowed to warm to room temperature with vigorous stirring. The THF is removed in vacuo and the residue diluted with water (50 mL). The mixture is extracted with ethyl acetate (2×100 mL), dried, filtered and concentrated in vacuo to give a yellow oil which is purified over silica (1:1 to 1:2 hexane/ethyl acetate to 100% ethyl acetate) to afford 731 mg (73% yield) as a clear, viscous oil.
Reaction SMILES: Cl.[C:2]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([N:9]1[CH2:10][CH2:11][C:12](=[O:13])[CH:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:8]1)=[O:17]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1CN(C(=O)C(C)(C)C)CCC1=O

Procedure:
To a mixture of 2.0 g of 3-carbethoxy-4-piperidone hydrochloride and 20 ml of 1M sodium carbonate is cooled in an ice bath and rapidly treated with 1.3 ml of trimethylacetyl chloride. Stirring is continued in the cold for 1.5 hours. The reaction mixture is filtered and the collected solid washed with water, air dried and then dried at 56° C. for 1.25 hours under high vacuum to afford 1.4 g of the desired product as a colorless solid, m.p. 46°-50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[N+]([O-])=O.[CH3:14][O-:15].[Na+]>CO>[CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)[n+]([O-])nc1OC

Procedure:
3-Methoxy-6-methyl-4-nitropyridazine 1-oxide (1 g) was converted and worked up analogously to example 1 g). Chromatography of the crude product was unnecessary. The solvent used was methanol (30 ml), and the base sodium methoxide (as 30% solution in methanol, 1.1 ml). Yield: 900 mg LC-MS Rt: 0.29 min [M+H]+:171.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[C:11]([CH:16](OC)[C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(c1c(F)ccc(OCc2ccccc2)c1Cl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OCc2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12
Yield: 84.5 %

Procedure:
A mixture of 3-[(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (P-1867, 0.1 g, 0.2 mmol), trifluoroacetic acid (0.6 mL, 8 mmol), and triethylsilane (0.3 mL, 2 mmol) in acetonitrile (10 mL) was refluxed for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide compound as an off-white solid (P-1852, 62 mg, 70%). MS(ESI) [M+H+]+=367.16.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([N:22]1[CH2:23][CH:24]=[C:25]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:26][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Reaction time: 15 h
Yield: 240.5 %

Procedure:
2.6 g potassium hydroxide are suspended in 25 ml of methanol and 2.5 g 1H-indole-6-carboxylic acid and 5.5 g 1-benzyl-piperidin-4-one are added. The reaction mixture is stirred for 15 hours at reflux temperature and then evaporated to dryness. The residue is combined with hydrochloric acid (1 M) and evaporated to dryness. The residue is treated with methanol and diethyl ether and the solid is suction filtered. 12.4 g product are obtained as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([C:43]([O:45]C(C)(C)C)=[O:44])=[N:15][C:16]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[C:22]([C:29](=[O:42])[NH:30][C:31]5[S:32][C:33]6[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=6[N:35]=5)[CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[CH:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([C:43]([OH:45])=[O:44])=[N:15][C:16]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[C:22]([C:29](=[O:42])[NH:30][C:31]5[S:32][C:33]6[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=6[N:35]=5)[CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[CH:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5cc(F)c(F)cc5s4)c3C2)ccc1-c1cnn(Cc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2cc(F)c(F)cc2s1)c1cccc2c1CN(c1ccc(-c3cnn(Cc4ccccc4)c3)c(C(=O)O)n1)CC2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 7D (0.085 g) in dichloromethane (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred overnight. The reaction mixture was concentrated and dried to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.98 (s, 1H), 8.20 (dd, 1H), 7.93-7.83 (m, 2H), 7.70 (d, 1H), 7.58 (dd, 2H), 7.47-7.19 (m, 7H), 6.94 (d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1S(Cl)(=O)=O.CN1C=CN=C1.[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([OH:38])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([O:38][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@H](O)COCc1ccc(OC)cc1
Agent: Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](COCc1ccc(OC)cc1)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 79.1 %

Procedure:
2.03 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.772 mL of 1-methylimidazole were added to a solution of 1.02 g of the (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 20 mL of acetonitrile at room temperature, and the obtained mixture was stirred at room temperature for 1.75 hours, and then at 40° C. for 1.25 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and a solid was removed by filtration. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentan al O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)nc4ccccc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
2-Methyl-quinolin-4-ol (213 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (7 mg, yield 2%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.58 g, 3.81 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopropylcarbamate (0.41 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopropylamino)carboxamide (0.53 g, 77%) as a white solid: mp 245-247° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.87-7.69 (m, 3H), 6.58 (t, J=5.7 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H) 5.19-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.65 (d, J=6.1 Hz, 2H), 2.96-2.83 (m, 1H), 2.64-2.40 (m, 3H), 2.08-2.04 (m, 1H), 0.62-0.55 (m, 2H), 0.40-0.34 (m, 2H); 3C NMR (DMSO-d6) δ 172.75, 169.82, 167.63, 167.04, 158.69, 141.11, 134.61, 133.26, 131.49, 126.94, 121.60, 48.83, 30.93, 22.37, 21.97, 6.59; Anal. Calcd. For C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.26; H, 4.82; N, 14.85.
Reaction SMILES: C[O:2][C:3](=[O:18])/[C:4](/[CH2:15][CH2:16][CH3:17])=[CH:5]/[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[OH-].[Li+]>C1COCC1.O>[C:9]1([S:6](/[CH:5]=[C:4](\[CH2:15][CH2:16][CH3:17])/[C:3]([OH:18])=[O:2])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(E)-3-benzenesulfonyl-2-propylacrylic acid methyl ester (5.0 g, 16.84 mmol) was dissolved in THF/water 3:1 (20 ml). Lithium hydroxide (0.86 g, 20.49 mmol) was added and the solution was stirred at room temperature overnight. The solvent was evaporated and the mixture was partitioned between ethyl acetate (50 ml) and water (40 ml). The aqueous layer was acidifed with 2M H2SO4 (6 ml) and the product was extracted into ethyl acetate (2×30 ml). The combined organic layers were washed with 2M H2SO4 (20 ml), brine, dried over magnesium sulfate, filtered and evaporated to give the title compound in 83% yield.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@H:13]2[C@H:18]([O:19][C:20]([CH3:22])=[O:21])[C@@H:17]([O:23][C:24]([CH3:26])=[O:25])[CH:16](OC(C)=O)[O:15][C@@H:14]2[CH2:31][O:32][C:33]([CH3:35])=[O:34])[C@H:9]([O:36][C:37]([CH3:39])=[O:38])[C@@H:8]([O:40][C:41]([CH3:43])=[O:42])[C@@H:7]1[O:44][C@H:45]1[O:50][C@H:49]([CH2:51][O:52][C:53]([CH3:55])=[O:54])[C@@H:48]([O:56][C:57]([CH3:59])=[O:58])[C@H:47]([O:60][C:61]([CH3:63])=[O:62])[C@H:46]1[O:64][C:65]([CH3:67])=[O:66])=[O:3].[BrH:68].CC(O)=O>C(Cl)Cl>[C:65]([O:64][C@@H:46]1[C@@H:47]([O:60][C:61](=[O:62])[CH3:63])[C@H:48]([O:56][C:57](=[O:58])[CH3:59])[C@@H:49]([CH2:51][O:52][C:53](=[O:54])[CH3:55])[O:50][C@@H:45]1[O:44][C@@H:7]1[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]([O:12][C@@H:13]2[C@@H:14]([CH2:31][O:32][C:33](=[O:34])[CH3:35])[O:15][C@H:16]([Br:68])[C@H:17]([O:23][C:24](=[O:25])[CH3:26])[C@H:18]2[O:19][C:20](=[O:21])[CH3:22])[C@H:9]([O:36][C:37](=[O:38])[CH3:39])[C@H:8]1[O:40][C:41](=[O:42])[CH3:43])(=[O:66])[CH3:67]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)O[C@@H]3COC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Maltotriose peracetate (71)36 (200 mg, 207 μmol) was taken up in DCM (1 mL) and 33% HBr/HOAc (0.7 mL) at 0° C. The mixture was stirred at 0° C. for four hours. The solution was diluted with DCM and washed with ice-water (×2), NaHCO3 (sat.) (×2) and brine (×1), before being dried (Na2SO4) and the solvent evaporated to yield the bromide 72 as white solid which was reacted on without further purification or characterisation.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[NH3:34]>>[NH2:34][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:30]=[CH:31][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:33])([F:32])[F:1])=[CH:8][CH:9]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1
Reactant: N
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Product: NC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4,4,4-trifluorobutoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (360 mg) prepared in Example 82 (82a) and ammonia (600 μL, 2 M methanol solution) to give 122 mg of the title compound (white powder).
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I.O>CS(C)=O>[CH:30]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]([CH3:35])[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:9])([CH3:32])[CH3:31]
Reactant: CI
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN(C(C)C)C(C)C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)N(C)CCN(C(C)C)C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.4 Parts of N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide is dissolved in 110 parts of dimethylsulfoxide. Then 0.24 part of sodium hydride, as a 56% suspension in mineral oil, is added. The mixture is stirred for 30 minutes at room temperature. 1.42 Parts of methyl iodide is added portionwise at room temperature and the resultant mixture is stirred overnight in a nitrogen atmosphere. The mixture is then poured into water and extracted with methylene chloride. The methylene chloride extract is dried over anhydrous calcium sulfate and stripped under reduced pressure to give N-(2-diisopropylaminoethyl)-6,7-dimethoxy-N-methyl-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.