Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][S:11][C:10]=1[CH:17]([CH3:19])[CH3:18])=S)([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[C:1]([N:5]=[C:6]=[N:8][C:9]1[C:13]([CH:14]([CH3:15])[CH3:16])=[CH:12][S:11][C:10]=1[CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(C(C)C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1csc(C(C)C)c1N=C=NC(C)(C)C
Reaction time: 2 h

Procedure:
2.50 g of the 1-tert.-butyl-3-(2,4-diisopropyl-3-thienyl)thiourea obtained according to Example 2 and 2.60 g of 2-chloro-1-methylpyridinium iodide are introduced into 25 ml of acetonitrile and, at room temperature, a solution of 1.90 g of triethylamine in 12 ml of acetonitrile is added. The reaction mixture is then stirred for 2 hours at approximately +45° C. After evaporation of the solvent, the residue is taken up in hexane/water. The separated organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane-1:20). The title compound of formula ##STR13## is obtained in the form of a colourless oil, nD23 =1.5249 (compound No. 4.01).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2occc2-c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3occc3-c3ccccc3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (140 mg, 0.48 mmol) in dioxane (5.0 mL) and water (3 drops) was added 4,4,5,5-tetramethyl-2-(3-phenylfuran-2-yl)-1,3,2-dioxaborolane (270 mg, 1.00 mmol), K3PO4 (211 mg, 0.99 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) with stirring for 1 h at 95° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylate as a light yellow solid (140.0 mg, 73%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:14](=[O:19])[NH:15]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 mmol) (see Example 8, supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (31.2 mg) and CuI (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 7 h to yield (Z)-5-[2,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 86 mg, 90%).
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]-phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (351.3 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.28 g) at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol-diethylether=1:1), and recrystallized from ethanol to give N-[4-[hydroxy(1oxidopyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 167) (184 mg) as colorless crystals.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O=P(Cl)(Cl)Cl.[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[O:6]([C:5](=[CH:21][N:22]([CH3:24])[CH3:23])[CH:4]=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(COc1ccccc1)OCC
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccccc1

Procedure:
An appropriate phenol or substituted phenol (i.e., a compound suitable for forming the Y2 substituent of formula I) is reacted with a molar excess of chloroacetaldehyde diethyl acetal (ClCH2CH(OCH2CH3)2) in the presence of potassium hydroxide to form a phenoxyacetaldehyde diethyl acetal. This procedure is taught by Lipinski et al., J. Med. Chem., 23, 1026 (1980) which is incorporated herein by reference. The phenoxyacetaldehyde diethyl acetal is then added to a mixture containing POCl3 and DMF and heated for a period of time sufficient to form 2-(phenoxy)-3-dimethylamino-propenal which is then reacted with malonamide (i.e., CH2 (CONH2)2) in the presence of t-BuOK and DMSO. The desired, 5-(phenoxy-2-hydroxy-3-pyridinecarboxamide may then be collected by conventional techniques. The isolated pyridinecarboxamide is then added to phenylphosphonic dichloride followed by the addition of PCl5. The mixture is heated and the desired 5-(phenoxy)-2-chloro-3-pyridinecarbonitrile is isolated. This product may then be treated with the desired alkylmercaptan in NaOH to form the 5-(phenoxy)-2-(R-thio)- 3-pyridinecarbonitrile which may then be oxidized to the R-sulfinyl or R-sulfonyl form and/or to the 3-pyridinecarboxamide compound if desired.
Reaction SMILES: C[Li].[CH3:3][C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1.[CH3:9][C:10]([CH3:12])=O>>[CH3:3][C:4]1[CH:8]=[CH:7][C:6](=[C:10]([CH3:12])[CH3:9])[CH:5]=1
Reactant: CC1=CC=CC1
Reactant: CC(C)=O
Agent: [Li]C
Product: CC1=CC(=C(C)C)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
150 ml of methylcyclopentadiene dimer was fractionally distilled from 100 ml of mineral oil and at 62° C. and collected at 0° C. 500 mmol of methyl lithium (1.4M; diethylether) were added, dropwise, to a mixture of 500 mmol of freshly distilled methylcyclopentadiene and 137 ml of dry acetone at 0° C. The solution was stirred for 1 hour at 25° C. 8 g (85% yield) of 3,6,6-trimethylfulvene were recovered from the organic layer by vacuum distillation after an extraction with 100 ml of saturated, aqueous NH4Cl and drying over MgSO4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr
Yield: 79.9 %

Procedure:
A solution of 1-bromo-2-methyl-3-nitro-benzene (16.095 g, 74.5 mmol), 1-Bromo-pyrrolidine-2,5-dione (13.26 g, 74.5 mmol), benzoyl peroxide (180 mg, 0.74 mmol) in CCl4(100 ml) was heated under reflux overnight. After removing the solvent by using rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 1-bromo-2-bromomethyl-3-nitro-benzene as a yellow solid (17.55 g, 80%). 1H NMR (CDCl3, 300 MHz) δ: 4.89(s, 2H), 7.35(dd, 1H, J1=J2=8.1 Hz), 7.88(dd, 2H, J1=1.6 Hz, J2=8.1 Hz).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[N:15]1([CH:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=2)[CH2:14]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNC2)C1
Yield: 96.9 %

Procedure:
In a round-bottom flask, a slurry of benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate (0.765 g, 1.48 mmol) and Palladium (10%) on Carbon (0.200 g) in methanol (10 mL) was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas for 3 h. The flask was purged with Argon, then the mixture was filtered and concentrated to afford N-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (0.551 g, 97%) as an off-white solid. 1H-NMR (CDCl3) δ: 1.32-1.53 (m, 2H), 1.52-2.04 (m, 6H), 2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00 (m, 3H), 4.00-4.20 (m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.08 (s, 1H). MS m/z: 399 (M+1).
Reaction SMILES: C([O-])(=[O:3])C.[K+].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([CH3:19])[CH3:18])[CH2:16][O:15]1.C1OCCOCCOCCOCCOCCOC1>O.CC(N(C)C)=O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]([OH:3])([C:17]([S:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)([CH3:19])[CH3:18])[CH2:16][OH:15]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
A solution of 1.12 g (11.4 mmol) of potassium acetate in 2 ml of water was added to a solution of 2.0 g (5.7 mmol) of (±)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane and 0.15 g (0.57 mmol) of 18-crown-6 in 12 ml of DMA, and the mixture was stirred at 110° C. for 30 hours. After being allowed to cool, 50 ml of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried, and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) as an eluent. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and diethyl ether to obtain 1.58 g (75%) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)- 3-methylbutane-1,2-diol as a colorless crystal.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:22])[CH2:21][CH2:20]2)=[C:15]([Cl:23])[CH:14]=1.[Li]CCCC.CN(C=O)C>>[Cl:23][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[C:19]1([CH3:22])[CH2:21][CH2:20]1)[CH:8]=[O:9]
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC1(c2ccc(Br)cc2Cl)CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC1(c2ccc(C=O)cc2Cl)CC1
Yield: 63 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 4-bromo-2-chloro-1-(1-methylcyclopropyl)-benzene (350 mg, 1.43 mmol), n-BuLi (980 μl, 1.6M solution in hexane, 1.57 mmol) and DMF (443 μl, 5.70 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 3-chloro-4-(1-methylcyclopropyl)-benzaldehyde (176 mg, 63%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.69 (dd, J=1.5, 8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 1.38 (s, 3H), 0.90-0.80(m, 4H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: OCCc1cnccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1cnccn1
Reaction time: 1 h
Yield: 223.9 %

Procedure:
To a solution of 2-(2′-hydroxyethyl)pyrazine (0.91 g) in 30 mL dichloromethane at 0° C. was added carbon tetrabromide (2.65 g) followed by triphenylphosphine (2.1 g) portionwise. The solution became very dark. After stirring for 1 h the reaction mixture was adsorbed onto HMN diatomaceous earth and purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to give a cream solid (3.07 g) that was purified further by silica gel chromatography eluting with 0-50% EtOAc/pentane to give the sub-titled compound (0.47 g, 34%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: CCCN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])O
Product: CCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
N-propylphthalimide (50 g) was nitrated in 500 g 99% nitric acid to produce 4-nitro-N-propylphthalimide under conditions described in Example 2.
Reaction SMILES: [CH:1]1([C@H:7]([OH:22])[C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:9]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:27][NH2:28]>C1COCC1>[CH:1]1([C@H:7]([OH:22])[C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][NH:28][CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude (2S,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropanal (3.22 g, 10.7 mmol, calculated according to theoretical yield) was dissolved in anhydrous THF (20 mL). The solution was cooled to 0° C. Acetic acid (5.5 mL, 90 mmol), methylamine solution (33% in EtOH, 5.0 mL, 40.0 mmol) and NaHB(OAc)3 (8.80 g, 40.0 mmol) were added sequentially and in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione (6.45 g) was used directly in the next step.