Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH3:47])=[C:37]([CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:38]1[C:39]([CH3:41])=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[CH3:48])[CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1c(C)cc(OB([O-])[O-])cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCOc1c(C)cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate crude crystals, which were collected by filtration, washed with ethyl acetate/hexane, recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 124) (0.32 g) as colorless crystal.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](O)CC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[C@H]2CC[C@@H](C)CC2)cc1

Procedure:
cis-4-Methyl-cyclohexanol (3.28 g, 28.7 mmol), NaH (1.09 g, 27.3 mmol, 60% suspension in mineral oil) and DMF (50 mL) were combined and sonicated as in general procedure L. The mixture was charged with 4′-fluoroacetophenone (2.18 mL, 17.8 mmol) and heated. After aqueous workup, the crude residue was purified on a silica gel column (gradient, hexane→2% EtOAc-hexane) to obtain 1-[4-(cis-4-Methyl-cyclohexyloxy)-phenyl]-ethanone (976 mg).
Reaction SMILES: BrC([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)C.[C:18]([O:24]CC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.[OH-].[K+].Cl>O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([CH:20]([CH3:22])[CH2:19][C:18]([OH:24])=[O:23])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 2-[1-(2',4'-biphenylyl)ethyl]butan-3-one acid ethyl ester, obtained by reacting 4-(1-bromoethyl)-2',4'-difluorobiphenyl with ethyl acetoacetate, and 15 ml. of 50% KOH are stirred for 45 minutes at 40° under N2. The mixture is cooled, diluted with water and brought to pH 10 with HCl. The reaction mixture is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](Cl)=[O:5].I.[CH3:8][N:9]([C:18]([S:20][CH3:21])=[NH:19])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.ClCCl>[CH3:1][S:2][CH2:3][C:4]([N:19]=[C:18]([N:9]([CH3:8])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:20][CH3:21])=[O:5]
Reactant: CSCC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
(Methylthio)acetyl chloride (5.6 g) was added portionwise to a solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboximidothioate hydroiodide (A) (10.4 g) in triethylamine (7.08 g) and dichloromethane (55 ml) and the mixture stirred at room temperature for 2 h. The mixture was washed with water and evaporated to give an oil which was chromatographed using 1:1 ether-petroleum ether (b.p. 60°-80°) followed by ether to give the title compound (4.6 g) as a cream solid, m.p. 68°-70°.
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:46])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][O:39]C2CCCCO2)[CH:36]=1)[CH3:13]>CO>[Cl:46][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:5])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][OH:39])[CH:36]=1)[CH3:13]
Reactant: C[C@@H](Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1)c1c(Cl)cncc1Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: C[C@@H](Oc1ccc2[nH]nc(/C=C/c3cnn(CCO)c3)c2c1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Charge a 3-neck, 250 mL round bottom flask equipped with an addition funnel, nitrogen inlet, internal temperature probe and magnetic stirrer with methanol (57 mL) and cool in an ice bath. To the resulting solution, add acetyl chloride (20 mL, 281.03 mmol) slowly through an addition funnel To the solution, add 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole (7.1 g, 11.59 mmol) dissolved in methanol (40 mL) via addition funnel. After addition is complete, remove the ice bath, warm to RT and stir the mixture for 4 hours. Concentrate the reaction mixture in vacuo to a yellow foam. Dissolve the yellow foam in methanol (10 mL) and add slowly to a saturated aqueous sodium bicarbonate solution (120 mL). Stir the mixture at RT for 30 minutes. Filter the mixture, wash the solid with water (100 mL), and dry under vacuum. Recrystallize the solid from hot EA/methanol/hexanes to give the title compound as a white solid. Yield: 2.1 g (41%). MS (ES) m/z 444 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in methylene chloride (5 mL) was treated with triethylamine (0.3 mmol), DMAP (0.01 mmol) and pivalyl chloride (0.15 mmol). The reaction was stirred for 3 h at room temperature and concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with water (2×5 mL). The organic layer was concentrated and the residue purified by Gilson reverse phase HPLC to provide the title product as a white powder (82%). ESMS [M+H]+: 563.2
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[C:11]([Br:18])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>O.O1CCOCC1>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:1])=[C:11]([Br:18])[CH:10]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1Br
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A solution of NaOH (7.8 g, 190 mmol) in water (60 mL) was cooled in an ice bath, and bromine (2.51 mL, 49 mmol) was slowly added. A solution of 1-(4-tert-butyl-2-bromophenyl)ethanone (3.1 g, 12 mmol) in dioxane (60 mL) was slowly added, and the cooling bath was removed. After being stirred at room temperature for 3 h the reaction was acidified with concentrated hydrochloric acid. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-tert-butyl-2-bromobenzoic acid (3.1 g, 100% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.3 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.41 (dd, J=8.3, 1.9 Hz, 1H), 1.34 (s, 9H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4].[CH2:31](I)[CH2:32][CH3:33]>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4]
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C#N)cn3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Sodium hydride (0.08 9, 3.16 mmol) was added to a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 264) (0.6 g, 1.58 mmol) in DMF (15 mL). The heterogeneous mixture was stirred at rt for 30 min. Propyl iodide (0.62 mL, 6.32 mmol) was added, and the mixture was stirred at rt for 18 h. The excess NaH was quenched by the addition of water (5 mL) and the aqueous phase extracted with Et2O. The combined Et2O extracts were washed with water and brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.63 g, 99%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.35 (dd, 1H), 7.54 (dd, 1H), 7.06 (d, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 4.17 (q, 2H), 3.99 (t, 2H), 3.72 (t, 2H), 3.56-3.44 (m, 3H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.46-2.35 (m, 2H), 2.12-2.05 (m, 2H), 1.72-1.58 (m, 3H), 1.28 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[N:4]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+]>O1CCCC1.O>[Cl:13][C:5]1[N:4]=[C:3]([CH2:2][O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: FC(F)(F)c1cc(Cl)nc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine (1.1 g, 4.1 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.0 g, 3.4 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. The reaction was treated with potassium tert-butoxide (763 mg, 6.8 mmol) portion wise. The reaction was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 837 mg (52%). 1H-NMR (CDCl3, 400 MHz) δ 7.31-7.38 (m, 6H), 7.18 (s, 1H), 4.48 (s, 2H), 3.74-3.79 (m, 2H), 3.50 (s, 2H), 2.99-3.06 (m, 2H), 2.21-2.25 (m, 2H), 1.83-1.86 (m, 2H), 1.42 (s, 9H). Mass spec.: 485.11 (MH)+.
Reaction SMILES: [CH2:1]([C:9](O)([OH:14])[C:10]([F:13])([F:12])[F:11])[C:2](O)([OH:7])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)O>>[CH2:1]([C:2]([C:3]([F:4])([F:5])[F:6])=[O:7])[C:9]([C:10]([F:11])([F:13])[F:12])=[O:14]
Reactant: OC(O)(CC(O)(O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Temperature: 80 °C

Procedure:
A 100-ml glass reaction vessel, equipped with a thermometer, a stirrer and a reflux condenser filled with glass spheres, was charged with 12.5 g of the obtained 1,1,1,5,5,5-hexafluoroacetylacetone dihydrate and 25 g of 98% sulfuric acid, while nitrogen gas was allowed to flow through the reaction vessel. Then, the mixture was gradually heated to 80° C. with stirring by a magnetic mixer. During this heating, 9.5 g of a distillate of about 70° C. were collected. This distillate was found by the same gas chromatography as that of Example 1 to be 1,1,1,5,5,5-hexafluoroacetylacetone having a purity of 99.9%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(C)N1CCC(N)CC1
Reaction time: 16 h

Procedure:
To 4.8 g (1-Isopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester in 15 ml methanol, 20 ml methanolic hydrochloric acid (8M) were added and the mixture was stirred for 16 h. Removal of the solvent under reduced pressure, followed by removal of residual volatiles by twice coevaporating with toluene, gave the product. Yield: 5.42 g. MS (ES+): m/e=143.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10](Br)=[CH:9][C:8](C(C2C=CC(CC)=CC=2)=O)=[C:7](Cl)[CH:6]=1)C=C.[CH2:23]([O:26][C:27]1[C:28]([Cl:40])=[C:29]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:30](N(OC)C)=[O:31])[CH:24]=[CH2:25]>>[CH2:23]([O:26][C:27]1[C:28]([Cl:40])=[C:29]([C:30]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:1])=[CH:6][CH:7]=2)=[O:31])[CH:36]=[C:37]([Br:39])[CH:38]=1)[CH:24]=[CH2:25]
Reactant: C=CCOc1cc(Cl)c(C(=O)c2ccc(CC)cc2)cc1Br
Reactant: C=CCOc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Product: C=CCOc1cc(Br)cc(C(=O)c2ccc(OC)cc2)c1Cl

Procedure:
Similar procedure with preparation of 31 proceeded except for using compound 182 to obtain the compound 183.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:20](=[CH:26][CH:27]=1)[C:21](=[O:22])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:24]2=[O:23])([O-:16])=[O:15]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: COC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (1.60 g, 42%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (2.00 g, 10.57 mmol) and 4-nitrophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[CH:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[N:5]=[C:4]([N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: Cc1cc(C2CC2)nc(N(N=CC(C)C)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C2CC2)nc(N(NCC(C)C)c2ccccc2)n1
Reaction time: 1 h

Procedure:
8.55 g (0.029 mol) of N-(4-methyl-6-cyclopropylpyrimidin-2-yl)-N-phenylisobutyraldehyde hydrazone are dissolved in 30 ml of methanol and 2 ml of glacial acetic acid. 2.14 g (0.029 mol) of sodium cyanoborohydride are then added in portions with stirring. The reaction proceeds exothermically; the temperature is maintained at 10°-15° C. by cooling. After 1 hour, the batch is worked up by extraction with ethyl acetate and water and the organic phase is concentrated using a rotary evaporator to give 8.5 g of crude product. Purification by column chromatography on silica gel (eluant: 85% hexane/15% ethyl acetate) affords 7.6 g (89% of the theoretical yield) of the title compound in the form of an oil having a refractive index of [n]D25 =1.5733.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][C:33]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45]>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:36][C:35]1[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[C:33]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:34]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOc1cc(CBr)ccc1OC
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C(C)C)ccc1OC
Temperature: -70 °C
Reaction time: 1.25 h

Procedure:
Under an inert atmosphere at -70° C. a solution of 4(R)-benzyl-3-isovaleroyl-oxazolidin-2-one (156.6 g) in tetrahydrofuran (500 ml) is added to a 1M lithium hexamethyldisilazide solution in tetrahydrofuran (600 ml, 0.60 mol) which has been diluted with anhydrous tetrahydrofuran (600 ml), and the batch is stirred for a further 75 minutes at -70° C. A solution of 4-methoxy-3-(3-methoxypropoxy)-benzyl bromide (145 g) in tetrahydrofuran (500 ml) is then added. The reaction temperature is allowed to rise from -70° C. to 0° C. over a period of 2 hours and the mixture is stirred at 0° C. for a further 18 hours. The reaction is quenched by the addition of a 10% aqueous ammonium chloride solution (250 ml) and the mixture is concentrated under reduced pressure and the aqueous phase is extracted with ethyl acetate (3×1.2 liters). The organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Purification of the residue by FC on silica gel (hexane/ethyl acetate 1:1) yields the title compound in the form of a white solid (202 g): m.p. 55°-56° C. (recrystallised from diethyl ether/hexane). Rf (ethyl acetate/hexane 1:2)=0.30. Anal. C27H35NO6 (469.58): calc. C, 69.06; H, 7.51; N, 2.98; found C, 68.64; H, 7.49; N, 3.12.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1)(=O)[CH3:2].[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:1]([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=2)[CH3:2])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(C(C)c2ccnc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 50 °C

Procedure:
To a suspension of tert-butyl 4-acetylpyridin-2-ylcarbamate (16-3, 187 mg, 0.79 mmole) in MeOH (3 mL) was added 1-acetylpiperazine (304 mg, 2.37 mmole), glacial HOAc (0.14 mL, 2.37 mmole), and NaBH3CN (149 mg, 2.37 mmole) then the mixture was heated to 50° C. After 6 hr additional NaBH3CN (149 mg, 2.37 mmole) was added and heating continued. After 18 hr the mixture was cooled to RT, diluted with saturated NaHCO3, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-10% EtOH/EtOAc) gave the titled compound as an oil: 1H-NMR (500 MHz, CDCl3) δ 8.17 (d, 1 H, J=5.13 Hz), 7.87 (s, 1H), 7.52 (bs, 1 H), 6.97 (d, 1 H, J=5.13 Hz), 3.64-3.57 (m, 2 H), 3.45-3.39 (m, 3 H), 2.49-2.35 (m, 4 H), 2.06 (s, 3 H), 1.54 (s, 9 H), 1.35 (d, 3 H, J=6.59 Hz).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9]1
Reactant: C=CC(=O)OC
Reactant: CN1CCNCC1
Product: COC(=O)CCN1CCN(C)CC1
Temperature: 0 °C

Procedure:
In a 500-mL 3-neck round bottom flask, 150.0 g (1.7 moles) of methyl acrylate is charged. The reactor is cooled to 0° C. using an ice bath. Then, 77.0 g (0.77 moles) of 1-methyl piperazine are added slowly to prevent overheating of the reaction mass. The temperature should be maintained below 50° C. by controlling the addition rate of 1-methyl piperazine. Overheating may cause polymerization of the excess methyl acrylate present in the reactor. Once the addition is completed, the mixture is agitated using a magnetic stirring bar and the temperature adjusted to 50° C. for at least 16 hours. Then, the reaction is allowed to cool to ambient temperature and the excess methyl acrylate is removed under vacuum. The final product is a light brown liquid at ambient temperature. The transformation is monitored with thin layer chromatography (TLC) using 9:1 CHCl3/MeOH. Complete conversion is apparent from the lack of olefinic protons in the 1H-NMR spectra. 1H-NMR (300 MHz, CDCl3): δ 3.20 (s, 3H), 2.12 (t, 7.3 Hz, 2H), 1.94 (m, 10H), 1.71 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.31, 54.00, 52.41, 51.78, 50.22, 44.92, 30.96.