Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)Cl>[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COCC1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC1CN(c2ccc(C3CCN(C(C)=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
177.1 mg (0.61 mmol) of (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine were dissolved in 20 ml of methylene chloride and treated with 68.5 mg (0.67 mmol) of acetic anhydride in the presence of 53.1 mg (0.67 mmol) of pyridine. After stirring at room temperature for 18 hours the mixture was washed with water and the organic phase was dried over sodium sulfate. After filtration and evaporation of the filtrate the product was dried in a high vacuum. 197.3 mg of (RS)-1-acetyl-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine were obtained as a yellowish oil. 1H-NMR (CDCl3) ppm: 7.49 (d,2H), 7.20 (d,2H), 4.80 (m,2H), 4.05 (t, 1H), 3.92 (m,2H), 3.64 (d,2H), 3.43 (s,3H), 3.21 (m,1H), 2.68 (m,2H), 2.14 (s,3H), 1.85 (m,2H), 1.60 (m,2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([NH2:36])[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:40]1[CH:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH2:43][CH:42](OC)O1>>[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([N:36]1[CH:42]=[CH:43][C:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[CH:53][C:54]([C:57]#[N:58])=[CH:55][CH:56]=3)=[CH:47][CH:46]=2)=[CH:40]1)[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reactant: CC(C)(C)[C@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(=O)Nc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 42 %

Procedure:
According to the procedure described in Example 1(c) for the preparation N-(1,7-diaza-4-oxa-8-oxo-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)sucinnamic acid benzyl ester, crude 3(R)-amino-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt and 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile were condensed to give 75 mg (42%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester as an off-white powder, mp 115-6° C. 1H NMR: δ 8.42 (d, 2H, J=5.6 Hz), 7.72 (s, 2H), 7.58 (s, 2H), 7.50 (d, 2H, J=5.0 Hz), 7.31 (s, 2H), 7.26 (s, 7H), 7.12 (m, 1H), 6.85 (dd, 1H, J=2.5, 2.5 Hz), 6.64 (dd, 1H, J=1.6, 2.8 Hz), 6.25 (m, 1H), 5.20-5.10 (m, 3H), 4.15 (d, 1H, J=8.1 Hz), 3.39 (dd, 1H, J=5.5, 17.3 Hz), 3.25 (dd, 1H, J=7.9, 17.3 Hz), 0.94 (s, 9H). IR (KBr): 3331, 2959, 2225, 1735, 1687, 1655, 1602, 1559, 1511, 1288, 1203, 825cm−1. HRFABMS: Calculated for C35H37N4O4 (M+H+): 640.2924. Found: 640.2908. Anal. Calculated for C39H37N5O4•1.1 EtOAc: C, 70.76; H, 6.27; N, 9.51. Found: C, 70.73; H, 6.19; N, 9.16.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[O:31]1[CH2:34][C:33](=O)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH:33]5[CH2:34][O:31][CH2:32]5)[CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: O=C1COC1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C2COC2)C1)C3
Yield: 32.3 %

Procedure:
A mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), 3-oxetanone (38 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (55 mg, 41%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.31 (m, 1H), 7.01 (dd, J=11.5, 2.2 Hz, 1H), 6.88 (td, J=8.4, 2.3 Hz, 1H), 5.05-4.95 (m, 1H), 4.85-4.78 (m, 2H), 4.69-4.48 (m, 2H), 4.47-4.37 (m, 2H), 4.37-4.21 (m, 2H), 3.60-3.48 (m, 1H), 2.90-2.70 (m, 1H), 2.84 (s, 1.5H), 2.80 (s, 1.5H), 2.62 (s, 1.5H), 2.59-2.53 (m, 2H), 2.56 (s, 1.5H), 2.42-2.15 (m, 2H), 1.84-1.70 (m, 1H). HPLC (max plot) 99.5%, Rt 2.74 min. UPLC/MS: (MS+) 486.5 ([M+H]+).
Reaction SMILES: COC([C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][C:15]3[S:16][C:17]4[C:18]([N:23]=3)=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:10][C:8]=2[CH:9]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)[C:35]([O-])=[O:36].[Na+].[K+]>C(Cl)Cl>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:14][C:12]1[CH:11]=[CH:10][C:8]2[C:9]([CH2:35][OH:36])=[CH:5][O:6][C:7]=2[CH:13]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: OCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carboxylic acid methyl ester (6.0 g, 18.3 mmol) in DCM (183 mL) was added DIBALH (1 M in THF, 54.8 mL, 54.8 g, 54.8 mmol) and the reaction mixture was stirred (0° C., 1 h). The reaction mixture was treated with saturated aqueous Rochelle's salt (100 mL) and partitioned with DCM (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×100 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as yellow solid (4.9 g, 90%). MS (ESI): mass calcd. for C16H10N2O3S, 298.04; m/z found, 299.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.53 (dd, J=4.8, 1.7, 1H), 8.40 (dd, J=8.0, 1.7, 1H), 8.00 (s, 1H), 7.86 (d, J=2.1, 1H), 7.84 (s, 1H), 7.45-7.37 (m, 1H), 7.38-7.31 (m, 1H), 5.25 (t, J=5.5, 1H), 4.67 (dd, J=5.5, 0.8, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]1[CH2:20][CH2:19][CH2:18]1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(S)ccc1Br
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(SC2CCC2)ccc1Br
Temperature: 70 °C
Yield: 95.2 %

Procedure:
A stirred mixture of 4-bromo-3-fluorobenzenethiol (Preparation 26, 400 mg, 1.93 mmol), cesium carbonate (691 mg, 2.12 mmol) and bromocyclobutane (287 mg, 2.12 mmol) in DMSO (8 mL) was heated at 70° C. for 19 hours. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with 2-methoxy-2-methylpropane (30 mL), washed with water (30 mL), dried over sodium sulfate and concentrated in vacuo. This gave the title compound as a colourless oil 95% yield, 480 mg.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[Si:21]([O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([F:1])[F:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: OCC(F)(F)c1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-difluoro-2-(pyridin-4-yl)-ethanol (0.15 g) prepared in (2) in DMF (3.0 mL) were added imidazole (0.076 g) and tert-butyldimethylchlorosilane (0.15 g). The reaction mixture was stirred at RT for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: ethyl acetate) to give the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.44 g, 29.64 mmol) in DMF (100 mL) was added NaN3 (2.89 g, 44.46 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 9.84 g, 75.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.65 (s, 1H), 7.45 (m, 1H), 7.33 (m, 4H), 7.24 (m, 2H), 6.95 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Yield: 92.3 %

Procedure:
2.44 g (5.5 mmol) of methyl 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylate in 50 ml of ethanol were treated with a solution of 1.4 g (21 mmol) of potassium hydroxide (content 86%) in 50 ml of water. After boiling under reflux for 4 hours 200 ml of water were added and the mixture was adjusted to pH 1-2 with 2N hydrochloric acid while cooling with ice. The precipitate obtained was filtered off, washed with water and dried. There were obtained 2.16 g (92%) of 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylic acid as yellow crystals with m.p. 227-229° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 12, piretanide can be reacted with chloromethyl pivalate, triethylamine and sodium iodide in DMF to yield_t-butylcarbonyloxymethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:23]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Yield: 97.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (15.0 g), 1-(2-pyrimidyl)piperazine dihydrochloride (19.8 g) and potassium carbonate (42.0 g) in dimethylformamide (200 ml) was stirred at 80° C. for 8.5 hr. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (24.0 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-brown oil (18.7 g). The obtained pale-brown oil was crystallized from ethyl acetate: hexane (5:1, 100 ml) and the crystals were recrystallized from ethyl acetate:hexane (10:1, 100 ml) to give the title compound (12.8 g) as white crystals,
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[O:16]1[C:25]2[CH:24]=[C:23]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:38]2[CH2:37][CH2:36][CH:35]([N:27]([CH2:26][C:23]3[N:22]=[CH:21][C:20]4[O:19][CH2:18][CH2:17][O:16][C:25]=4[CH:24]=3)[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:40][CH2:39]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(Br)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.5 %

Procedure:
To 7.00 g of (7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, a solution of 10.07 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 140 mL of chloroform and 1.57 g of acetic acid were added, and the mixture was stirred at room temperature for 19 hours, then, 8.77 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred for 2 hours. To the reaction mixture, 140 mL of a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, then washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and gradient elution with hexane:ethyl acetate=50:50 to 5:95, and then recrystallized in 24 mL of ethanol to obtain 11.26 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (9.51 g, 24.9 mmol) was dissolved in CH2Cl2 (150 mL) and treated with isovaleraldehyde (2.7 mL, 24.9 mmol). The reaction was stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as the ice melted, and stir overnight. The reaction was diluted with CH2Cl2 (300 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 9.59 g (85%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][C:13](B(O)O)=[CH:12][CH2:11]1>>[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][C:13]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:12][CH2:11]1
Reactant: Nc1ccccc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CC1(C)CC=C(c2ccccc2N)CC1

Procedure:
The title compound was prepared by Suzuki coupling of 2-bromoaniline and 4,4-dimethyl-1-cyclohexen-1-yl boronic acid according to the procedure in Example 44, step (b). Mass spectrum (ESI, m/z): Calcd. for C14H19N, 202.1 (M+H), found 202.1.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH:8]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)C1CCNCC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cooled, solution of ethyl isonipecotate (78.5 g, 0.50 mole) and triethylamine (200 ml, 1.4 mole) in CHCl3 (1000 ml), triphenylmethyl chloride (15.33 g, 0.55 mole) was added. After stirring overnight at room temperature, the reaction mixture was washed with H2O, dried (Na2SO4) and the solvent evaporated. The oily residue was crystallized from MeOH-CHCl3, yielding 108.19 (96 percent) of 4-piperidine carboxylic acid, 1-(triphenylmethyl)ethyl ester as a white solid; mp 154°-155° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:28][CH:27]([OH:29])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:28][C@H:27]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.02 ml of methanesulfonyl chloride, followed by 3.65 ml of triethylamine were added, whilst ice-cooling, to a solution of 6.1 g of methyl 1-(t-butoxycarbonyl)-4-hydroxyprolinate [prepared as described in step (6) above] dissolved in 120 ml of dry tetrahydrofuran. The mixture was stirred first at 0° to 5° C. for 1 hour and then at room temperature for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 8.13 g of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[Cl:14].C[N+]1([O-])CC[O:19]CC1>O1CCOCC1.[Cl-].[Na+].O>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: COCCOc1ccc(Cl)c(CBr)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1ccc(Cl)c(C=O)c1
Temperature: 80 °C

Procedure:
To a solution of 2-(bromomethyl)-1-chloro-4-(2-methoxyethoxy)benzene from the previous step (1 eq.) in dioxane (0.2 M) was added 4-methylmorpholine N-oxide (3 eq.). The reaction mixture was heated at 80° C. The resulting solution was allowed to cool to RT, poured into brine and then extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→2:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[O:24][C:25]1[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=1[OH:31])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:27]=[C:26]1[O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]([OH:31])=[C:25]1[OH:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC2=C(O)[C@@H]([C@@H](O)CO)OC2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
2-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)ascorbic acid (300 mg, 0.6 mmol) was dissolved in methanol (10 ml), and to the solution was added a solution in which potassium carbonate (600 mg) had been dissolved in water (9 ml). The mixture was stirred for 30 minutes. The reaction solution was neutralized with AMBERLITE® IR-120 (H+), and filtered to remove the resin. The filtrate was washed successively with methanol and 50% aqueous methanol solution. The filtrate and the washing solution were combined, and concentrated, and then water was added thereto, followed by freeze-drying to obtain 2-O-β-D-glucopyranosyl)ascorbic acid as amorphous crystals (190 mg, yield: 100%). PMR (δ ppm, D2O); 3.1-3.3 (4H, m), 3.4-3.5 (3H, m), 3.58(1H d) , 3.80(1H, t), 4.61(1H, d), 4.66(1H, d). FABMS(−) m/z: 337.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH3:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:26]
Reactant: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCNCC1

Procedure:
A solution of methyl N-tert-butoxycarbonyl-4-(3-methyl-benzoyl)piperidine-4-carboxylate (77 mg) in ethyl acetate (10 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was stirred at 0° C. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound.