Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH3:12][O:13][C:14](=[O:27])[C@H:15]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[NH2:16].CN1CCOCC1.Cl.[CH3:36][N:37]([CH3:54])[C:38]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43][CH2:42][CH:41]([CH2:44][C:45](O)=[O:46])[CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:12][O:13][C:14](=[O:27])[C@@H:15]([NH:16][C:45](=[O:46])[CH2:44][CH:41]1[CH2:40][CH2:39][C:38]([N:37]([CH3:54])[CH3:36])([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:42]1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 20.4 %

Procedure:
1-Hydroxybenzotriazole (546 mg, 4.0 mmol), L-tryptophan methyl ester hydrochloride (509 mg, 2.0 mmol) and N-methylmorpholine (0.666 ml, 6.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (596 mg, 2.0 mmol) in dry dimethylformamide under argon. Dicyclohexylcarbodiimide (834 mg, 4.0 mmol) was added at 0° C. and the mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the solid which had precipitated out (1.1 g), which comprised a mixture of dicyclohexylurea and the hydrochloride of the amide. The filtrate was added to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). The filtrate of the mixture was extracted by shaking with methylene chloride (3×50 ml) and, after drying, the organic phase was concentrated. An oily crude product was thereby obtained (660 mg), from which it was possible to obtain the product (188 mg) after purification by chromatography on silica gel with EA/methanol (4:1). The substance mixture which had precipitated out at the start of the working up was taken up in methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The organic phase was concentrated (517 mg) and separated by chromatography with EA/methanol (4:1), it being possible for a further fraction of the amide (357 mg) to be isolated. The total yield of the product was 59% (545 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C.S([Cl:29])(C)(=O)=O>C(Cl)Cl>[Cl:29][CH:12]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cl)c1cc(OC)c(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 139A (280 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.12 mL, 1.5 mmol). After stirring at rt overnight, the reaction was filtered, concentrated and purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 139B (268 mg, 89%).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.O>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:45][C:36]2[CH:37]=[CH:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:35]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(C=Cc2ccc3ccccc3c2)c1
Temperature: -30 °C
Yield: 83.9 %

Procedure:
In the step, 35.00 g (77.55 mmol) of (3-fluorobenzyl)triphenylphosphonium bromide was suspended in 150 ml of THF, and the suspension was cooled to −30° C. and added with 10.25 g (=88.61 mmols) of potassium t-butoxide under stirring. After the addition was finished, the reaction solution was stirred at the same temperature for 1 hour, a 50 ml THF solution of 8.65 g (=55.38 mmol) of 2-naphthoaldehyde was dropped into the same, and then the mixture was slowly heated to room temperature. After being stirred for 18 hours, the reaction mixture was added into iced water, and the mixture was extracted thrice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 43.34 g was purified with silica gel chromatography using heptane as the eluent to obtain 11.54 g of 2-[2-(3-fluorophenyl)vinyl]naphthalene as a white solid.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.[NH3:24]>>[NH2:24][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Reactant: N
Product: CCCOc1ccccc1-c1nc2nnc(N)nc2c(=O)[nH]1

Procedure:
5,6-Dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (0.7 g) was heated for 30 hours with ethanolic ammonia (50 ml) at 100° C. in a pressure vessel. The cooled mixture was filtered to give the crude product (0.21 g) which was recrystallized from ethanol to give the pure title compound, m.p. 322-325° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: O=C1CCCc2cc(S)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCCC2=O
Reaction time: 16 h

Procedure:
To a solution of 6-mercapto-3,4-dihydro-2H-naphthalen-1-one (3.5 g, 20 mmol) in acetonitrile (100 mL), under nitrogen atmosphere, was added %-chloromethyl-4-methyl-2-(4-trifluoromethylphenyl)thiazole (5.7 g, 20 mmol) followed by cesium carbonate (6.4 g, 20 mmol). The resulting mixture was stirred 16 h, diluted with water (100 mL). The precipitate was collected by filtration, dried, dissolved in EtOAc, and filtered through a plug of silica gel. The filtrate was concentrated under vacuum and the residue purified by recrystallization in iso-propanol to give 5.21 g (61%) of cream colored crystals. (mp 123–124° C.) Analyzed for C22H18F3NOS2: Calcd: C, 60.95%; H, 4.19%; N, 3.23%; Found: C, 60.79%; H, 4.09%; N, 3.09%.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C@@H:8]1[O:13][S:12](=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1.Cl.CC[O:25]C(C)=O>C(#N)C.O>[CH3:7][C@@H:8]1[O:13][S:12](=[O:25])(=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][CH2:9]1
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium periodate (341 g, 1.6 mol) is added to a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (250 g, 1062 mmol) in acetonitrile (2.5 L) and water (1.5 L) at 0° C. The pH of the mixture is adjusted to 7 by the addition of saturated Na2HPO4 solution. A solution of RuCl33H2O (2.20 g, 10.62 mmol) is added at 5° C. and the pH of mixture is kept at 7 by addition of saturated Na2HPO4 solution. The reaction is stirred at room temperature for 2 h. Water is added and pH is adjusted to 6 by addition of 2.0 M HCl solution. EtOAc (1.0 L) is added and the aqueous layer is separated and extracted with EtOAc (2×500 mL). The organic layers are combined, washed with saturated NaHCO3 solution and brine, dried (Na2SO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in hexane to afford the title compound (140 g, 52%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.C(OO)(=O)C>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCO
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)OO
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 35 °C
Reaction time: 8 h

Procedure:
144.5 G. of 2,4-diamino-6-chloropyrimidine are suspended in 2000 ml. of ethanol. While stirring, the suspension is warmed to 35° C. (about 15 minutes), the greater part of the substance passing into solution. The mixture is then cooled to 6°-8° C. and, at this temperature, there are added dropwise within the course of 40 minutes 175 ml. of 40% peracetic acid in glacial acetic. After completion of the addition, the mixture is stirred at 6°-8° C. for a further 30 minutes. The mixture is then left to warm up to room temperature and stirred at this temperature for 3 hours. 2000 Ml. of petroleum ether are then added, the mixture is left to stir for 1 hour and then left to stand overnight. The separated precipitate is filtered off, back-washed with 200 ml. of petroleum ether and dried under reduced pressure, there being obtained 2,4-diamino-6-chloropyrimidine-3-oxide. Recrystallization yields analytically pure product, having a melting point of 193° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:36]3[CH2:38][CH2:37]3)=[N:19][C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:21][C:22]=2[CH2:23][O:24][CH3:25])=[CH:11][C:10]=1[CH3:39])([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH:36]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[C:10]([CH3:39])[CH:11]=3)=[C:22]([CH2:23][O:24][CH3:25])[N:21]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[N:19]=2)[CH2:38][CH2:37]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Yield: 80.3 %

Procedure:
A solution of 215 mg (0.385 mmol) 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml 1N LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude residue was suspended in AcOEt/heptane 1:19. The resulting amorphous crystals were filtered off to provide 164 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:60])[CH3:59])[C@H:55]([CH:61]=O)[O:54][C:53]1([CH3:64])[CH3:63])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]([N:52]1[C@@H:56]([CH2:57][CH:58]([CH3:59])[CH3:60])[C@H:55]([CH:61]=[C:11]([CH:17]([CH3:18])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:54][C:53]1([CH3:63])[CH3:64])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C(C)C)P(=O)(OCC)OCC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C

Procedure:
123 mg of lithium chloride was suspended in 10 ml of dry tetrahydrofuran under an argon stream, and 0.69 ml of ethyl 2-diethylphosphono-3-methylbutanoate was added under stirring. The mixture was stirred for 5 minutes at room temperature, and then 2.7 ml of a 20% dry tetrahydrofuran solution of diazabicycloundecene was added thereto. The mixture was stirred at room temperature for 10 minutes. Then, 2.0 ml of a dry tetrahydrofuran solution of 773 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine was added thereto, and the mixture was stirred overnight at room temperature. A precipitated inorganic salt was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in 300 ml of benzene and washed with 200 ml of water. The separated aqueous layer was extracted with 75 ml of benzene. The organic solvent layer thus obtained was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (32 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (10/1) to obtain 623 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate as a colorless oily substance.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Br)o1
Reactant: Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Nc2ccccc2)o1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 5-bromo-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (1.0 mmol) in toluene (7.5 mL) was added aniline (1.3 mmol), tris(dibenzylidineacetone)dipalladium(0) (“Pd2 dba”) (Aldrich) (0.05 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (“BINAP”) (0.1 mmol), and potassium tert-butoxide (“t-BuOK”) (1.5 mmol), and the resulting mixture was refluxed overnight. The reaction was then cooled to room temperature, passed through a plug of silica and concentrated. Purification of the dark brown residue by HPLC afforded the product. Yield: 40%. MS: 362 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(N)cc1)c1ccccc1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3cc(F)ccc3C)cc1)c1ccccc1-2
Reaction time: 18 h

Procedure:
To a stirred solution of 0.235 g of 5,6-dihydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the dropwise addition of 2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H2O, saturated NaHCO3 and brine. The organic layer is treated with activated carbon, filtered through MgSO4 and the filtrate evaporated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ethyl acetate in methylene chloride to give 300 mg of the desired product as a white solid; Anal. Calc'd for C27H22FN3O2S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7; H,4.6; N,8.5; F,3.7; S,6.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11](Cl)[C@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:21]([NH:26][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:10]1[OH:20])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CCN
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCN[C@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O

Procedure:
Under argon a solution of (1R,2S,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (BOC-amino-cis-chlorohydrin) (500 mg) in anhydrous tetrahydrofuran was refluxed with isoamylamine (1.0 ml) and triethylamine (250 μl) for 5 hours at 90° C. The mixture was poured in aqueous 5% sodium bicarbonate and extracted with methylene chloride. The organic solution was dried over magnesium sulfate and evaporated under vacuum to yield an oil. Crystallization of this oil in hexane yielded the title compound as a white solid (270 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][CH2:32][CH2:33][CH:34]=O.C([BH3-])#N.[Na+].Cl>CO.C(OCC)C>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.7 g, 1.7 mmol) was dissolved in dry methanol. Butyric aldehyde (0.153 ml, 1.7 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) was added. A solution of anhydrous hydrogen chloride in diethylether (2 M) was added dropwise until pH 6. The resulting mixture was stirred for 24 hours at room temperature under a nitrogen atmosphere and evaporated in vacuo. Addition of 1M sodium hydroxide (50 ml), extraction of the product with diethylether (2×50 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo gave the title compound as a crude oil (0.644 g). Purification of the crude product on a silica gel column (Eluent: methylene chloride/methanol (19:1)) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-butylpyrrolidine (0.243 g, yield: 30%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g, 2.2 mmol) in dry CHCl3 (100 mL), NBS (0.320 g, 1.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (700 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A mixture of 8.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.1 g of potassium hydroxide and 100 ml of dimethylsulfoxide is stirred at room temperature for 30 minutes. Then, 4 g of 2-(dimethylamino)ethyl chloride hydrochloride are added to the mixture, and said mixture is stirred at room temperature for 20 hours. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is extracted with ethyl acetate, and the ethyl acetate layer is further extracted with 20% hydrochloric acid. The hydrochloric acid layer is alkalized with conc. aqueous ammonia, and the precipitated crystals are collected by filtration, washed with water and then dried. 6.4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[C:6]([CH2:14][C:15]([O:17]CC)=O)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.C(O)C>[C:7]1([C:6]2[O:13][N:4]=[C:15]([OH:17])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of sodium hydroxide was dissolved in 200 ml of water and 300 ml of ethanol. 69.5 g of hydroxylamine hydrochloride was added to the solution. A mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water was added to the solution so that the pH thereof was adjusted to 10.0. 192 g of ethyl benzoylacetate and a mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water were added dropwise to the solution at the same time under cooling with ice in such a manner that the pH thereof was 10±0.3. After the dropwise addition was finished, the solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture of 500 g of conc. hydrochloric acid and 500 g of ice. 2.5 l of ethanol was added to the reaction mixture. The reaction mixture was heated under reflux for 3 hours. 2 l of water was added to cool the solution. The resulting crystals were filtered off, washed with water, and dried. (Yield: 98 g (61%); m.p.: 150°-151° C.)