Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][S:4]1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>[Cl-]>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][S:4]1)=[O:33])([CH3:20])[CH3:21]
Reactant: CCCCCC1=C(CCCCC)CC(CN)SC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Cl-]
Product: CCCCCC1=C(CCCCC)CC(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)SC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Part D. The amine product from Part C above (ca. 1.8 mmol) was dissolved inmethylene chloride (10 mL), and cooled to 0° C. The solution was treated with 2,6-diisopropylphenyl-isocyanate (0.50 mL, 2.10 mmol) by syringe. The mixture was allowed to stir for 12 hours, then evaporated, and the residue was separated by flash chromatography (7:93 ethyl acetate-hexane) to afford the title product as a solid, mp 65°-67° C. (490 mg, 1.04 mmol, 58%). 1H NMR (CDCl3): δ 7.40-7.07 (3H, m); 6.06 (1H, br s); 5.30 (1H, br s);3.61-3.46 (2H, m); 3.29 (2H, heptet, J=6.6 Hz); 3.19-2.87 (3H, m); 2.39-2.29 (1H, m); 2.08-1.96 (5H, m); 1.40-1.15 (24H, m); 0.88 (6H, t, J=6Hz); 0.87 (6H, t, J=6 Hz). 13C NMR (CDCl3): δ 157.9, 148.1, 131.1, 128.4, 128.0, 124.0, 123.4, 43.7, 40.0, 34.1, 33.9, 33.2, 32.0, 31.9, 28.6, 28.4, 28.3, 28.0, 25.6, 24.1, 23.9, 22.6, 14.1, 14.0. IR(KBr): 3320, 2960, 2928, 1638, 1590, 1556, 1466, 1362, 1256 cm-1. Massspectrum (NH3 -CI/DDIP): m/z 475 (10%); 474 (34%); 473 (100%); 381 (99%); 252 (2%). High-resolution mass spectrum: for C29H49N2OS, calculated 473.3566, measured 473.3566, difference 0 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:34]1(C)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>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.C(O)C>[C:34]1([CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]([F:27])([F:26])[F:15])[CH:14]=[CH:13][CH:12]=3)[CH2:7]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1ccccc1
Reactant: Brc1cccc(CN2CCOCC2)c1
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: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cccc(CN2CCOC(c3ccccc3)C2)c1
Temperature: 120 °C

Procedure:
100 mg of 4-(3-Bromo-benzyl)-morpholine was combined with 86 mg of 2-(Trifluoromethyl)phenyl boronic acid, 17 mg of tetrakis(triphenylphosphine)palladium(0), 1.0 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography using flash chromatography using an ethyl acetate/hexanes gradient. 122 mg of product was obtained. ES MS (+) m/z 398
Reaction SMILES: [S:1](=[O:3])=[O:2].[N:4]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5]1.[OH2:10]>>[OH:9][CH2:8][CH2:7][NH:4][CH2:5][CH2:6][S:1]([OH:10])(=[O:3])=[O:2]
Reactant: O=S=O
Reactant: O
Reactant: OCCN1CC1
Product: O=S(=O)(O)CCNCCO
Temperature: 10 °C

Procedure:
N-(β-hydroxyethyl)-2-aminoethanesulfonic acid, ##STR7## was prepared as follows: 2250 parts water was saturated with sulfur dioxide at 10° C. in a three-necked, round-bottom flask which was fitted with an electrical stirrer, thermometer, dropping funnel, and a gas inlet tube, 261 parts 1-aziridine-ethanol dissolved in 750 parts water was added via the dropping funnel while sulfur dioxide was bubbled into the flask and the temperature maintained at 10° C. After the addition was completed, the contents of the flask were concentrated to 600 parts and added to 3000 parts ethanol (F-30). The resulting solid was washed with 2000 parts ethanol, filtered, and dried to give 340 parts of the desired product.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[CH3:27])=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
1,1-dimethylethyl[(1R)-2-({6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 35, 60 mg) was dissolved in 4 mL of dry dichloromethane. To this solution, at 0° C., were added dropwise 40 equivalents of TFA (0.480 mL). The reaction was stirred for 3 hours 30 at 0° C. The reaction mixture was evaporated and then purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (49 mg)
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2N=CNC=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>C(Cl)(Cl)Cl>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][NH:42][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])=[CH:21][CH:20]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCC[Si](C)(C)C)c1ccc(C(=O)c2c[nH]cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.2 g. of 1-[4-[N-(tert-butyloxycarbonyl)-4-[14-(trimethylsilyl)tetradecylamino]benzoyl)imidazole, 50 ml. of chloroform, and 50 ml. of 5N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized to yield the product as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[CH:10]=1)(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:5][C:6](=[O:21])[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[CH:10]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1

Procedure:
The title compound was prepared from 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester (Example K13) by stirring in TFA/acetone with TFAA according to general procedure L (method b). Obtained as a beige solid (7.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=Cc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CCNCc2ccccc2Cl)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)-ethylamine (80.3 g, 0.443 mol) and o-chlorobenzaldehyde (62 g, 0.443 mol) are boiled (1 hour) in toluene (500 ml) using a water separator. The reaction mixture is evaporated, the oily residue is taken up in methanol (500 ml) and combined, under vigorous stirring and intensive cooling, with a solution of sodium borohydride (16.9 g, 0.443 mol) in water (50 ml). After it has all been added, the resulting mixture is stirred (1 hour) at ambient temperature, concentrated in vacuo and the residue is distilled in vacuo. Yield: 108.8 g. Bp16.9 Pa : 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27](O)([CH3:29])[CH3:28])[O:25][CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.P([Cl:46])(OCC)(OCC)=O.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C@@H:27]([CH2:29][Cl:46])[CH3:28])[O:25][CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc([C@H](C)CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
(S)—N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide (0.116 mmol, 0.05 g) was dissolved in DMF (5 ml) and triethylamine (0.255 mmol, 0.026 g) was added. Diethyl chlorophosphate (0.232 mmol, 0.040 g) was carefully added with a syringe. The resulting mixture was stirred at RT overnight. A mixture of ice and water was added and the mixture was neutralized with 1 M NaOH. The mixture was extracted twice with DCM. The combined organics were washed with water, dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.0047 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 2.04 (d, 6H), 4.29-4.36 (m, 1H), 4.38-4.46 (m, 1H), 4.54-4.66 (m, 1H), 6.64 (d, 1H), 7.39 (d, 1H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.72-7.75 (m, 1H), 8.17 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[NH:5])#[N:2].Cl.C(CC(=N)OCC)#N.Br[CH:17]([CH3:27])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=O.O>C(O)C>[NH2:5][C:4]1[NH:6][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:17]([CH3:27])[C:3]=1[C:1]#[N:2]
Reactant: CC(Br)C(=O)c1ccccc1F
Reactant: N#CCC(=N)N
Agent: CCOC(=N)CC#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N

Procedure:
To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2'- fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). the physical constants of this product were in agreement with those of the product obtained in Example 5-(1).
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:4]([OH:7])([F:6])[F:5].C(N(CC)CC)C.F[C:21](=[CH2:25])[C:22](F)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:7][C:4]([F:5])([F:6])[C:3]([CH3:12])([CH2:2][F:1])[C:8]([F:9])([F:10])[F:11])(=[O:23])[CH:21]=[CH2:25]
Reactant: CC(CF)(C(O)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(F)(F)C(C)(CF)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Into a 200-ml, four-necked glass flask provided with a thermometer, a dropping funnel, a stirrer and a reflux condenser were placed 58.83 g (0.3 mol) of hexafluoroneopentyl alcohol, 30.36 g (0.3 mol) of triethylamine and 50 g of chloroform. Subsequently, to the mixture was added dropwise 30.37 g (0.33 mol) of 2-fluoroacrylic fluoride at a temperature of up to 10° C. with ice-cooling. After addition, the mixture was stirred at room temperature for 30 minutes. The mixture was washed with an aqueous solution of sodium bicarbonate (5%) and then with pure water, followed by evaporation to remove chloroform, producing hexafluoroneopentyl acrylate. The amount of the obtained product was 67.17 g and the yield was 76.7%. To the product was further added 0.1 g of t-butyl catechol as a polymerization inhibitor and the mixture was distilled under reduced pressure for purification. The boiling point was 55° to 56° C./20 mm·Hg. The identification was performed with 1H-NMR spectrum, 19 F-NMR spectrum and 13C-NMR spectrum (in every case, sovent: acetone-d6).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:3])=[O:2].[CH:12](=[O:15])[CH2:13][CH3:14].CC(O)C>CCCCCC>[CH:6]1([C@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[C@H:13]([CH3:14])[CH:12]=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC=O
Reactant: O=[N+]([O-])/C=C/C1CCCCC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])C1CCCCC1

Procedure:
The title compound was prepared from (E)-(2-nitrovinyl)cyclohexane and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=1:99), 1 mL/min, tmajor=17.0 min, tminor=19.1 min, the diastereomeric ratio was determined by
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH3:23])[C:18]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)[CH2:4]1.C(=O)([O-])O.[Na+].Cl.[C:39](=[NH:44])(OCC)[CH3:40]>O1CCCC1.O>[ClH:1].[ClH:1].[C:39]([N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH3:23])[C:18]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:17]=4[N:16]=3)=[CH:31][CH:32]=2)[CH2:4]1)(=[NH:44])[CH3:40]
Reactant: CCOC(C)=N
Reactant: COCCn1c(COc2ccc(OC3CCNC3)cc2)nc2cc(C(=N)N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCn1c(COc2ccc(OC3CCN(C(C)=N)C3)cc2)nc2cc(C(=N)N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 167.6 %

Procedure:
To a solution of 2-[4-(pyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine dihydrochloride (44 mg) in a mixture of tetrahydrofuran (2 ml) and water (0.6 ml) were added sodium hydrogencarbonate (38 mg), and ethyl acetoimidate hydrochloride (33 mg), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. The obtained residue was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). To the obtained residue was added dil. hydrochloric acid and the solvent was evaporated and dried under reduced pressure to give the title compound (40 mg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH:12]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])Cl)(C(C)(C)C)(C)C.[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][NH:32]1.C(Br)C=C.C(N(CC)C(=O)C1C=CC=CC=1)C>>[CH3:30][C@H:31]1[CH2:36][NH:35][C@@H:34]([CH3:37])[CH2:33][N:32]1[CH:12]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[O:18])[C:11]1[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=1
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: CCN(CC)C(=O)c1cccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCN(CC)C(=O)c1ccccc1
Solvent: C=CCBr
Product: CCN(CC)C(=O)c1cccc(C(c2cccc(O)c2)N2C[C@H](C)NC[C@@H]2C)c1

Procedure:
3-(α-((2S,5S)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was prepared as a mixture of epimers from 3-(3-((tert-butyldimethylsilyl)oxy)-α-chlorobenzyl)-N,N-diethylbenzamide (Example 1, infra) and (+)-(2S,5S)-2,5-dimethylpiperazine [prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described by Jung and Rohloff (J. Org. Chem. 50, 4909-13 (1985))] according to the methods of Example 1. This material was then alkylated with allyl bromide by methods similar to that in Example 4 to give a mixture of diastereomers that was separated by chromatography on silica gel (Waters Prep 500A, 0.1% triethylamine in dichloromethane). The first isomer to elute was deprotected by the method in Example 4 to give 3-((αR or αS)-α-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. NMR (DMSO-d6, 200 MHz): δ0.890 (d, J=5.6 Hz, 3H); 0.981 (d, J=6.4 Hz, 3H); 1.00-1.25 (m, 6H); 2.10-2.48 (m, 4H); 2.59 (d, J=11.1 Hz, 1H); 2.73 (dd, J1 =7.8 Hz, J2 =14.1 Hz, 1H); 2.90-3.60 (m, 6H); 4.54 (s, 1H); 5.13 (d, J=9.0 Hz, 1H); 5.19 (d, J=16.2 Hz, 1H); 5.84 (m, 1H); 6.58 (d, J=8.0 Hz, 1H); 6.86 (s, 1H); 6.88 (d, J=7.1 Hz, 1H); 7.08 (t, J=7.6 Hz, 1H); 7.14 (d, J=7.8 Hz, 1H); 7.34 (t, J=7.6 Hz, 1H); 7.43 (s, 1H); 7.48 (d, J=7.7 Hz, 1H); 9.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O>C1(C)C=CC=CC=1>[CH3:27][Si:26]([N:1]([Si:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Yield: 92.6 %

Procedure:
About 9.24 g of ethyl 4-aminobenzoate, 14.88 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 32.68 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 8 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 4-[bis(trimethylsilyl)amino]benzoate (4-BTMSAEBz) as a yellow oil (16.04 g, 93% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet, 2 H, aromatic protons), 6.76 (doublet, 2 H, aromatic protons), 4.12 (quartet, 2 H, CH2 protons), 1.00 (triplet, 3 H, CH3 protons), 0.02 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: Br[C@@:2]1([O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:14]([O:15][CH:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:4]1[O:5][C:6](=[O:8])[CH3:7])O.CC1C=C(C)C=C(C)N=1.[Br:55][CH2:56][CH2:57][OH:58]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:6]([O:5][C@@H:4]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:14]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:2]1[O:58][CH2:57][CH2:56][Br:55])(=[O:8])[CH3:7]
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: OCCBr
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 23 h
Yield: 76.2 %

Procedure:
A solution of the crude acetobromo sugar 49 (20.5 g; 29.3 mmol) in dry methylene chloride (100 ml) was added dropwise (ca 20 min) to a cold (-78°) solution of silver trifluoromethanesulfonate (nonpurified, commercial material; 10.3 g; 40 mmol), 2,4,6-tri-methylpyridine (3.6 g; 30 mmol) and 2-bromoethanol (17.5 g; 140 mmol) in methylene chloride (250 ml) under nitrogen. The reaction mixture was stirred in the dark for 23 h during which time it had reached room temperature. The yellowish-white precipitate, that had formed, was removed and the resulting colorless solution was washed consecutively with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water. Drying (sodium sulfate), filtration and evaporation gave a residue which crystallized spontaneously. Recrystallization from ethyl acetate, followed by evaporation of the mother liquor and recrystallization from methanol, gave a total of 16.6 g (77%) of the title compound 15. Melting point and optical rotation are shown in Table 1 and the 13C- and 1H-NMR data are shown in Table 2 and 3 , respectively.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19](Cl)(=[O:21])=[O:20])=[CH:14]2.C(N(C(C)C)CC)(C)C.ClC1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH:1]1([NH:7][S:19]([C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[Cl:8])[CH:14]=2)(=[O:20])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Reactant: NC1CCCCC1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NC1CCCCC1)c1ccc2c(Cl)cccc2c1
Reaction time: 8 h

Procedure:
The title compound was prepared from the coupling of cyclohexylamine and 5-chloro-2-naphthalenesulfonyl chloride. Cyclohexylamine (1.0 g, 3.8 mmol) and diisopropyl ethylamine (1.35 ml, 7.7 mmol) were dissolved in 30 ml chloroform. 5-Chloro-1-naphthalenesulfonyl chloride (0.88 m., 7.7 mmol) in 20 ml chloroform was added dropwise to the solution. After stirring overnight, the CHCl3 solution was washed with saturated sodium bicarbonate solution and brine. Drying over magnesium sulfate and evaporation of the CHCl3 followed by recrystallization with isopropyl ether/methanol gave 0.92 g (75% yield) of a yellow solid: mp 133°-134° C.; 1H NMR (CDCl3): 8.48 (d, J=1.8, 1 H, H1), 8.38 (d, J=9.0, 1 H, H3), 8.00 (d, J=9.0, 1 H, H4), 7.88 (d, J=8.3, 1 H, H6), 7.71 (d, J=7.5, 1 H, H8), 7.51 (t, J=7.8, 1 H, H7), 5.07 (d, J=7.7, 1 H, NH), 3.23-3.15 (m, 1 H, NHCH, 1.77-1.72 (m, 2 H, ring H's), 1.61-1.55 (m, 2H, ring H's), 1.51-1.45 (m, 1H, ring H), 1.22-1.10 (m, 6H ring H's); anal. calcd. for C16H18NO2SCl; C, 59.34; H, 5.60; N, 4.33; found: C, 59.27; H, 5.60; N, 4.30.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].S(Cl)([Cl:11])=O.[C:13]1([CH3:19])C=CC=CC=1>>[ClH:11].[Cl:11][CH2:13][CH2:19][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: ClCCN1CCOCC1
Reaction time: 12 h
Yield: 55 %

Procedure:
Into 5 g (57 mmol) morpholine dissolved in 15 ml toluene, 4.6 ml (69 mmol) of 2-chlorohydrin was added dropwise. The mixture was heated to the reflux temperature and reacted for 5 h. After cooling, 20 ml of 5% NaOH solution was added to wash the reaction mixture. The organic layer obtained was washed with a saturated saline solution and dried over anhydrous sodium sulfate, then filtrated. Into the filtrate cooled in an ice bath, 8.3 ml (114 mmol) of thionyl chloride was added dropwise. After reacting for 12 h at room temperature, the reaction mixture was concentrated to dry in reduced pressure. The residue was recrystallized with ethyl acetate to obtain 5.9 g white solid with the yield of 55%. m.p. 182-184° C.