Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH:11][CH2:12][C:13](=O)[CH3:14]>[Pd].CO>[OH:11][CH2:12][CH:13]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([F:9])[C:2]=1[F:1])[CH3:14]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: CC(=O)CO
Agent: [Pd]
Solvent: CO
Product: CC(CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
2,3,4-Trifluoroaniline was reductively alkylated in the presence of hydroxyacetone using a palladium on carbon catalyst. 30 g of a 5% Pd/C catalyst (57.3% H2 0)) was slurried in 200 ml of absolute methanol. The mixture was allowed to settle and 90-95% of the liquid was decanted. The process was then repeated three times. 2,3,4-trifluoroaniline (118 g, 0.8 mole) of was charged into a glass autoclave liner containing the catalyst. Hydroxyacetone (80 g, 1.08 mole) was then added and the mixture was purged with nitrogen. Hydrogenation was initiated at 65° C. and continued to a maximum temperature of 107° C. Hydrogen uptake continued for one hour at a pressure of between 430 and 450 psi at which time 75% of the alkylated product (3) was obtained with the remainder being unreacted 2,3,4-trifluoroaniline and hydroxyacetone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=1>>[Br:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:22]=1
Reactant: ClCc1csc(Br)n1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-bromo-4-(chloromethyl)-1,3-thiazole (Example 311A): MS (ES) m/z 400 (M+1) and 402 (M+1, isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18]C)([CH3:10])[CH3:9])[CH:7]=1.C(C1C=C(F)C=CC=1O)(C1C=C(F)C=CC=1O)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])([CH3:10])[CH3:9])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)c1cc(Cl)ccc1O
Agent: CC(C)(c1cc(F)ccc1O)c1cc(F)ccc1O
Product: CC(C)(c1cc(F)ccc1O)c1cc(Cl)ccc1O

Procedure:
2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-hydroxyphenyl)propane (m.p. 125° C.) was prepared from 2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane following the method described in Example 3 for the preparation of 2,2'-isopropylidene bis(4-fluorophenol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>CC(C)=O>[CH3:15][O:16][CH:17]([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:19]
Reactant: COC(C)C(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CC(C)=O
Product: COC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 70.6 %

Procedure:
20.3 g (107 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone were stirred with 14.7 g (0.12 mole) of 2-methoxypropionyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 20.8 g (76%) of 6-[p-(2-methoxypropionylamino)-phenyl]4,5-dihydro-3(2H)-pyridazinone were obtained. Mp.: 245°-247° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([C:40]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (4 ml) and thereto are added morpholine (0.03 ml) and 1-hydroxybenzotriazole (50 mg) at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (70 mg) is added to the mixture under ice-cooling, triethylamine (0.04 ml) is added thereto dropwise, and the mixture is stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-carbonyl) pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (142 mg). MS (m/z): 697 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C.O>[C:25]([O:9][CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccccc1)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(c1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a stirred solution of (6-chloropyridin-3-yl)(phenyl)methanol (1.5 g, 6.8 mmol), diisopropylethylamine (2.5 mL, 15 mmol), 4-dimethylaminopyridine (86 mg, 0.7 mmol) in anhydrous dichloromethane (4 mL) was added acetic anhydride (1.4 mL, 15 mmol) dropwise at 0° C. under argon. After the reaction mixture was stirred at room temperature for 2 hours, water (1 mL) and then saturated aqueous sodium bicarbonate solution (20 mL) were added slowly to quench the reaction. The mixture was stirred at room temperature for 30 minutes and then extracted with dichloromethane (3×10 mL). The combined dichlormethane extracts were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave (6-chloropyridin-3-yl)(phenyl)methyl acetate (1.7 g, 6.5 mmol, 96% yield) as a colorless liquid. MS found: (M+H)+=262.13.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]2[O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[CH:13]([C:14](O)=[O:15])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:25]=1[NH2:26]>>[C:1]([C:5]1[CH:22]=[CH:21][C:8]2[O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[CH:13]([C:14]([NH:26][C:25]3[C:24]([Cl:23])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[O:15])[C:7]=2[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: Nc1c(Cl)cccc1Cl
Product: CC(C)(C)c1ccc2c(c1)C(C(=O)Nc1c(Cl)cccc1Cl)c1ccccc1CO2
Yield: 69.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-(tert-butyl)-6,11-dihydrodibenz[b,e]oxepine-11-carboxylic acid obtained in Example 42 (Compound D) in place of Compound A and 0.49 g of 2,6-dichloroaniline in place of aniline to obtain 0.92 g of Compound 45.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:30][O:31][CH2:32]Cl>O>[CH3:30][O:31][CH2:32][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1COC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (98 mg) and DMF (6 ml), 60% of sodium hydride (in oil) (29 mg) and chloromethyl methyl ether (25 μl) were sequentially added under ice-cooling. The mixture was heated room temperature, and stirred for 4 hours. Then, water was poured thereinto, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 72 mg of 3-methoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 37).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=1.CN(C)CCN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:34][CH:35]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2[nH]1
Reactant: Ic1ccc(OCCCN2CCCC2)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 100 °C

Procedure:
2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1H-indole (0.11 g, 0.4 mmol) and 1-[3-(4-Iodophenoxy)propyl]pyrrolidine (0.16 g, 0.48 mmol) were dissolved in toluene (0.4 mL), and N,N-dimethylethylenediamine (0.017 mL, 0.16 mmol), copper(I) iodide (30 mg, 0.16 mmol), and potassium phosphate (0.18 g, 0.84 mmol) were added. The reaction was heated at 100° C. overnight. The mixture was filtered through Celite with dichloromethane. The filtrate was concentrated, and taken forward without purification (crude product contains some starting material). LC-MS (C29H42N2O2Si calc'd 478) m/z 479 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.O>C(OCC)C>[CH3:15][S:16]([O:1][CH2:2][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:18])=[O:17]
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(COS(C)(=O)=O)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
To a solution of 5 g of methyl α-(hydroxymethyl)-4-chlorophenylacetate and 3.5 g of methanesulphonyl chloride in 30 ml of anhydrous diethyl ether, cooled at 0° C., a solution of 2.6 g of triethylamine in 10 ml of anhydrous diethyl ether is added dropwise. The temperature is allowed to rise again to room temperature, the reaction mixture is poured into water and is extracted with diethyl ether. The ether solution, washed with water, and dried over Na2SO4, is concentrated under vacuum, to yield 7.2 g of raw product. By crystallization thereof from 5 ml of ethanol, 5.4 g of a white solid product (m.p. 77°-8° C.) is obtained, having the structure indicated in the title of this example.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](O)=[O:20])=[C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:13]=[CH:12]2.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40].C(N(CC)CC)C.OP(O)(O)=O>C(Cl)Cl>[CH3:35][O:36][C:37](=[O:41])[CH2:38][N:39]([C:19]([C:15]1[C:16]2[C:11](=[C:10]([C:30]([F:33])([F:31])[F:32])[C:9]([O:8][CH3:7])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:40]
Reactant: CNCC(=O)OC
Reactant: COc1ccc2c(C(=O)O)c(OCc3ccccc3)ccc2c1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)c1c(OCc2ccccc2)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
A solution of oxalyl chloride (0.51 mL, 5.8 mmol) in CH2Cl2 (6 mL) was added dropwise to a suspension of 6-methoxy-2-(phenylmethoxy)-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (2.00 g, 5.3 mmol, described in Example 8) in 50 mL of CH2Cl2 under a nitrogen atmosphere. The suspension became homogeneous upon stirring for 1.5 hours. The mixture was then placed under mild vacuum for about 5 minutes to remove the dissolved gases and then was transfered via syringe to a flask containing a suspension of N-methylglycine methyl ester hydrochloride (11.1 g, 8.0 mmol) and triethylamine (3.7 mL, 27 mmol) in 50 mL of CH2Cl2. The suspension was stirred for 20 hours then was poured into additional CH2Cl2 and 1M H3PO4. The organic phase was separated and washed successively with 1M H3PO4, water, saturated NaCl and then dried over Na2SO4. After filtration, concentration and silica gel chromatography with 20:1 CH2Cl2 :ethyl acetate as eluent, the residue was recrystallized from ethanol to give 1.51 g (62% yield) of the title compound as a white powder, m.p. 95°-98° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>O>[OH:8][CH2:7][C@H:5]([NH:6][C:11]([O:13][CH3:14])=[O:12])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](CO)C(=O)OC
Yield: 91.9 %

Procedure:
To a solution of 72.03 g L-serine-methylester hydrochloride in 400 ml of water were added at 0° C. 49.5 g of methyl chloroformate. The pH was kept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After 2½ h at 0° C. the mixture was extracted with 6 portions of ethyl acetate, the combined extracts were dried and evaporated to give 75.39 g (92%) of pure methyl 3-hydroxy-(S)-2-methoxycarbonylamino-propionate. IR (neat): 3380 m (NH, OH), 1720 s, br. (C=O), 1535 s (amide II). MS (El): 178/20 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][CH2:33][CH2:34]CC.C(I)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:33][CH3:34])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (17.5 g, 28.4 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.6 M in hexanes, 19.5 mL, 31.2 mmol) was added keeping the temperature between about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. The mixture was treated with EtI (6.2 mL, 77 mmol) then the temperature of the mixture was raised to about 15° C. over about 5 to 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min at about 20° C. then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL) the layers were separated and then the aqueous layer was extracted with Et2O (100 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was applied to a 120 g silica column and eluted with 9:1 heptane/EtOAc. The fractions largely free of impurities were collected. The impure fractions were combined and evaporated then a second 80 g silica column was run on this material with 9:1 heptane/EtOAc as an eluent to give a second lot of material largely free of impurities. The material from the two columns were combined then further purified by flash chromatography on a 220 g silica gel cartridge with a gradient of 0 to 10% EtOAc/heptane to give 2-bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (7.16 g, 49%): LC/MS (Table 2, Method g) Rt=2.0 min; MS m/z 518 (M+H)+.
Reaction SMILES: CC1CCCCC1=O.C(C1CCCCC1=O)C.C(C1CCCCC1=O)CC.[CH3:28][O:29][C:30](=[O:42])[CH2:31][CH2:32][C:33]1([CH2:40]C)[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=[O:39].COC(=O)CCC1(CCC)CCCCC1=O>>[CH3:28][O:29][C:30](=[O:42])[CH2:31][CH2:32][C:33]1([CH3:40])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=[O:39]
Reactant: CCC1(CCC(=O)OC)CCCCC1=O
Agent: CCC1CCCCC1=O
Agent: CCCC1(CCC(=O)OC)CCCCC1=O
Agent: CCCC1CCCCC1=O
Solvent: CC1CCCCC1=O
Product: COC(=O)CCC1(C)CCCCC1=O

Procedure:
in the same manner but replacing 2-methylcyclohexanone with an equivalent amount of 2-ethylcyclohexanone or 2-propylcyclohexanone, 1-ethyl-2-oxocyclohexanepropionic acid methyl ester, bp 117° - 120° C/0.4mm, and 1-propyl-2-oxocyclohexanepropionic methyl ester, νmaxCHCl3 1735, 1700cm-1, are obtained, respectively.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:21]2[CH:17]([NH:18][C:19](=[O:22])[NH:20]2)[CH2:16][S:15]1.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[O:22]=[C:19]1[NH:18][CH:17]2[CH2:16][S:15][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:23])[CH:21]2[NH:20]1
Reactant: NCCCCCC(=O)O
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (2; 0.35 g, 1.03 mmol) was completely dissolved in DMF (3 mL) with gentle warming. After cooling the 2 solution to room temperature without reprecipitation, it was mixed with a solution of ε-aminocaproic acid (0.18 g, 1.37 mmol) in sodium bicarbonate buffer (0.1 M, pH 8.0; 4 mL) while stirring. After 4 h at room temperature, the reaction mixture was acidified by HCl solution (1 N) to assist in the formation of white precipitate. The white solid was washed with cold HCl solution, dried over ether, and air-dried to afford 3 (0.30 g; 80.5%). 1H NMR (400 MHz) (DMSO) δ: 7.78 (s, 1H, CONH), 6.46 (s, 1H, CONH), 6.38 (s, 1H, CONH), 4.32 (t, 1H, CHN), 4.14 (t, 1H, CHN), 3.11 (dd, 1H, CHS), 3.02 (t, 2H, CH2NH), 2.84 (d, 1H, CHHS), 2.59 (d, 1H, CHHS), 2.18 (t, 2H, CH2COOH), 2.05 (t, 2H, CH2CO), 1.23-1.68 (m, 12H). 13C NMR (100.67 MHz) (DMSO) δ: 174.45, 171.79, 162.70, 61.03, 59.18, 55.43, 35.21, 33.60, 28.90, 28.02, 25.97, 25.33, 24.22. HRMS (ESI) calculated for C16H27N3O4S, [M+Na]+ 380.1620 (calcd.), 380.1617 (found).
Reaction SMILES: [C:1]([O:5][C:6](NC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=O)(C)(C)C.[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:41])=[O:40]>>[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44]([CH2:1][O:5][CH3:6])[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:40])=[O:41]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropylamine IV k3 is allowed to react and worked up by the same procedure as described in (4). m.p. 41.5°-43° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OC(=O)C)(=O)C.[CH3:22][O:23][C:24](=[O:34])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:26]>>[CH3:22][O:23][C:24](=[O:34])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:26][C:13](=[O:14])[C@H:8]([CH2:9][C:10](=[O:11])[OH:12])[NH:7][C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O

Procedure:
This invention encompasses a method and intermediates for preparing a commercial sweetening agent, α-L-aspartyl-L-phenylalanine methyl ester. The process involves reacting L-aspartic acid with diketene to form N-acetoacetyl-L-aspartic acid which is converted to N-acetoacetyl-L-aspartic anhydride by reaction with acetic anhydride. N-acetoacetyl-L-aspartic anhydride is reacted with L-phenylalanine methyl ester to provide N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester which is converted to α-L-aspartyl-L-phenylalanine methyl ester by reaction with hydroxylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8](O)[CH2:7]1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:27])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 36, 180 mg, 0.56 mmol) in methylene chloride (0.28 mL) was treated with diethylaminosulfur trifluoride (0.11 mL, 0.85 mmol). The resulting mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL). This solution was extracted with methylene chloride 3×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (71.2 mg, 39.3%) as a light yellow oil.