Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:8][C:9](=[O:33])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:19](=[O:32])[CH2:18][CH2:17]3)C=CC=CC=1>[Pd]>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:20]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10][C:9]([OH:33])=[O:8])[CH2:17][CH2:18][C:19]2=[O:32])=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)N2C(=O)CCc3cccc(CCC(=O)OCc4ccccc4)c32)cc1
Agent: [Pd]
Product: COc1ccc(C(=O)N2C(=O)CCc3cccc(CCC(=O)O)c32)cc1

Procedure:
A solution of 1-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-2-oxo-8-quinolinepropanoic acid phenylmethyl ester (10 g, 0.023 mole) is dissolved in tetrahydroferan (250 ml) and 1 g of 20% Pd/C is added. The mixture is shaken under an atmosphere of H2 gas until H2 absorption is complete. The mixture is filtered and concentrated at reduced pressure to yield after trituration with anhydrous diethylether and drying, 1-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-2-oxo-8-quinolinepropanoic acid.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([OH:40])(=[O:39])[C@H:36]([CH3:38])[OH:37]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([O-:40])(=[O:39])[CH:36]([CH3:38])[OH:37]
Reactant: C[C@H](O)C(=O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: O
Product: CC(O)C(=O)[O-]

Procedure:
A suitable reactor is charged with acetone (50 mL). The acetone solution is sequentially charged with carvedilol (15.0 grams) and water (7 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution is added 1N aqueous D, L-Lactic acid (1 equiv., 36.9 mL). The reaction mixture is stirred at between 17° C. and 35° C. and seeded in one portion. The solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 2 volume or 30 mL. The cake is dried under vacuum to a constant weight. The final weight is 9.16 grams.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:19]([C:27]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Br:36][C:34]1[CH:35]=[C:27]2[C:28](=[CH:32][CH:33]=1)[C:29](=[O:30])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH3:18])=[C:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
To a solution of 4-[(2-hydroxybutylamino)methyl]benzenesulfonamide hydrochloride (842 mg) and 2-benzoyl-4-bromobenzoic acid (915 mg) and 1-hydroxy-1H-benzotriazole (643 mg) in DMF (20 ml) was added triethylamine (1.25 ml) and then WSC (1.03 g) was added at room temperature, and the mixture was stirred at room temperature for 15 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between dichloromethane and water, washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9). The obtained colorless amorphous form was dissolved in dichloromethane (20 ml) and 4-methylmorpholine N-oxide (612 mg) and molecular sieves 4A (500 mg) were added. Under ice-cooling, tetra-n-propylammonium perruthenate (31 mg) was added, and the mixture was stirred at room temperature for 3 hrs. The molecular sieves 4A was removed from the reaction solution by filtration. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→1/1). The obtained colorless amorphous form was dissolved in ethanol (20 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.84 ml) was added. The mixture was heated under reflux for 12 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid, washed with aqueous sodium hydrogen carbonate and brine and sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→1/1) to give the title compound (267 mg, 17%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41][OH:42])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[S:50](Cl)([CH3:53])(=[O:52])=[O:51]>>[CH2:1]([O:19][CH2:20][CH:21]([CH2:41][O:42][S:50]([CH3:53])(=[O:52])=[O:51])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(COS(C)(=O)=O)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: -15 °C
Reaction time: 1 h

Procedure:
1,2-Dilinoleylglycerol (26) (11.0 g, 18.7 mmol), triethylamine (5.04 mL, 36 mmol), and a stir bar were added to a 250 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous DCM (75 mL) was added, and the mixture cooled to −15° C. (Ice and NaCl). Mesyl Chloride (2.80 mL, 36 mmol) was added via syringe over a 5 minute period, and the reaction stirred at −15° C. for 1 hour. At this point TLC showed that the starting material had been consumed. The solution was diluted with DCM (120 mL) and washed with saturated NaHCO3 (2×150 mL). The organic phase was then dried (MgSO4), filtered, concentrated, and the product purified by column chromatography (10.6 g, 85%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH:9]2
Reactant: Oc1ccc2c(ccn2-c2ccccc2)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCCCOc1ccc2c(ccn2-c2ccccc2)c1
Yield: 52.4 %

Procedure:
864 mg (4.1 mmol) 1-Phenyl-1H-indol-5-ol in 10 ml acetone were treated with 2.44 g (10 mmol) 1,6-dibromohexane and 2.8 g (20 mmol) K2CO3 at reflux for 4 h. The solution was filtered, concentrated and purified by column chromatography on silica gel with hexane/EtOAc 39:1 to yield 800 mg (52%) 5-(6-Bromo-hexyloxy)-1-phenyl-1H-indole as colorless oil, MS: 371 (M, 1Br).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[C:21]([Br:22])=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Br:22][C:21]1[CH:20]=[C:19](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[CH3:11])=[CH:4][CH:5]=2)[CH:18]=[N:17][C:16]=1[O:15][CH2:14][CH2:13][OH:12]
Reactant: OCCOc1ncc(I)cc1Br
Reactant: C=Cc1ccc(N(C)C)cc1
Product: CN(C)c1ccc(/C=C/c2cnc(OCCO)c(Br)c2)cc1

Procedure:
Compound 14a was prepared from 4-dimethylaminostyrene (0.031 g, 0.212 mmol) and 9b (0.073 g, 0.212 mmol) as a light yellow solid (0.022 g, 29% yield). 1H NMR δ 8.07 (d, 1H, J=2.1 Hz), 8.03 (d, 1H, J=2.1 Hz), 7.39 (d, 2H, J=8.8 Hz), 6.94 (d, 1H, J=16.3 Hz), 6.78-6.69 (m, 3H), 4.57-4.52 (m, 2H), 3.99 (t, 2H, J=4.3 Hz), 3.21 (br s, 1H), 3.00 (s, 6H). 13C NMR δ 158.3, 150.4, 143.0, 138.2, 129.9, 129.8, 127.6, 124.9, 118.3, 112.3, 107.5, 69.6, 62.1, 40.3. HRMS calcd for C17H19BrN2O2 (M+), 362.063; found, 362.0629.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:30])([F:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][C@@H:22]3[CH2:24][C:25](=[O:27])[CH2:26][N:21]3[C:20]2=[O:28])=[CH:15][CH:14]=1>CS(C)=O.[Cl-].[Na+].O>[F:30][C:10]([F:9])([F:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][C@@H:22]3[CH2:24][C@:25]4([CH2:2][O:27]4)[CH2:26][N:21]3[C:20]2=[O:28])=[CH:15][CH:14]=1
Reactant: O=C1C[C@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@@H]2C[C@]3(CO3)CN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
To a mixture of trimethyl sulfoxonium iodide (70 mg, 0.350 mmol) and NaH (20 mg, 0.477 mmol), was added dry DMSO (0.3 mL) drop wise at 0° C. and stirred for 30 min. (S)-2-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-tetrahydro-pyrrolo[1,2-c]imidazole-3,6-dione (100 mg, 0.318 mmol) dissolved in DMSO (0.6 mL) was added to this mixture and stirred at room temperature for 2 h. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified through column chromatography over silica (elution with 30% ethyl acetate in hexane) to obtain 20 mg of isomer (2R,7a′S)-2′-[4-(2,2,2-trifluoroethoxy)phenyl]tetrahydro-3′H-spiro[oxirane-2,6′-pyrrolo[1,2-c]imidazol]-3′-one (off white solid) LC-MS: 329.0 [M+1]+ and 5 mg of isomer (2S,7a′S)-2′-[4-(2,2,2-trifluoroethoxy)phenyl]tetrahydro-3′H-spiro[oxirane-2,6′-pyrrolo[1,2-c]imidazol]-3′-one (off white solid) LC-MS: 329.0 [M+1]+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]([CH2:31][CH2:32][CH:33]([OH:36])[CH2:34][CH3:35])[CH2:8][CH:9]1[CH2:30][CH2:29][CH2:28][CH2:27][N:10]12)(=O)C.OC(CC)CCC1N2C3C(CCC2CCC1)=CC=C(OC(CCCC1C=CC=CC=1)C)C=3.[OH-].[Na+]>O.N1C=CC=CC=1>[OH:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]([CH2:31][CH2:32][C:33](=[O:36])[CH2:34][CH3:35])[CH2:8][CH:9]1[CH2:30][CH2:29][CH2:28][CH2:27][N:10]12
Reactant: CCC(O)CCC1CC2CCCCN2c2cc(OC(C)CCCc3ccccc3)cc(OC(C)=O)c21
Agent: CCC(O)CCC1CCCC2CCc3ccc(OC(C)CCCc4ccccc4)cc3N21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)CCC1CC2CCCCN2c2cc(OC(C)CCCc3ccccc3)cc(O)c21

Procedure:
A solution of 5.0 g. (0.02 mole) chromic anhydride in 5.0 ml. water is added with stirring and ice cooling to 50 ml. pyridine. To this is added at 10° C., 4.93 g. (0.01 mole) dl-7-acetoxy-6-(3-hydroxypentyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido-[1,2-a]quinoline (prepared from dl-7-hydroxy-6-(3-hydroxypentyl-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline by the procedure of Example 62, Part A) and the resulting mixture is stirred at ambient temperature for three hours. The mixture is then poured into water, made alkaline with sodium hydroxide and extracted with methylene chloride. The combined extracts are washed with water, brine, dried (MgSO4) and the solvent evaporated in vacuo. The residue is purified by silica gel chromatography.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3](CC(O)=O)([C:5]([OH:7])=[O:6])[OH:4].O1B([C@@H](NC(=O)CNC(=O)C2C=C(Cl)C=CC=2Cl)CC(C)C)OB([C@@H](NC(=O)CNC(=O)C2C=C(Cl)C=CC=2Cl)CC(C)C)O[B:15]1[C@@H](NC(=O)CNC(=O)C1C=C(Cl)C=CC=1Cl)CC(C)C>CCOC(C)=O>[O:12]=[C:1]1[O:13][BH:15][O:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)c1cc(Cl)ccc1Cl)B1OB([C@H](CC(C)C)NC(=O)CNC(=O)c2cc(Cl)ccc2Cl)OB([C@H](CC(C)C)NC(=O)CNC(=O)c2cc(Cl)ccc2Cl)O1
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)O)OBO1
Reaction time: 3 h

Procedure:
To a solution of citric acid (10.1 g, 52.6 mmol) in EtOAc (300 mL) with an internal temperature of about 74° C. was added a solution of N,N′,N″-{boroxin-2,4,6-triyltris[[(1R)-3-methylbutane-1,1-diyl]imino(2-oxoethane-2,1-diyl)]}tris(2,5-dichlorobenzamide) (20.0 g, 19.5 mmol) in EtOAc (60 mL). The solution was cooled slowly (about 0.33° C./min) until the internal temperature was about 60° C. and the mixture was stirred for 3 h. The resulting slurry was cooled slowly (rate of about 0.12° C./min) until the internal temperature was about 25° C. and the mixture was stirred overnight. The resulting precipitate was collected by filtration to yield 4-(R,S)-(carboxymethyl)-2-OR)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid Form 2 as a crystalline solid (26.7 g, 98%). 1H NMR (500 MHz, DMSO-d6, δ 110° C.): 10.08 (s, 1H), 8.69 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=1.3 Hz, 2H), 4.26 (d, J=5.5 Hz, 2H), 2.70 (q, J=14.5 Hz, 4H), 2.70 (bs, 1H), 1.72 (sept, J=6.5 Hz, 1H), 1.42 (ddd, J=5.2 Hz, J=8.6 Hz, J=13.9 Hz, 1H), 1.28 (ddd, J=5.3, J=9.4 Hz, J=14.3 Hz, 1H), 0.91 (dd, J=3.3 Hz, J=6.6 Hz, 6H). 13C NMR (100 MHz, DMSO-d6, δ 100° C.): 21.65, 23.34, 25.09, 38.39, 38.98, 42.07, 76.25, 128.97, 129.14, 130.94, 131.48, 131.73, 137.05, 165.44, 170.23, 175.74, 177.43. MS (m/z) in CH3CN: [M+Na] calculated for C20H23BCl2N2NaO9, 539.1. found, 539.1.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH2:16][CH2:17][NH:18][CH3:19]>C1COCC1>[CH3:14][N:15]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)[CH2:16][CH2:17][NH:18][CH3:19]
Reactant: CNCCNC
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Product: CNCCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 18 %

Procedure:
Dissolve 2-chloro-6-nitro-benzothiazole (2.20 g, 10.3 mmol) in THF (50 mL). Add N,N′-dimethyl-ethane-1,2-diamine (10.0 mL) and stir overnight at room temperature. Concentrate the reaction mixture in vacuo (adsorbing onto silica gel). Subject the mixture to silica gel flash column chromatography (120 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (0.500 g, 18%). mass spectrum (m/e): 267.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>O1CCCC1>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:34]
Reactant: CCOC(=O)CN
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 56.3 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (9.50 g, 0.033 mole), 1,1'-carbonyldiimidazole (5.35 g, 0.033 mole) and anhydrous tetrahydrofuran (300 ml) was stirred at room temperature for 2 hrs with a stream of nitrogen bubbling through it. To the resulting suspension was added glycine ethyl ester (8.0 g, 0.078 mole) and the solution stirred over the weekend. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate (150 ml) and potassium bicarbonate solution (75 ml). The organic layer was washed with potassium bicarbonate solution (2×50 ml), water (50 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (10 g) was recrystallized from tetrahydrofuran-isopropyl ether to give 6.93 g (56%) of an off-white solid, m.p. 144°-145° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.CN.Cl.[C:17]([BH3-])#[N:18].[Na+]>CO.O1CCOCC1>[CH3:17][NH:18][CH2:12][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)s1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution 13 (90 mg, 0.48 mmol) was added a solution of methylamine (2.0 M, 1.43 mL, 2.85 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.24 mL, 0.95 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (30 mg, 0.48 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 24 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water and washed with Et2O (3×10 mL). The aqueous fraction was adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.13) to afford the title compound 40 (39 mg, 40% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.84 (m, 1H), 8.49 (m, 1H), 7.82 (m, 1H), 7.28 (m, 1H), 7.21 (d, J=3.6 Hz, 1H), 6.93 (d, J=3.5 Hz, 1H), 3.96 (s, 2H)2.31 (s, 3H); LRMS (ESI) m/z calcd for C11H13N2S [M+H]+ 205. found 205; m/z calcd for C10H8NS [M−NH(CH3)]+ 174. found 174; HRMS (ESI) m/z calcd for C11H13N2S [M+H]+ 205.0799. found 205.0781; HPLC>95%=4.34 min, 80 (A):20 (B): 0.05 (C); tR=3.60 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][O:9][C:10]([C@@H:12]([NH:20][C:21]([C@@H:23]([NH2:28])[CH2:24][C:25]([OH:27])=[O:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]>>[CH3:1][C:2]([CH2:3][CH2:4][NH:28][C@H:23]([C:21]([NH:20][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])[CH2:24][C:25]([OH:27])=[O:26])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C

Procedure:
3,3-Dimethylbutyraldehyde and the acid salt of aspartame or the N-protected aspartame are reacted for a time and at a temperature sufficient to produce neotame. Generally, the time ranges from about 1 to about 24 hours, preferably from about 2 to about 4 hours after addition of the 3,3-dimethylbutyraldehyde is complete. If the 3,3-dimethylbutyraldehyde is added to the reaction mixture all at once, then the time sufficient to produce neotame preferably ranges from about 6 to about 24 hours. Generally, the temperature sufficient to produce neotame according to the present invention ranges from about 20° C. to about 60° C., preferably from about 22° C. to about 40° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([O:17]C)=[O:16])=[N:6][O:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>CO>[CH:1]1([C:4]2[C:5]([C:15]([OH:17])=[O:16])=[N:6][O:7][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1noc(-c2ccccc2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1noc(-c2ccccc2)c1C1CC1
Yield: 77.4 %

Procedure:
A solution of methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate (170 mg, 0.699 mmol) and 1N aqueous sodium hydroxide (1 mL, 1.05 mmol) in methanol (6 mL) was heated to 80° C. in a sealed tube for 1 hr. The reaction mixture was acidified with acetic acid until the pH was ˜4. The mixture was concentrated, and the residue was purified by preparative HPLC to give 4-cyclopropyl-5-phenylisoxazole-3-carboxylic acid (124 mg). The compound had an HPLC ret. time=2.81 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90%
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[C:13]3[C:18]([C:19](=[O:22])[C:20](=[O:21])[C:10]=2[S:9][CH2:8]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)=O.[N:23]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[O:21]=[C:20]1[C:10]2[S:9][CH2:8][CH:7]([CH2:6][N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27]3)[O:12][C:11]=2[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:22]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(CC2CSC3=C(O2)c2ccccc2C(=O)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of (5,6-dioxo-2,3,5,6-tetrahydronaphtho[1,2-b][1,4]oxathiin-2-yl)methyl methanesulfonate (0.15 g, 0.44 mmol) in DMSO (1.5 mL) was added ethyl piperazine-1-carboxylate (0.065 mL, 0.88 mmol) and triethylamine (0.12 mL, 0.88 mmol). The reaction mixture was shaken at 50° C. for 2 hours. The crude product was purified by reverse phase HPLC to give the desired product as a purple solid (0.015 g, 5%). M.p.=185-187° C.; 300 MHz 1H NMR (CDCl3) δ: 8.04 (d, J=7.2 Hz, 1H), 7.66 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 4.66 (m, 1H), 4.15 (m, 2H), 3.51 (m, 4H), 3.23 (m, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.54 (m, 4H), 1.27 (m, 3H); LCMS: 403 [M+H].
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(#N)C.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of diethyl 3,5-pyrazoledicarboxylate (2.17 g, 10 mmol) in acetonitrile (10 ml), under nitrogen, was added potassium carbonate (2.07 g, 15 mmol), and 2-bromoethoxy-t-butyldimethylsilane (2.90 g, 12 mmol). The mixture was stirred at reflux for 18 hr. It was then cooled to room temperature, diluted with ethyl acetate (20 ml), and filtered through Magnesol. The filter pad was eluted with 2×10 ml of ethyl acetate, and the combined filtrate was evaporated. The residue was dissolved in hexanes and passed through a column of silica gel (70 g). After eluting with hexanes (100 ml), the column was eluted with ethyl acetate. The ethyl acetate eluent was evaporated to give 3.71 g of a colorless oil; MS m/e 371 (MH+).