Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(=O)C(C(C)(C)C)=O)(=[O:3])C.C(N[C:17](=[O:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])(=O)C>>[C:20]1([C:18](=[O:19])[C:17]([OH:26])=[O:3])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)NC(=O)C(=O)c1ccccc1
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Product: O=C(O)C(=O)c1ccccc1
Yield: 89.3 %

Procedure:
The procedure followed is as described in Example B 2. (a), but instead of trimethylpyruvic acid N-acetylamide, the equivalent amount (0.1 mole) of phenylglyoxylic acid N-acetylamide was employed. 13.4 g (89.3% of theory) of phenylglyoxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:23]([OH:25])=[O:24])[CH:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:23]([O:25][CH3:27])=[O:24])[CH:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[CH2:18][C:19]([F:22])([F:21])[F:20])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Yield: 21.3 %

Procedure:
To a solution of N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (1.3 g, 5.23 mmol) in CH2Cl2:MeOH (4:1) TMSCHN2 (6 mL, 12 mmol) was added dropwise over 10 min at 0° C. until a neon yellow color persisted. When the dropwise addition was completed, the reaction mixture was allowed to warm to 25° C. over 19 h. The solvent was removed in vacuo to obtain methyl N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvalinate (0.5 g, 37.31%). Mass Spectrum (−ESI): 445 (M−H)−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:8]=2[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in DMF (5 mL) was added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) at 0° C. The resulting mixture was stirred for 30 min before 2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL, 1.1 eq) was added. The mixture was then warmed up to room temperature and stirred for 1 hr. Water was added to quench the reaction. Extraction with CH2Cl2 followed by drying combined organic layers, evaporation, and chromatography on silica gel (20% EtOAc in heptane as eluent) gave the desired product in 84% yield (570 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Yield: 35.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(oxazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.29 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]4[O:39]C(C)(C)C(C)(C)[O:36]4)=[CH:31][C:30]=3[F:44])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C1(B(O)O)C=CC=CC=1.Cl>O1CCCC1>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([B:35]([OH:39])[OH:36])=[CH:31][C:30]=3[F:44])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A suspension of 5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.32 mmol), polymer supported benzeneboronic acid (600 mg, 1.60 mmol) and aqueous 5N HCl (0.45 mL, 2.24 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 24 h. The solution was filtered, concentrated to dryness, and purified by reverse phase HPLC to afford 4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronic acid (61 mg, 0.11 mmol, 35% yield) as a white solid. 1H NMR (METHANOL-d4) δ 8.03 (s, 1H), 7.97-7.79 (m, 2H), 7.57 (dd, 3H), 7.24 (dd, 3H), 3.29 (s, 3H), 2.94 (s, 3H), 2.42 (s, 1H), 1.00 (d, 2H), 0.69 (s, 2H). LCMS (m/z, ES+)=541 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].[CH2:17]([SH:19])[CH3:18].CCOCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([S:19][CH2:17][CH3:18])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
A solution of 5-chloro-2-nitrobenzotrifluoride (150 g., 0.67 mole) and benzyltriethylammonium chloride (15 g., 0.067 mole) phase transfer catalyst in methylene chloride (1500 ml) is added to a cold (0°-5° C.) stirred solution of sodium hydroxide (53.2 g., 1.33 moles) and ethanethiol (97.47 g., 1.57 moles) in water (1200 ml) over a 1.5-2 hour period. The reaction mixture is allowed to come to room temperature and is stirred for 17 hours. Thin layer chromatography on silica gel with 10 percent ether-90 percent petroleum ether (b.p. 30°-60° C.) diluent indicates all of the 5-chloro-2-nitrobenzotrifluoride has reacted. The methylene chloride layer is then separated from the aqueous layer and washed with water. The methylene chloride is removed by evaporation leaving 2-nitro-5-ethylthiobenzotrifluoride as an oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>ClCCl>[C:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][N:45]([CH3:44])[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3])([CH3:54])([CH3:53])[CH3:52]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNCCC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 125 mg of tert-butyl 3-(methylamino)propanoate, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 209 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow formed solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>CO.O.O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH2:21]([O:20][C:18]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)CC1O
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CO)C(O)C1
Reaction time: 0.5 h

Procedure:
A solution of the 1-Benzyl-4-hydroxymethyl-piperidin-3-ol from Step 1 above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psi over 20% palladium hydroxide on charcoal (10 g) for 48 h in three batches. The combined reaction mixtures were filtered and the filtrate evaporated to give an oil. This oil was dissolved in water (100 mL) and dioxane (100 mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) was added slowly. 1M NaOH was added to maintain pH of 10–11. After 30 min, the cooling bath was removed and reaction mixture stirred for 30 min. The reaction mixture was concentrated to remove dioxane and the residue extracted with EtOAc (×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give a mixture of cis and trans products. Purified by flash column chromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cis isomer and the lower Rf trans isomer.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[Cl:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH:6][S:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([Cl:11])[S:13][C:14]=2[CH:20]=1)(=[O:22])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=S(=O)(Cl)c1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Cl)sc2c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(D)-valine methylester hydrochloride (0.33 g, 2.0 mmol) was dispersed in dichloromethane (5 mL) and cooled down to 0° C. 2-Chloro-6-benzthiazolsulfonyl chloride (0.5 g, 1.0 equi.) prepared in Example 13 was dissolved in dichloromethane (3 mL) to give a dichloromethane solution. Triethylamine (0.83 mL, 3 equi.) and the dichloromethane solution were added while maintaining the temperature of 0° C. When starting material was exhausted after 5 hours, the organic phase was washed with 1N HCl, dried over MgSO4 and distilled under reduced pressure. Then, the product was eluted and purified on silica gel chromatography using ethylacetate/n-hexane (1/3) solvent to prepare the titled compound, (2R)-3-methyl-2-[(2-chlorobenzthiazol-6-sulfonyl)amino] butanoic acid methylester (0.65 g, 90%).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[Cl:9][C:10]1[C:11]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[N:14][N:13]([CH3:19])[C:12]=2[S:20]([O-:22])=[O:21].[Li+]>O>[Cl:9][C:10]1[C:11]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[N:14][N:13]([CH3:19])[C:12]=2[S:20]([NH2:1])(=[O:22])=[O:21]
Reactant: NOS(=O)(=O)O
Reactant: Cn1nc2cccc(Cl)c2c1S(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2cccc(Cl)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
45.2 g (0.4 mol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 16 g (0.4 mol) of sodium hydroxide in water (300 ml) under cooling with ice (<10° C.). This solution was added all at once to a solution of the previously prepared crude lithium 4-chloro-2-methyl-2H-indazole-3-sulfinate in water (100 ml). The mixture was stirred at room temperature for 12 hours. Formed crystals were collected by filtration to obtain 17.1 g (yield: 69.8%) of the desired 4-chloro-2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 173°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:27]1([C:31]([NH:24][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclobutanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropylethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-(cyclobutanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 89%; MS (ESI+APCI) M+1=411.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].O=C1C[CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:2]1[CH2:4][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CC1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(CC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a cooled (0° C.) suspension of methyl triphenylphosphonium bromide (8.58 g, 23.5 mmol) in THF (60 mL) was added KOtBu (3.17 g, 28.3 mmol) in portions under N2. The reaction was slowly warmed to rt and stirred for 1 h. The resulting mixture was cooled to 0° C. and added a solution of ethyl 2-(4-oxocyclohexyl)acetate (2.9 g, 15.7 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h and at 50° C. overnight. After cooling to RT, the reaction was quenched by addition of saturated NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product as colorless oil (2.11 g, 73.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:16])[CH2:12][CH2:11][N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+].C(Cl)Cl>Cl.O>[CH2:13]([N:10]1[CH2:11][CH2:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][NH2:17])=[CH:3][CH:4]=2)([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: CCN1CCC(C)(c2ccc(N)cc2)C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN1CCC(C)(c2ccc(NN)cc2)C1=O
Reaction time: 0.75 h

Procedure:
A solution of 676 mg (3.1 mmol) of (±)-3-(4-aminophenyl)-1-ethyl-3-methylpyrrolidin-2-one (from Step 3) in 3.1 mL of concentrated hydrochloric acid was then stirred at about −5° C. in an ice-acetone bath as a solution of 222 mg (3.2 mmol) of sodium nitrite in 1.25 mL of water was added dropwise over about 15 minutes. Stirring was continued at −10° to −5° C. for 45 minutes. The mixture was kept cold and added gradually to a solution of 3.50 g (15.5 mmol) of stannous chloride dihydrate in 2.5 mL of concentrated hydrochloric acid stirred under nitrogen at <0° C. in an ice-acetone bath. After completion of the addition, stirring was continued in the cooling bath for about 30 minutes, and then the mixture was partitioned between 25 mL of ethyl acetate and 4 mL of water. The aqueous layer was washed with an additional 10 mL of ethyl acetate. The combined ethyl acetate fractions were treated cautiously with 25 mL of saturated aqueous sodium carbonate solution, resulting in heavy precipitation and some gas evolution. After dilution with additional ethyl acetate and water, the mixture was filtered. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was washed with saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 396 mg (55%) of a viscous, yellow oil; primarily one spot by TLC in 95:5 CH2Cl2. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[F:33].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(F)c(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 3-chloro-4-fluorophenylisocyanate (0.31 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3-chloro-4-fluoro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.47 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.40 min (98.65%); mp: 224-226° C.; 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H), 2.29-2.47 (m, 1H), 2.55-2.66 (m, 1H), 2.81-3.01 (m, 1H), 4.31 (m, J=17.2 Hz, 1H), 4.37-4.53 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.86 (t, J=5.9 Hz, 1H), 7.18-7.33 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.78 (dd, J=6.8, J=1.7 Hz, 1H), 8.88 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.1, 42.7, 47.0, 51.5, 116.6 (d, J=22.0 Hz), 117.8 (d, J=6.6 Hz), 119.0 (d, J=11.0 Hz), 121.9, 122.9, 126.9, 130.3, 137.7 (d, J=3.3 Hz), 142.3, 144.6, 150.2, 153.4, 155.0, 167.9, 170.9, 172.8; LCMS: MH=445/447; Anal Calcd for C21H18ClFN4O4: C, 56.70; H, 4.08; N, 12.59. Found: C, 56.54; H, 3.93; N, 12.23.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CON)C1
Product: CC(C)(C)OC(=O)N1CC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 76 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl 3-((aminooxy)methyl)azetidine-1-carboxylate (564 mg) described in Reference Example 25, 699.7 mg of the title compound was afforded (yield 76%).
Reaction SMILES: Br[C:2]([CH3:25])([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:26][C:27]1[C:28]([OH:34])=[N:29][CH:30]=[N:31][C:32]=1[NH2:33].Cl>CCO>[NH2:33][C:32]1[C:27]2[N:26]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:16][CH2:15][C:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])([CH2:13][CH2:12]4)[CH2:17][CH2:18]5)=[CH:7][CH:6]=3)[C:2]([CH3:24])([CH3:25])[O:34][C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: Nc1ncnc(O)c1N
Agent: Cl
Solvent: CCO
Product: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 25 °C
Yield: 6 %

Procedure:
To a solution of methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (648 mg, 1.59 mmol) in absolute EtOH (15 mL) was added 5,6-diaminopyrimidin-4-ol (221 mg, 1.75 mmol) followed by 1M HCl (1.75 mL). The reaction mixture was heated under reflux overnight then allowed to cool to ambient temperature and evaporated to dryness. The residue was treated with 2M NaOH to adjust the pH to 11 and then the mixture was extracted into EtOAc (4×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave the crude ester product. The aqueous phase was acidified with 2M HCl and then re extracted with EtOAc (2×100 mL), the organic extracts were combined, dried (MgSO4) and concentrated to give some of the corresponding acid {4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}acetic acid (40 mg, 0.095 mmol, 6%). The ester was purified on a 12 g silica redisep cartridge dry loading the sample on celite and eluting with DCM-MeOH 0-2%-5% using an Isco Companion to provide the title compound as a solid 122 mg (0.281 mmol, 17.6%);
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[O:4].[CH:6]1[CH:7]=[CH:8][C:9]2N[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]=[CH:12][C:10]=2[CH:11]=1>C(O)(=O)C>[CH:6]1[CH:7]=[CH:8][C:9]2[N:2]([C:3]([NH2:5])=[O:4])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:10]=2[CH:11]=1
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea hydrochloride (100 g, 1.036 mols) in acetic acid (125 ml), iminostilbene (25 g, 0.129 mols) was added under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.