Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@@H:5]([NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.CN(C)C=O.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]([C:6]1[S:7][C:8]([Br:36])=[CH:9][CH:10]=1)[NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-thiophen-2-yl-propionic acid methyl ester (0.420 g, 0.000971 mol;) was dissolved in N,N-Dimethylformamide (20 mL, 0.2 mol;) and N-Bromosuccinimide (0.19 g, 0.0011 mol;) was added. The reaction was allowed to stir o/n and LC-MS showed formation of product at 1.87 510.95. The reaction was diluted with methylene chloride and washed 1× with saturated bicarbonate, 1× with 5% citric acid, and 1× with brine. The organic layer was then dried with magnesium sulfate and concentrated to give the crude material. The crude was dissolved in methylene chloride and purified by combiflash 0-100% hexanes/ethyl acetate to give the pure product. ES (+) MS m/e=510.95
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1cccnc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1cccnc1
Yield: 19 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 3-pyridylmethylamine to give Compound 18 (0.07 g, 19%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2)CC1)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-n3ccnc3)cc2)CC1)c1ccc(F)cc1

Procedure:
Trans-4-(4-Bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 115, 80 mg, 0.166 mmol), imidazole (14 mg, 0.199 mmol), polyethylene glycol (30 mg), Cs2CO3 (76 mg, 0.232 mmol), and Copper II oxide (2 mg, 0.01 mmol) were weighed into a microwave vial. The vial was flushed with N2, NMP was added and the reaction mixture was microwaved at 200° C. After 20 min. the reaction mixture was diluted with EtOAc (50 ml) and filtered through celite. The filtrate was concentrated in vacuo and the residue was passed through a 25+S biotage column with an isocratic gradient of 10% MeOH in EtOAc. Product fractions combined and concentrated. The crude product was repurified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA) and the fractions containing the product were lyophilized to yield the title compound as a white solid (6.3 mg). MS MH+ 471.1
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][N:21]1[CH2:20][CH2:19][C:18]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([F:17])[F:16])=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)([C:24]#[N:25])[CH2:23][CH2:22]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: N#CC1(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound prepared in example 1 (19.8 g) in N,N-dimethylformamide (53 ml) were added potassium carbonate (18.4 g) and ethyl bromoacetate (5.89 ml) and the mixture was stirred for 1.5 hours at 50° C. To the reaction mixture was added water (160 ml) and it was extracted by tert-butyl methyl ether (160 ml). The organic layer was washed by water (80 ml×2) and concentrated to give the title compound (23.4 g) having the following physical data.
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(OCC2C=CC=CC=2)=O)[CH2:8][C@H:7]1[CH3:29])=[O:5])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[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]([NH2:18])[CH2:8][C@H:7]1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
(2R*,4S*)-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.83 g) is dissolved in a mixture solvent of ethanol (60 ml) and tetrahydrofuran (60 ml), then thereto is added 10% palladium/carbon (500 mg), and the mixture is stirred at room temperature under hydrogen for 7 hours. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure to give (2R*,4S*)-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (3.85 g). MS (m/z): 266 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[Cl-:26].[Cl-].[CH3:28][Zr:29]([CH3:51])(=[SiH2:50])([CH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[CH3:49])[CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH3:39]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O-:15])([CH3:4])([CH3:3])[CH3:2].[Cl-:26].[CH3:51][Zr:29]([CH3:28])(=[SiH2:50])([CH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[CH3:49])[CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH3:39]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc([O-])c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.03 g (5 mmol) of 2,4-di-tert-butylphenol in 10 ml of toluene/1 ml of THF were admixed at room temperature with 1.85 ml (5 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 1.19 g (2.5 mmol) of dimethylsilanediylbis-(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred for 2 hours at 60° C. and subsequently filtered hot through Celite. The filter cake was extracted 3 times with 10 ml each time of toluene (60° C.). After evaporation of part of the solvent, the yellow solid which precipitated was filtered off and dried under reduced pressure. This gave 0.87 g (53%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2,4-di-tert-butylphenoxide) (2).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[O-:13][C:14]#[N:15].[K+]>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:14]([NH2:15])=[O:13]
Reactant: N#C[O-]
Reactant: OCCNCCO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)N(CCO)CCO
Temperature: 90 °C

Procedure:
212.4 g diethanolamine in 212.4 g of water was neutralized with 101.85 g concentrated sulfuric acid to a pH of 4. A solution of 168.99 g potassium cyanate in 260 g of water was then added and the mixture was heated to 90° C. for 3 hours. After cooling to ambient temperature, potassium sulfate precipitated and was filtered out. The filter cake was washed with 425 g of hot ethanol. The recovered ethanol was then added to the contents of the filtrate, causing the filtrate to become cloudy. The white precipitate was removed by filtration and then the ethanol was removed by distillation to give a viscous liquid solution of N,N-bis(2-hydroxyethyl)urea. The product similarly could be obtained using other acids to neutralize the amine, e.g. sulfuric acid. Also, other cyanate salts could be used, e.g. sodium cyanate.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[Br:2][C:3]1[C:4]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CSc1ccc(Nc2ncc(Br)c(NC(C)C)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CC(C)Nc1nc(Nc2ccc(S(C)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.77 g (4.6 mmol) of 5-bromo-N4-isopropyl-N2-[4-(methylsulfanyl)phenyl)-pyrimidine-2,4-diamine hydrochloride is taken up in 40 ml of DCM and mixed with 1.73 g (5.5 mmol) of 3-chloroperoxybenzoic acid (55%). The batch is stirred for 90 minutes at room temperature and then diluted with DCM. It is washed with saturated NaHCO3 solution and saturated NaCl solution. The organic phase is dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 553 mg (1.5 mmol, corresponding to 33% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>O>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N(C)Cc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.12 gms. (0.02 mole) of 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) in 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature of the reaction mixture at circa 0° C. Stirring is continued for 30 minutes and then the reaction mixture is allowed to stand at room temperature overnight. Solvent is stripped and the residue suspended in water. Upon removal of the water there is obtained 1-(p-acetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: [Na+].[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([O-:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[C:8]=4[N:9]=3)=[O:14])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: Cc1cccc2oc(C(=O)[O-])nc12
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To 4-methyl-benzooxazole-2-carboxylic acid sodium salt (180 mg, 0.93 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (450 mg, 1.2 eq), BOP (490 mg, 1.2 eq), N,N-diisopropylethylamine (144 mg, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 158 mg of (S)-3-methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester as a white solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH3:18])[C:12]3=[O:19])=[CH:7][CH:6]=1)(=O)C.Cl.C(=O)(O)[O-].[Na+]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH3:18])[C:12]3=[O:19])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C23CC2C(=O)N(C)C3=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 130 mg of 1-(4-acetylaminophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione and 1 ml of approx. 18% hydrochloric acid is stirred for about 4 hours at 100° C. The reaction mixture is adjusted at 0° C. to pH 9-10 with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic phases are washed until neutral with a small amount of water and a dilute solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. Recrystallisation from ethyl acetate/petroleum ether affords the title compound which is identical with the title compound of Example 3(a).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: NS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(S(N)(=O)=O)sc2c1
Reaction time: 5 h
Yield: 26.2 %

Procedure:
6-Nitro-2-benzothiazolesulfonamide (2.93 g., 0.0113 mole) suspended in absolute ethanol (200 ml.) was hydrogenated in the presence of 5% palladium on carbon (2.9 g.) in a Parr apparatus. After 5 hrs. the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to dryness to give the solid product. Recrystallization from ethyl acetate and reprecipitation by dissolution in dilute aqueous hydrochloric acid followed by treatment with aqueous sodium bicarbonate solution gave 680 mg 6-amino-2-benzothiazolesulfonamide, m.p. 227°-9° C. dec.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH2:7]([NH:11][C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][CH3:10]>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[C:12](=[O:13])[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: CCCCNC(N)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCn1c(N)cc(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 46 g (0.55 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 58 g (0.5 mol) of n-butylurea. The solution was stirred at 70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 68 g (74%) (VII). This was stirred in 500 ml of water and 20 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 50.6 g (75%) (VIII), NMR.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:21]([CH3:23])=[O:22])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]#[N:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:9]=1.C.[CH2:25]([OH:27])[CH3:26]>>[CH3:1][CH2:2][N:3]([C:21]([CH3:23])=[O:22])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]#[N:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:9]=1.[C:25]([C:8]1[CH:9]=[C:4]([NH:3][C:21](=[O:22])[CH3:23])[CH:5]=[CH:6][CH:7]=1)(=[O:27])[CH3:26]
Reactant: CCO
Agent: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Product: CC(=O)Nc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Zaleplon (22.8 g) is dissolved in ethanol (230 cm3) at reflux temperature then treated with charcoal (2.3 g, 10 m/m %). The solution is stirred for 10 minutes and filtered. The charcoal is washed with hot ethanol (20 cm3). The solution is cooled to 25° C. in 6 hours and kept at this temperature for 2 hours. Crystals are filtered and washed with ethanol (30 cm3). The product is dried under vacuum at 60° C. for 8 hours to afford zaleplon form 1 (18.7 g, 82%).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:32]([O:34][C:35]([C@@:37]1([NH2:42])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:36])[CH3:33]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:42][C@:37]1([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: -23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF was added 2.03 mL (20.0 mmol) of N-methylmorpholine. A suspension formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of N-methylmorpholine was added. To this mixture was added the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. The salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of ethyl acetate. The extract was washed with 40 mL of water and 40 mL of aqueous sodium carbonate solution (10% w/w), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:23]([NH:25][CH2:26][CH3:27])=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:16][C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:18])[F:1])[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=2)[CH2:35][CH2:36]1)[C:23]([NH:25][CH2:26][CH3:27])=[O:24]
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)c(Cl)c1

Procedure:
Using 403A and 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide 286 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 1.39-1.46 (m, 3H) 2.52-2.61 (m, 4H) 3.05 (br. s., 4H) 3.21-3.30 (m, 2H) 3.45 (s, 2H) 4.70-4.78 (m, 1H) 6.78-6.83 (m, 2H) 7.13-7.21 (m, 2H) 7.77 (dd, J=8.59, 2.02 Hz, 1H) 7.87 (d, J=2.02 Hz, 1H) 8.43 (t, J=5.56 Hz, 1H) 10.81 (s, 1H). ESI-MS: m/z 509.3 (M+H)+. mp 101.7-104.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CCN(CC)CC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].O.CCOC(C)=O.CC#N>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:7][CH:6]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 75 °C
Yield: 98.4 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (4.0 g, 11.2 mmol), t-butyl acrylate (7.2 mL, 6.3 g, 49.2 mmol, 4.4 eq), Pd(OAc)2 (0.52 g, 2.3 mmol, 0.21 eq), Et3N (9.5 mL, 6.90 g, 68.2 mmol, 6.1 eq), P(o-tolyl)3 (1.3 g, 4.2 mmol, 0.38 eq), and CH3CN (100 mL). The reaction mixture was heated overnight at 75° C. with stirring under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then transferred to a separatory funnel with the aid of EtOAc and H2O. The layers were separated, and the organic phase washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give the crude product as a red-orange oil. The crude product was purified by flush chromatography on silica gel with hexanes:EtOAc (9:1 to 4:1) to give 4.46 g (98%) of compound 10 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (s, 9 H), 1.50 (m, 8 H), 2.21 (m, 4 H), 6.42 (d, J=16.1 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.90 (d, J=8.4 Hz, 2 H), 7.10 (d, J=8.2 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.28 (s, 1 H).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>C(OCC)C>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCC(C(=O)OC)c1ccccc1
Reaction time: 8 h

Procedure:
To 102 g. of 2-phenylbutyric acid dissolved in 1 liter of methanol was added 2 ml of thionyl chloride. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo to yield an oil which was dissolved in diethyl ether, washed successively with dilute sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo. Distillation yielded 101 g of the title compound as a water-white oil, b.p. 62°-65°/0.5 mm, having the following elemental analysis: