Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[N:45]([CH3:47])[CH3:46])C(O)=O.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:34])[C:38]2[CH:42]=[CH:43][C:44]([N:45]([CH3:47])[CH3:46])=[C:36]([Cl:35])[CH:37]=2)[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1Cl
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N(C)C)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 44 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 3-chloro-4-dimethylamino-benzoic acid according to the procedure used to prepare 98a to afford 82 mg of title compound (44% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.18-1.53 (m, 3H), 1.70-2.40 (m, 4H), 2.55-3.10 (m, 2H), 2.84 (s, 6H), 3.45-3.94 (m, 2H), 4.25-4.95 (m, 5H), 5.46 (s, 0.3H), 5.51 (s, 0.2H), 5.63 (d, 0.4H), 5.73 (d, 0.1H), 7.05 (d, 1H), 7.15-7.95 (m, 7H). Analytical HPLC: 11.85, 12.19 min. LC-MS (ES+): m/e=557.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[N:6]=5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C3CCC3)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added cyclobutanone (30 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E25). MS (ES+) m/e 350 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34](Cl)=[O:35]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:31]([Cl:30])[CH:32]=2)[N:13]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml triethylamine and 251 mg of 3,4-dichlorobenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 1 hour. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 237 mg of expected product is obtained.
Reaction SMILES: [CH:1]1(/[CH:8]=[C:9](\[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)/[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:32][C:15]1[S:14][C:13]([NH:12][C:10](=[O:11])/[C:9](/[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)=[CH:8]/[CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A suspension of (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 17, 63 mg, 0.133 mmol) and N-bromosuccinimide (26 mg, 0.146 mmol) in carbon tetrachloride (2 mL) at 25° C. was treated with benzoyl peroxide (2 mg, 0.006 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL). The organic phase was then washed with water (1×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-thiazol-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (35.5 mg, 48%) as an amorphous white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@@H:6]1[CH2:12][C@H:11]([CH3:13])[O:10][CH:8](O)[CH2:7]1)=[O:4].[N+](C1C=CC(C([Cl:25])=O)=CC=1)([O-])=O>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@@H:6]1[CH2:12][C@H:11]([CH3:13])[O:10][CH:8]([Cl:25])[CH2:7]1)=[O:4]
Reactant: C[C@H]1C[C@@H](NC(=O)C(F)(F)F)CC(O)O1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](NC(=O)C(F)(F)F)CC(Cl)O1
Reaction time: 12 h

Procedure:
To a solution of 1 g of compound (IX) in 10 ml of anhydrous pyridine, 2 g of p-nitrobenzoyl chloride were added. After 12 hours at room temperature, the reaction mixture was poured onto ice and the resulting precipitate was washed with water until the water was neutral. The resulting crude 1-p-nitrobenzoate (mixture of α and β anomer) was dried over phosphorus pentoxide for several hours under vacuum, and then dissolved in dry methylene dichloride and saturated at 0° with anhydrous hydrogen chloride. The precipitated p-nitrobenzoic acid was filtered off under anhydrous conditions, and the 1-chloro derivative (II) was obtained in quantitative yield by evaporation of the solvent. Compound (II) can be used for the ensuing condensation reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O>O1CCCC1>[Cl:1][C:2]1[C:10]2[S:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2cccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 7-chloro-1-benzothiophene-2-carboxylic acid (synthesized by the method of Journal of Chemical Society Perkin Trans. 1, 1984, 385, 1.00 g, 4.70 mmol) in tetrahydrofuran (17 mL) was added a solution of 0.95 mol/L borane-tetrahydrofuran complex in tetrahydrofuran (9.90 mL, 9.41 mmol) at 0° C. The mixture was stirred at room temperature overnight, and then to the reaction solution was added water, and the mixture was concentrated under reduced pressure to remove solvent. To the resulting residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with hexane-diisopropyl ether to give (7-chloro-1-benzothien-2-yl)methanol (842 mg, 90%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-:3])=[O:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[N+:17]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]([Cl:14])[CH:12]=[C:11]2[C:6]=1[NH:7][C:8](=[O:16])[C:9](=[O:15])[NH:10]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c([N+](=O)[O-])c2[nH]c1=O
Temperature: 4 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
To a solution of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.50 mmol) in concentrated H2SO4 (1.0 mL) was added KNO3 (61 mg, 0.60 mmol, Baker). The mixture was stirred at 4° C. for 2 days, then ice (2 g) was added. The precipitate was collected by filtration and the solid was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl (~1.2 mL) to give a yellow precipitate, which was collected by filtration and was washed with water (2×1 mL), then was dried at 50° C. for 4 h, affording crude title compound (101 mg, 70%) as a yellow powder. The crude compound (100 mg) was dissolved into acetone (2 mL) and the insoluble material was removed by centrifugation. Water (1 mL) was added to the clear solution of acetone and the resultant solution was allowed to stand at 4° C. overnight to give purer compound. Recrystallization from acetone/water again gave pure title compound (55 mg). Mp: 298°-300° C. (dec.); IR (KBr, cm-1): 3434, 3295, 3111, 2920, 1716, 1571. 1H NMR (DMSO-d6): δ 12.560 (s, 1H), 12.421 (s, 1H), 7.442 (s, 1H). HRMS; calcd for C8H3ClN4O6 (M+) m/z: 285.9740, found: 285.9741.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:8][C:7]1[C:2]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:33])[N:28]=[CH:27]3)[S:21]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:10])(=[O:35])=[O:34])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(C)c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3,5-trichloropyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 26).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[F:20])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=1)[CH2:24][N:8]([C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[F:20]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (2.10 g) is dissolved in N,N-dimethylformamide (10 ml) and thereto is added sodium hydride (62.7%) (345 mg) under ice-cooling and the mixture is stirred for 30 minutes, and thereto is added 1-bromomethyl-3,5-bis-trifluoromethyl-benzene (2.76 g) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (3.30 g). MS (m/z): 576/578 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCCCc1nc(C)n(-c2cccc(O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(-c2cccc(OCCO[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.95 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.45 g), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.13 g, 83%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Zinc powder (2.4 g) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (1.85 g) in a mixture of dimethylformamide (10 ml) and acetic acid (3 ml), and the mixture was stirred for 2 hours, after which the reaction mixture was filtered. The filtrate was poured into a mixture of ethyl acetate (50 ml), ice-water (50 ml) and 10% hydrochloric acid (2 ml), and then the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined, and the combined solution was in turn washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off. The residue was crystallized by adding a small quantity of acetonitrile and the precipitated crystals were collected by filtration and dried to give colorless crystals of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (1.2 g), mp 109° C. (dec.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:17][CH:16]=[N:15][C:14]=3[C:18]([O-:20])=[O:19])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:17][CH:16]=[N:15][C:14]=3[C:18]([OH:20])=[O:19])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])c1ncoc1-c1cccc(N2CCOCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ncoc1-c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(3-morpholinophenyl)oxazole-4-carboxylate (900 mg, 2.98 mmol) in THF (29 mL) was added 1N aq. NaOH-solution (14 mL) and the resulting mixture was stirred at rt overnight. The reaction mixture was poured into 1N aq. HCl-solution and extracted with EtOAc (85 mL). The org. layer was dried (MgSO4), filtered and concentrated to dryness to afford the title compound as a yellow solid which was used without further purification. LC-MS conditions A: tR=0.70 min, [M+H]+=274.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])[CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(5-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 10, 22.3 g, DMF (260 ml), potassium carbonate (35.6 g), and iodomethane (26.9 ml) is stirred at 20°-25° for 16 hr. Aqueous workup (ether, water and saline washes, drying over magnesium sulfate) gives the title compound, mp 87°-89°; IR (Nujol) 3349, 2954, 2925, 1737, 1606, 1489, 1330, 1263, 1230, 1149 and 752 cm-1 ; NMR (CDCl3) 8.48, 8.15, 6.65, 6.54, 3.77 and 1.69 δ; MS (EI) 272 and 213 m/z.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Cl:39]C1C=CC(CC(=O)C(OCC)=O)=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][C:25]([Cl:39])=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccc(Cl)cc1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(4-chlorophenyl)-2-oxopropanoate B7 (100 mg, 0.441 mmol), sodium hydride (11.65 mg, 0.485 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-glucose bromide (181 mg, 0.441 mmol). The resulting compound was isolated in the form of white solid in 22% yield.
Reaction SMILES: [F:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=4[C:31]([O:33]C(C)(C)C)=[O:32])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45].Cl>O1CCOCC1>[F:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=4[C:31]([OH:33])=[O:32])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C(C)(F)c4ccccc43)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(F)C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2ccccc2C(=O)O)CN3c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.1 g, 0.16 mmol) was added concentrated 4M HCl in dioxane (1.6 mL) and triethylsilane (0.02 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated, isolated by preparatory TLC (10% methanol/dichloromethane) and lyophilized with 4M HCl in dioxane (1 mL) to obtain the title compound as a hydrochloride salt (0.039 g, 40%); 1H NMR (DMSO-d6): δ 1.72 (d, 3H, J=23.2 Hz), 1.97 (d, 2H, J=14 Hz), 2.07 (br, 2H), 2.93 (t, 2H, J=10 Hz), 3.17 (br, 2H), 3.44-3.79 (m, 8H), 4.64 (s, 2H), 4.92 (s, 2H), 6.80 (t, 1H, J=7.2 Hz), 6.99 (d, 1H, J=8.4 Hz), 7.07 (d, 1H, J=8 Hz), 7.15 (t, 1H, J=7.6 Hz), 7.20-7.26 (m, 2H), 7.31 (d, 1H, J=7.6 Hz), 7.40-7.48 (m, 2H), 7.57 (t, 1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.2 Hz), 10.27 (br, 1H), 13.21 (s, 1H); MS for C33H35FN4O4 m/z 571.3 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[N:34](=[CH:42][CH2:43]Cl)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Cl>>[N:34]1([CH2:42][CH2:43][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:19]3[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]3)=[N:15][CH:14]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCC=NCCCCCCCl
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethyl chloride.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])([CH3:19])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C:17]([CH3:18])([CH3:19])[C:16]([O:15][CH3:14])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.