Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: CCC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
A solution of 4-[4-(sec-butyl)-1-piperazinyl]benzenamine (3.5 g, 15 mmol) (from Step B above) in N,N-dimethylformamide (40 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (2.68 g, 15.03 mmol) (Aldrich) in N,N-dimethylformamide (15 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water (800 ml) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum to give 1-(4-isothiocyanatophenyl)-4-(sec-butyl)piperazine (3.6 g, 87%) as a purple solid.
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].[C:22]([OH:27])(=[O:26])[CH:23]([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[C:22]([O:27][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC1(CNC(=O)OC(Cl)C(C)C)CCCCC1
Reactant: CC(C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol), and isobutyric acid (442 μL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) was added, and the resulting mixture was stirred for another 24 h. After filtration, the filtrate was concentrated and the resulting residue purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane, to afford 560 mg (63%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 0.94 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H), 1.17 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 10H), 2.01 (m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, J=4.8 Hz, 1H). MS (ESI) m/z 372.38 (M+H+).
Reaction SMILES: [NH:1]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:2]([C:12]([NH:14][C@H:15]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:16])=[O:13])[CH2:3][NH:4]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:2]([C:12]([NH:14][C@H:15]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH3:16])=[O:13])[CH2:3][NH2:4]
Reactant: C[C@H](NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@H](CN)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound (247) (0.51 g, 1.02 mmol) from above was dissolved in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the crude residue (248) (0.49 g) was used in the next step without further purification.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](/[C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)\[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:18][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(CC2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O

Procedure:
10% palladium-activated carbon (50 mg) was added to a mixed solution of 6-{(E)-2-cyclopentyl-1-[4-(cyclopropylsulfonyl)phenyl]ethenyl}-3-methylpyridin-2(1H)-one synthesized in Example 1-11 (50 mg) in tetrahydrofuran and methanol (2 mL, 1:1), and the mixture was stirred in a hydrogen gas stream at room temperature for three hours. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:1→0:1) to give the title compound as a colorless amorphous (33 mg, 60%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC)(OC)([O:20][CH3:21])[CH:17]([CH3:19])[CH3:18]>CCCCCC>[CH3:21][O:20][C:16](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(OC)(OC)C(C)C
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1nc(-c2ccccc2)ns1)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and and 11 ml of trimethyl orthoisobutyrate was warmed to about 90° using an oil bath. After 2.5 hours, the solution was allowed to cool to room temperature, whereupon a precipitate formed. Hexane (25 ml) was added to complete the precipitation. The solid was collected, washed with hexane and vacuum dried (P2O5) to give 3.34 g of solid, m.p. 123°-124°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 66.9 %

Procedure:
A mixture of 1.48 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.64 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.66 g of potassium carbonate, 45 ml of acetone and 0.5 ml of water is refluxed for 22 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and diisopropyl ether is added to the residue. The precipitated crystals are collected by filtration and then recrystallized from ethyl acetate. 1.18 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:8]=1)#[N:2].[CH2:21]=[O:22].O>C(O)=O>[C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([N:9]([CH2:21][OH:22])[C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:8]=1)#[N:2]
Reactant: C=O
Reactant: N#Cc1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Solvent: O
Solvent: O=CO
Product: N#Cc1cn(N(CO)c2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
Two grams of 5-cyano-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione is added to 1.6 ml of 35% formaldehyde in enough 95% formic acid to effect stirring. The mixture is heated to reflux and 95% formic acid is added dropwise until the solid is dissolved. The mixture is refluxed overnight, after which 3.2 ml of aqueous formaldehyde is added and refluxing is continued for another 8 hours. The reaction mixture is poured into water and the precipitate is filtered to yield the compound 5-cyano-1-(N-hydroxymethyl-2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.>300°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1Cl)[C:5]([NH2:7])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S-:20])=[CH:16][CH:15]=1.[K+]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:10]2[C:9]([Cl:12])=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=2[Cl:1])=[CH:16][CH:15]=1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [S-]c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
A solution of 3,4,5-trichlorobenzamide (25.0 g, 111 mmol) and potassium 4-chlorothiophenolate (29.0 g, 159 mmol) in dimethylformamide (220 ml) was stirred for 3 days at ambient temperature under nitrogen atmosphere, poured into ice water (2.2 L), and filtered. The solid was washed with water, partially dried under vacuum, suspended in diethyl ether (200 ml), filtered, and washed with diethyl ether (2×75 ml). The residue was triturated with diethyl ether (75 ml), filtered, again triturated with diethyl ether (75 ml), filtered, and dried under vacuum to provide 21.2 g (57%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzamide, m.p. 171°-174° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>O1CCCC1>[N:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC1
Temperature: 0 °C

Procedure:
To an ice bath-cooled solution of 213.4 g (3 mol) of pyrrolidine in 450 mL of tetrahydrofuran was added dropwise over about 2 hours 250.5 g (1.5 mol) of ethyl bromoacetate, maintaining the temperature below 30° C. To this solution was added 150 mL of toluene to precipitate pyrrolidinium bromide, which was separated by filtration. The filtrate was evaporated under vacuum to provide a residue of about 241 g of ethyl 1-pyrrolinidineacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([NH:25]CC2C=CC=CC=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([OH:24])[C@@H:21]([NH:25][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of 1-bromo-4-fluoro-3-nitrobenzene (0.125 mol, 26.0 g) in ethyl acetate (300 mL) add (3S,4S)-3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.113 mol, 23.0 g) and triethylamine (0.339 mol, 35.0 g), reflux for 14 h, cool to room temperature, and wash with water and brine. Dry over anhydrous sodium sulfate, evaporate the solvent, and purify by flash column chromatography to give the title compound as a yellow solid (43.0 g, 90%). APCI MS m/z 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:23]=[N+:24]=[O:25].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH:14]([CH3:15])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:7]=1[N+:24]([O-:25])=[O:23]
Reactant: O=[N+]=O
Reactant: COC(=O)CC(C)(c1ccc(Cl)cc1)C(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC(C)(c1ccc(Cl)c([N+](=O)[O-])c1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.3 g (9.03 mmol) of methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoate were dissolved in 50 ml of dichloromethane and cooled to 0° C. 1.44 g (10.8 mmol) of nitronium tetrafluoroborate were then added a little at a time. After the addition had ended, the reaction solution was initially stirred at 0°-10° C. for 1 h. The mixture was then slowly warmed to room temperature and stirred at this temperature for another 2 h. The reaction mixture was then added to about 50 ml of water, the phases were separated and the organic phase was dried over magnesium sulphate. The solution was concentrated by evaporation and the residue obtained was then purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 2.3 g (85% of theory) of the target compound.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH:13]=[O:14])[CH:4]=1>CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][OH:14])[CH:4]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc2ccccc2c1
Yield: 86 %

Procedure:
Sodium borohydride (240 mg, 6.4 mmol) was added in portions to a solution of 3-Quinoline-carboxaldehyde (910 mg, 5.8 mmol) in methanol at room temperature. Reaction was quenched after 3 hours stirring with 10 mls (aq) sat. NH4Cl. Mixture was extracted with ethyl acetate (3×30 ml). Combined organics were washed with brine and dried over MgSO4. Crude Quinolin-3-ylmethanol was obtained upon filtration and concentration (795 mg; 86% yield).
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]([N:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:5][N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7]1.ClC1C=CC=C(C(OO)=[O:40])C=1.Cl>>[CH3:3][C@@H:4]([N:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:5][N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[S:13](=[O:40])[CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Agent: Cl
Product: C[C@H](CN1CC=C(C2=CC=CS2=O)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Yield: 45.7 %

Procedure:
The title compound was prepared from cyclohexanecarboxylic acid (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-(pyrid-2-yl)-amide dihydrochloride (1.5 g, 3.6 mmol) and meta-chloroperbenzoic acid (0.632 g, 3.6 mmol) to yield 0.7 g of the title compound as the 1.8 hydrochloride, m.p. 109°-11° C.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:5]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([CH2:7][CH2:8][CH3:9])[CH2:15][CH2:14]2)[CH2:17][CH2:18]1)#[CH:6]
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC1(O)CCC(C2CCC(CCC)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24.32 ml of (trimethylsilyl)acetylene are added dropwise at −30° C. to a solution of 30.0 g of 4′-propylbicyclohexyl-4-one and 3.41 g of tetrabutylammonium fluoride trihydrate in 300 ml of THF. The cooling bath is removed after 5 minutes, and the reaction mixture is stirred at RT for 2 hours. A suspension of 39.2 g of potassium fluoride in methanol is subsequently added, and the mixture is stirred at RT for 3 days. Conventional work-up gives 4-ethynyl-4′-propylbicyclohexyl-4-ol.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])=[CH:12][CH:11]=1)([O-:9])=[O:8]>>[CH2:1]([NH:6][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C(Cl)CCCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)CCCc1ccc([N+](=O)[O-])cc1

Procedure:
Isopentylamine was reacted with 4-(4-nitrophenyl)butanoyl chloride to provide N-isopentyl-4-(4-nitrophenyl)butyramide, which when reduced by reaction with diborane afforded N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of the latter compound with acetyl chloride under the conditions of Example 22 gave N-acetyl-N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of 21.8 g. of N-acetyl-N-isopentyl-4-(4-nitrophenyl)butylamine with 220 ml. of 1 M diborane in tetrahydrofuran provided, after workup according to the method of Example 22, 19.8 g. of N-ethyl-N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of the amine with para-toluenesulfonic acid in ethyl acetate afforded N-ethyl-N-isopentyl-4-(4-nitrophenyl)butylaminium tosylate. M.P. 78°-80° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:21]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:21][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C2CC2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 88.4 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (0.50 g, 1.591 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.188 g, 0.159 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (400 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 6.32 (d, J=8.7 Hz, 1H), 5.92 (s, 2H), 2.03 (s, 3H), 1.95 (m, 1H), 0.76 (s, 4H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [C:1]([O:5][CH:6](Cl)[CH3:7])(=[O:4])[CH2:2][CH3:3].[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([OH:41])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([O:41][CH:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH3:7])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cscn1)OC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3cscn3)C(=O)N12
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
1-Chloroethyl propionate (0.6 g) was added to the mixture of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in dimethyl sulfoxide (13 ml) and potassium carbonate (0.3 g) and the mixture was stirred for 2 hours at 40° C. The reaction mixture was added to the mixture of ice-water and ethyl acetate and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated to give 1-propionyloxyethyl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylate (syn isomer) (1.3 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[ClH:16].CO>C(Cl)Cl.CO>[ClH:16].[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)ethylamine (10.0 g, 66.2 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added a 1 M solution of BBr3 in CH2Cl2 (200 mL, 3 eq.) and the solution was allowed to slowly warm to RT. After stirring for 3 h at RT the resulting precipitate was filtered off, washed with CH2Cl2 (200 mL) and dried. The off-white solid was dissolved in cold H2O (50 mL) and the insoluble material was filtered off. The acidic filtrate (pH 1.2) was made basic (pH 13.0) with 10 N NaOH and the resulting yellow solution was extracted with ether (100 mL) and the organic layer was discarded. The aqueous layer was re-acidified with conc. HCl to pH 1.5 and then made alkaline (pH 9-10) with conc. NH4OH. The aqueous layer was then extracted with n-butanol (2×150 mL), dried (K2CO3) and concentrated to dryness to afford a viscous oil. The oily residue was then dissolved in MeOH (10 mL) and a solution of saturated HCl/MeOH was added. The solution was concentrated to small volume and ether was added to give a precipitate. The ether was decanted off to afford the desired compound as an off white solid (6.5 g, 57%). 1H NMR (D2O) 2.79 (t, 2H, J=7.2 Hz), 3.08 (t, 2H, J=7.2 Hz), 6.60-6.78 (m, 3H), 7.11 (t, 1H, J=7.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([F:23])=[CH:21][CH:22]=1)[CH2:5][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8].[CH3:24][Si:25]([CH3:68])([CH3:67])[CH2:26][CH2:27][O:28][C:29](=[O:66])[C@H:30]([CH2:42][C:43]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:45][C:44]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl>[CH2:59]([O:58][C:44]1[CH:45]=[CH:46][C:47]([C:2]2[CH:22]=[CH:21][C:20]([F:23])=[C:4]([CH2:5][C@H:6]([N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=2)=[CH:48][C:43]=1[CH2:42][C@H:30]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:29](=[O:66])[O:28][CH2:27][CH2:26][Si:25]([CH3:68])([CH3:67])[CH3:24])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COC(=O)[C@H](Cc1cc(Br)ccc1F)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.68 g (4.09 mmol) of methyl 3-bromo-N-(tert-butoxycarbonyl)-6-fluoro-N-methyl-L-phenylalaninate (Example 14O) in 8 ml of 1-methyl-2-pyrrolidone is rendered inert and saturated with argon (pass argon through for about 30 min). Then 334 mg (0.41 mmol) of bis(diphenylphosphino)ferrocenepalladium(II)chloride (PdCI2(dppf)) are added, and the mixture is stirred at RT for 10 min. Thereafter, 3.45 g (4.92 mmol) of 2-(trimethylsilyl)ethyl-2-(benzyloxy)-N-[(benzyloxy)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-L-phenylalaninate (Example 16A) in 8 ml of 1-methyl-2-pyrrolidone and 2.67 g (8.19 mmol) of cesium carbonate are added. A gentle stream of argon is passed over the reaction mixture, which is stirred at 50° C. for 20 h. The mixture is cooled, taken up in dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, and the solvent is concentrated in vacuo. The residue is purified by column chromatography on silica gel (cyclohexane:ethyl acetate 7:3).