Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([F:25])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 4-fluoro-3-trifloromethyl aniline (0.077 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.043 g of desired product. 1H NMR (DMSO-d6): δ 7.46-7.59 (m, 3H), 7.69 (t, J=6.3 Hz, 1H), 8.11 (br s, 5H), 8.26 (m, 1H), 10.59 (br s, 1H), 12.72 (br s, 1H); MS (m/z): 495.07[M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH2:50].[H-].[Na+]>CN(C=O)C>[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH:50][C:37](=[O:38])[C:36]([NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=1)=[O:34])([CH3:40])[CH3:41]
Reactant: Nc1nncs1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nncs4)c3)cc12
Reaction time: 8 h
Yield: 47 %

Procedure:
DIEA (44 μL, 0.253 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169 mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and the slurry became a clear solution after 10 min. It was allowed to stir overnight. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (22 mg, 45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1H, br. s.), 8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3H, m), 7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d, J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=11.23 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=10.56 min, purity=96%.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[CH3:42][O:43][N:44]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([CH2:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: COC(=O)C(CCc1ccccc1)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(CCc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine. The two (Z) and (E) compounds are not separated.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]1=[O:13]>O1CCCC1>[C:1]([C:8]1([OH:12])[CH2:9][CH2:10][CH2:11][N:6]([CH3:5])[C:7]1=[O:13])#[CH:2]
Reactant: CN1CCCC(=O)C1=O
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CCCN(C)C1=O
Reaction time: 0.02 h
Yield: 30 %

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in tetrahydrofuran, 4 mL, 2 mmol) maintained under nitrogen at −20° C. was added a solution of 1-methylpiperidine-2,3-dione (220 mg, 0.87 mmol) in tetrahydrofuran (3 mL) dropwise with stirring within 1 min. The reaction mixture was stirred for 2 hr at room temperature and then quenched by the addition of saturated ammonium chloride solution (1 mL). The mixture was diluted with DCM (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:0) afforded the title compound (40 mg, 30%) as a brown oil: 1H NMR (400 MHz, CDCl3) delta 4.23 (s, 1H), 3.35-3.30 (m, 2H), 2.95 (s, 3H), 2.47 (s, 1H), 2.35-2.16 (m, 2H), 1.97-1.90 (m, 2H). LC-MS m/z=+154 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Se](=O)=[O:12]>O1CCOCC1>[C:1]([C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ncccc1C#N
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1C=O
Yield: 9.7 %

Procedure:
To a solution of 3-cyano-2-picoline (166 mg, 1.41 mmol) in dioxane (3 mL) was added water (0.2 mL) and selenium(IV) oxide (228 mg, 2.05 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1 then 1:1) to afford the title compound (18 mg, 10%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.69 (dd, 1H, J=9, 6 Hz), 8.20 (d, 1H, J=9 Hz), 9.00 (d, 1H, J=3 Hz), 10.13 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a flask containing a solution of 29, Et3N (0.26 g, 2.55 mmol) and DMAP (0.032, 0.26 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (0.24 g, 2.13 mmol), dropwise at RT and the reaction allowed to stir overnight. After 18 h the reaction was diluted with CH2Cl2 (15 mL) and the reaction rinsed with 10% aqueous HCl (25 mL). The CH2Cl2 layer was dried (MgSO4) and concentrated to a dark amber oil. The crude product was purified by silica gel column chromatography to afford 170 mg (46%) of the title compound (269) as a colorless oil. An additional 90 mg of a mixture of 269 and N,N-bissulfonylated product was also isolated. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 2.82 (s, 3H), 3.85 (s, 3H), 6.54 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 7.15-7.32 (m, 5H), 7.58 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[N:15][C:14]=2[CH:28]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[N:15][C:14]=2[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1-c1nc2cc(C)ccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1nc2cc(CBr)ccc2o1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
N-Bromosuccinimide (2.35 g) and azo(bisisobutyronitrile) (60 mg) were added to a solution of compound C (3.2 g) in carbon tetrachloride (60 ml). The mixture was heated under reflux for 4 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was recrystallised from hexane to give methyl 2-(5-bromomethyl-benzoxazol-2-yl)benzoate (D) (2.1 g), m.p. 92°-95° C; NMR: 3.9(s, 3H), 4.65(s, 2H), 7.45(dd, 1H), 7.55(dd, 1H), 7.6-7.7(m, 2H), 7.8-7.85(m, 2H), 8.0-8.1(m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Cl>CN(C=O)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: ClCCOCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 162.8 %

Procedure:
Potassium tert-butoxide (4.00 g, 35.6 mmol, 2.20 eq) was added to a stirred solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (2.53 mL, 16.2 mmol, 1.0 eq) in DMF (30 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (2.09 mL, 17.8 mmol, 1.1 eq) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (6.73 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([NH2:35])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(O)C>[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:24][C@@H:23]([NH:35][C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175 mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int. Application WO2004/016611), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine (0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol (10.0 mL) was refluxed overnight. The reaction was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.0768 g, 82%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:13]2[N:14]([CH3:24])[C:15](=[O:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:13]2[N:14]([CH3:24])[C:15](=[O:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cn1c(C(CC=O)c2ccc(Cl)c(Cl)c2)cc2ccccc2c1=O
Product: Cn1c(C(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)cc2ccccc2c1=O

Procedure:
3-[1-(3,4-Dichlorophenyl)-3-oxopropyl]-2-methyl-2H-isoquinolin-1-one (0.303 g) was coupled to 4-hydroxy-4-phenyl-piperidine (0.15 g) by method similar to that described in Example 1. After aqueous work up, the product was purified by column chromatography. Eluting with ethyl acetate, followed by dichloromethane:methanol, (9:1) afforded the title compound as a solid; mp 100°-102° C.; MS: m/z=521(M+1); NMR: 1.55 (t,2, J=12), 1.89 (m,2), 2.10 (m,1), 2.28 (m,5), 3.35 (s,3), 4.46 (broad,1), 6.90 (s,1), 7.17-7.71 (m,11), 8.18 (d,1, J=8). Analysis for C30H30Cl2N2O2.0.5 H2O Calculated: C, 67.92; H, 5.89; N, 5.28; Found: C, 68.22; H, 5.86; N, 5.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C1(C)C=CC=CC=1.C(O)C>[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)C(Cc1cccc(Br)c1)CS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
3-(3-Bromo-phenyl)-2-benzylsulfonylmethyl-propionic acid (0.5 g, 1.26 mmol) was dissolved in toluene (20 mL) and ethanol (5 mL). Tetrakistriphenylphosphine palladium (146 mg, 0.126 mmol) was added and the mixture was stirred at ambient temperature under nitrogen for 30 minutes. Powdered potassium carbonate (870 mg, 6.3 mmol) and phenylboronic acid (200 mg, 1.64 mmol) were added, and the reaction mixture was heated at 75° C. for 2 hours. After cooling, the mixture was acidified with 1N aqueous HCl and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and evaporated. The acid was purified by flash chromatography on silica gel (ethyl acetate/hexane; 1:1) to yield 3-biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (0.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].IC.[C:16](=O)(O)[O-].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1

Procedure:
3-Methyl-4-nitrobenzoic acid (67 g, 0.37 mole) is added to a mixture of dimethylacetamide (300 ml), iodomethane (85 g, 1.0 mole) and anhydrous sodium bicarbonate (84 g, 1.0 mole). The mixture is stirred and heated at reflux for two hours. The mixture is cooled, and filtered and the solids are washed with methanol before being discarded. The filtrate and washings are evaporated to a residue which crystallizes. Recrystallization from diethyl ether gives pure methyl 3-methyl-4-nitrobenzoate, 65.1 g, m.p. 73°-75.5° C.
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 4-(dihydroxyboryl)benzoic acid (1.03 g, 6.21 mmol) and 2-bromopyridine (0.59 mL, 6.21 mmol) in ACN (20 mL) was added sodium carbonate (0.396 g, 3.74 mmol) in water (20 mL). The reaction mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium (0.108 g, 0.09 mmol) was added. The reaction mixture was allowed to stir at 90° C. overnight and then filtered. The solution was concentrated to remove ACN and the aqueous solution was washed with DCM. The aqueous solution was acidified with 1N HCl and the resulting white precipitate was filtered and dried to give 4-pyridin-2-ylbenzoic acid (1.06 g, 85%). LCMS: (FA) ES+ 200.1.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:21]>O>[Cl:21][C:6]1[CH:7]=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cl
Reactant: CC(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 0.25 h

Procedure:
Solution of sodium nitrite (1.2 g, 0.017 mol) in demineralized water (7 mL) is added to a solution of 1-(3-amino-4-cyclohexylphenyl)ethanone (3.4 g, 0.016 mol) in concentrated hydrochloric acid (34 mL) at 0-5° C. & is allowed to stir for 15 minutes at this temperature. It is then poured into a slurry of cuprous chloride (3.1 g, 0.03 mol) in demineralized water (10 mL) at 60-65° C. & stirred for 30 minutes. The reaction mixture is extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; toluene:n-hexane, 3:2) to yield 1-(3-chloro-4-cyclohexyl-phenyl)ethanone.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11](=[O:12])[CH2:10]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:6]([CH:10]2[C:9](=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11]2=[O:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)C2CCCC2)C(=O)O1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of cyclopentanecarbonyl chloride (1.100 mL, 9.05 mmol) in DCM (5 mL) was added dropwise to a stirred solution of isopropylidene malonate (1.304 g, 9.05 mmol), and pyridine (1.464 mL, 18.10 mmol) in DCM (20 mL) at 5° C., over a period of 10 minutes under nitrogen. The resulting solution was stiffed at 5° C. for 1 hour and then allowed to warm to 20° C. and stirred for another hour. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with 2M HCl (2×50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, 5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.100 g, 97%) as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:79])C=1>ClCCl.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@H:21]3[S:20](=[O:79])[CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS(=O)[C@H]23)cs1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (511 mg: 0.5 mMol.) in a mixture of dichloromethane (10 ml) and methanol (10 ml) is added m-chloroperbenzoic acid (purity: 80%: 54 mg: 0.25 mMol.) at -30° C., and the mixture is stirred for 1 hour. The reaction mixture is diluted with aqueous 5% sodium thiosulfate and extracted with ethyl acetate. The extract solution was washed with aqueous sodium hydrogencarbonate, diluted hydrochloric acid, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (toluene-ethyl acetate=2:1 to 1:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (232 mg). Yield: 45%. A part of the starting material (236 mg: 48%) was recovered.
Reaction SMILES: C(OC(=O)[N:10]([C:15]1[N:44]=[C:18]2[N:19]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:20]([CH3:33])=[C:21]([C:31]#[N:32])[C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:17]2[N:16]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>CO.[Pd]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([C@H:22]2[N:17]3[N:16]=[C:15]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[N:44]=[C:18]3[N:19]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:20]([CH3:33])=[C:21]2[C:31]#[N:32])=[CH:24][CH:25]=1)#[N:30]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(2-methylpropyl)-carbamate (25.0 mg, 41 μmol) was dissolved in degassed methanol (5 ml). After addition of palladium on activated carbon (10%; 5 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.75 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (13.6 mg, 70% of theory).