Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@H:6]([C:23](O)=[O:24])[NH:7][C:8](=[O:22])[CH:9]([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.Cl.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH2:40][O:41][CH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[NH2:44])[CH:37]=[CH:38][CH:39]=1)=[O:33].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@H:6]([C:23]([NH:47][C:45](=[O:46])[C@H:43]([CH2:42][O:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:32]([O:31][CH3:30])=[O:33])[CH:35]=1)[NH2:44])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Reactant: COC(=O)c1cccc(COC[C@H](N)C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(COC[C@H](N)C(=O)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine (1.0 g, 2.68 mmol) and O-[[3-(methoxycarbonyl)phenyl]methyl]-L-serinamide HCl (0.774 g, 2.68 mmol), 1-hydroxybenzotriazole hydrate (0.452 g, 2.95 mmol, and N-methylmorpholine (1.18 mL, 1.085 g, 10.72 mmol) in CH2Cl2 (50 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (0.771 g, 4.02 mmol) in one portion and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residual solid is triturated with hot methanol to yield N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-O-[[3-(methoxycarbonyl)phenyl]methyl]-L-serinamide as a white solid.
Reaction SMILES: C([NH:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=O)C.[CH3:19][NH:20][CH3:21].O>C(O)(=O)C>[NH2:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:20]([CH3:21])[CH3:19]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC1CO1
Reactant: CNC
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.085 mol (21.5 g) of 1-(2'-acetylamino-4'-nitrophenoxy)-2,3-epoxypropane (compound described in Example (4) is introduced into 100 ml of a 40% strength aqueous solution of dimethylamine, and the reaction mixture is stirred for 30 minutes at ambient temperature. After dilution by the addition of 225 ml of iced water, followed by neutralisation with acetic acid, the mixture is evaporated to dryness in vacuo. The dried residue is taken up in 150 ml of ethyl acetate. After washing with acetone, the material which is insoluble in ethyl acetate consists of 28.5 g of 1-(2'-acetylamino-4'-nitrophenoxy)-3-dimethylaminopropan-2-ol. This acetylated derivative is heated under reflux for two hours in 220 ml of ethanol saturated with hydrogen chloride. After the reaction medium has cooled, the expected product in the form of the hydrochloride is filtered off. After this hydrochloride has been dissolved in water and the aqueous solution has been rendered alkaline with sodium hydroxide solution, the 1-(2'-amino-4' -nitrophenoxy)-3-dimethylaminopropan-2-ol is precipitated in the form of crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[OH-:15].[Na+]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:15])[N:4]=2)=[CH:9][CH:10]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: [OH-]
Agent: [Na+]
Product: OCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
6 g (26.307 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole were heated under reflux in 526 ml (52.613 mmol) of 0.1 N aqueous sodium hydroxide solution for 3 h. The mixture was then cooled to room temperature, and the precipitated solid was filtered off, washed with 0.1N aqueous sodium hydroxide solution and dried under high vacuum. This gave 4.79 g (85% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>[Cl-].[Zn+2].[Cl-]>[C:23]([O:20][C:19]1[CH:21]=[CH:22][C:14](/[CH:13]=[C:7]2\[CH2:8][CH2:9][CH2:10][C:11]3[C:2]([CH3:1])=[CH:3][CH:4]=[N:5][C:6]\2=3)=[CH:15][C:16]=1[O:17][CH3:18])(=[O:25])[CH3:24]
Reactant: Cc1ccnc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc(/C=C2\CCCc3c(C)ccnc32)ccc1OC(C)=O

Procedure:
A mixture of 5,6,7,8-tetrahydro-4-methylquinoline (5.2 g), vanillin (5.37 g), zinc chloride (0.3 g) and acetic anhydride (50 ml) were refluxed under nitrogen for 16 hours. The solvent was removed by evaporation and the resulting residue was neutralised (Na2CO3) in the presence of ethyl acetate and was then extracted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (6 mL), sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added. After 25 min, 1-bromo-3-phenyl propane (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 3 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.33 g (62%) of a yellow solid: mp 113.5-115.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.14 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 4.02 (m, 2H), 3.70 (m, 4H), 3.50 (m, 2H), 2.93 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.99 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 2976, 1686, 1447, 1416, 1366, 1360, 1247, 1180, 1168, 1152, 1108, 930, 788, 747, 701 cm−1; MS (FAB) m/z 473 (M+H+), 475, 474, 473, 472, 419, 418, 417, 416, 91, 57; HRMS (FAB) calcd for C26H30Cl2N2O2+H 473.1762, found 473.1759; Anal. Calcd for C26H30Cl2N2O2: C, 65.96; H, 6.39; N, 5.92, found: C, 66.00; H, 6.41; N, 5.85.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([S:16][C:17]#N)[N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([S:16][C:17]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[CH:29]=3)[N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CSc1csc(Nc2ccc([N+](=O)[O-])cn2)n1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(Sc2csc(Nc3ccc([N+](=O)[O-])cn3)n2)ccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Methanol (115 mL) was added to N-(5-nitropyridin-2-yl)-4-thiocyanatothiazol-2-amine (3.24 g, 11.6 mmol) and dithiothreitol (3.6 g, 23.3 mmol) at 23° C. Methyl 4-chloropicolinate (2.18 g, 12.8 mmol) was then added followed by potassium phosphate (3.27 g, 15.4 mmol) and DMF (115 mL). The reaction was stirred overnight, then poured into ice/water (1.5 L). The resulting precipitate was filtered on paper and dried under vacuum to give the title material (4.05 g, 90%). LC/MS (M+H)+: 390, (M−H)−: 388. HPLC ret. time (Condition E): 1.683 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]2[C:10]=1[CH2:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9]2
Reactant: CCOC(=O)C1=C(C(=O)OCC)c2c(OC)ccc(Br)c2C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: CCOC(=O)C1Cc2cccc(OC)c2C1C(=O)OCC
Yield: 96.9 %

Procedure:
The diester from Example 2 (19.39 g) was dissolved in 250 ml ethanol. To the solution was added 5.20 g of 10% Pd/BaSO4 and 7.15 g NaOAc.3H2O. The reaction was hydrogenated at 4 atm pressure. The catalyst was filtered and the solvent evaporated. The product was dissolved in ether, washed with 5% NaHCO3, dried (MgSO4), and the solvent was evaporated to yield 14.87 g of the desired product as a colorless oil. NMR (CDCl3) δ1.20 (t, 3H), 1.27 (t, 3H), 3.13 (dd, 1H), 3.48-3.56 (m, 2H), 3.82 (s, 3H), 3.95-4.22 (m, 4H), 4.39 (d, 1H), 6.70 (d, 1H), 6.87 (d, 1H), 7.21 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[CH2:30]([Li])CCC.[F:35][C:36]([F:72])([F:71])[C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[C:50]3[CH:54]=[CH:53][CH:52]=[CH:51]3)=[CH:45][CH:44]=2)=[CH:39][CH:38]=1.Cl>CCCCCC.COC(C)(C)C>[F:35][C:36]([F:71])([F:72])[C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:68])[F:69])=[CH:65][CH:66]=4)=[CH:57][CH:56]=3)([CH:50]3[CH:51]=[CH:52][CH:53]=[CH:54]3)[C:7]3([CH3:30])[C:6]4[C:5]([CH3:23])([CH:12]5[CH2:13][CH2:14][CH:15]=[CH:16][C:11]5=[C:10]5[C:18]=4[CH2:17][C:19]4[CH:20]=[CH:21][CH:22]=[CH:8][C:9]5=4)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]3([CH3:1])[CH3:29])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Reactant: [Li]CCCC
Reactant: FC(F)(F)c1ccc(-c2ccc(C(=C3C=CC=C3)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CC12C(=C3Cc4ccccc4C3=C3C=CCCC31)C(C)(C(c1ccc(-c3ccc(C(F)(F)F)cc3)cc1)(c1ccc(-c3ccc(C(F)(F)F)cc3)cc1)C1C=CC=C1)C(C)(C)C(C)(C)C2(C)C
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, 0.81 g (2.20 mmol) of octamethyloctahydrodibenzofluorene and 100 ml of dehydrated tert-butyl methyl ether were added, and the mixture was stirred. This solution was cooled to 0° C., and 1.59 ml (2.42 mmol) of a 1.52 mol/l hexane solution of n-butyllithium was added. Subsequently, the mixture was stirred at room temperature for 24 hours. The resulting solution was cooled to −78° C., and 1.04 g (2 mmol) of 6,6-bis(4-(p-trifluoromethylphenyl)-phenyl)fulvene was added. The mixture was stirred at room temperature for 3 hours. When the completion of reaction was checked, 1 N hydrochloric acid was added to the reaction solution to perform liquid-liquid phase separation. The aqueous layer was subjected to extraction with diethyl ether two times, and the extract was combined with the organic layer previously obtained. The liquid was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to separation by silica gel chromatography to obtain a target product (yield 0.92 g (47%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH3:12][C:13]1[S:14][CH:15]=[N:16][N:17]=1>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[CH:12][C:13]1[S:14][CH:15]=[N:16][N:17]=1
Reactant: Cc1nncs1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nncs1

Procedure:
0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5nitroimidazol-2-carboxaldehyde which has been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride and the whole is dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, over a period of 5 hours at reflux temperature. After 24 hours the reaction mixture is freed of the solvent by evaporation and ether is added. After the reaction product has been washed with water it is recrystallized from xylene. 9.3 of product, corresponding to 39% of the theory, is obtained. The compound melts at 214° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10]O)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[C:1]([C:5]1[N:9]=[C:8]([CH2:10][Cl:14])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nsc(CO)n1
Solvent: ClCCl
Product: CC(C)(C)c1nsc(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.71 g of 3-t-butyl-5-hydroxymethyl-1,2,4-thiadiazole was dissolved in 20 ml of dichloromethane, and 1.4 ml of thionyl chloride was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.76 g of 3-t-butyl-5-(chloromethyl)-1,2,4-thiadiazole hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[C:39]([F:44])[CH:38]=1>C(OCC)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:41][C:40]1[CH:42]=[CH:43][C:37]([Br:36])=[CH:38][C:39]=1[F:44])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.54 g, 4.5 mmol) was dissolved in 50 mL diethyl ether under an Ar atmosphere, cooled in an ice water bath, added dry pyridine (1.4 mL, 17.8 mmol), followed by the dropwise addition of oxalyl chloride (0.58 mL, 6.7 mmol). Reaction was stirred at 0° C. for 1 hour, then at ambient temperature for 1 hour. Diluted reaction with 50 mL diethyl ether, filtered off solids and concentrated filtrates. Redissolved filtrate in 30 mL dry DCM under an Ar atmosphere, cooled in an ice water bath, added 1 mL dry pyridine followed by 4-bromo-2-fluoroaniline (0.85 g, 4.5 mmol). Stirred reaction at ambient temperature for 20 hours. Concentrated solution, redissolved in EtOAc (150 mL), washed with 10% citric acid (3×100 mmL), water (2×100 mL), brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluting with an automated system with gradient of 0-60% EtOAc in hexanes over 40 minutes. Combined and concentrated pure fractions to yield title compound as a clear oil. (0.96 g, 42%) APCI (AP−): 515.1, 517.1 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCO>[Pd].C(Cl)Cl.O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: Cc1cccc(B(O)O)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mls), and H2O (0.5 mls) were combined and heated at 80° C. for 4 hours. The reaction was shown complete by TLC (CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CH2Cl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.
Reaction SMILES: C([O:8][C:9]([CH:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([NH:14][C@H:15]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]1=[O:27])=[O:13])=[O:10])C1C=CC=CC=1.[Na+].C(=O)([O-])O.[Na+]>[Pd].C(O)C>[C:9]([CH:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([NH:14][C@H:15]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([OH:26])(=[O:25])=[O:24])[C:16]1=[O:27])=[O:13])([OH:10])=[O:8]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(C(=O)O)c2ccccc2)C(=O)N1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 6 ml of 80% ethanol are added 106 mg of sodium cis-3-(2-benzyloxycarbonyl-2-phenylacetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate, 106 mg of 5% palladium-on-carbon and 16.8 mg of sodium hydrogen carbonate, and the mixture is vigorously stirred under hydrogen atmosphere for 3.5 hours at ambient temperature under atmospheric pressure. The reaction mixtue is subjected to filtration, and the filtrate is concentrated under reduced pressure. The concentrate is purified by column chromatography on Amberlite XAD-II, followed by lyophilization to give cis-3-(2-carboxy-2-phenylacetamido)-4-methoxycarbonyl-1-sulfo-2-oxoazetidine.disodium salt as a mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[OH-].[Na+].Cl.[NH2:25]O>C(O)C>[NH2:25][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])=[O:19])=[CH:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC(=O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(CN2CCC(N)CC2)cc1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
N,N-Diethyl-4-[(4-oxo-1-piperidinyl)methyl]benzamide (58.74 g, 193 mmol) is dissolved in 580 mL of ethanol and treated with 290 mL of 30% NaOH followed by hydroxylamine hydrochloride (26.82 g, 386 mmol). The mixture is refluxed for 45 minutes, the heating mantle removed and the reaction mixture stirred with an overhead stirrer as 38.4 g of 50/50 aluminum-nickel alloy (powder) are added in small portions with ice cooling. After the addition, the mixture is refluxed for 1.75 hours, then allowed to stand at room temperature overnight, filtered through Solka Floc and most of the ethanol is evaporated in vacuo from the filtrate. The resulting aqueous phase is extracted with 3×100 mL of ether. The pooled extracts are concentrated in vacuo and the oily residue is poured into 500 mL of brine and continuously extracted with ether overnight. Concentration of the extract affords 37 g of product which is purified by flash chromatography on silica gel (110 mm column, 5% ammonia saturated methanol in methylene chloride eluent) affording 7.08 g (24.4 mmol, 13% yield) of product: 1H NMR (Me2SO-d6, 300 MHz) δ7.33 (d,J=8.2 Hz, 2H), 7.27 (d,J=8.2 Hz, 2H), 1.0-3.5 (m, 21H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH2:20]O.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]=[CH:53][N:52](C(OC(C)(C)C)=O)[CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]([CH2:20][C:19]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]([CH3:16])[CH:18]=2)[CH:53]=[N:52][CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc([N+](=O)[O-])c(C)c1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
Trifluoromethanesulfonic anhydride (10.00 g, 0.0354 mol) and dry methylene chloride (60 ml) were placed into a 500 ml separable flask having its interior atmosphere replaced with well dried nitrogen gas, and cooled to -70° C. Then a solution of 3-methyl-4-nitrobenzyl alcohol (5.34 g, 0.0325 mol) and N,N-diisopropylethylamine (6.2 ml, 0.0356 mol) in dry methylene chloride (40 ml) was added dropwise over a period of 15 minutes, followed by stirring for 30 minutes, after which a solution of N,1-bis-t-butoxycarbonyl-L-histidine methyl ester (XI-2) (10.00 g, 0.0271 mol) in dry methylene chloride (40 ml) was further added dropwise over a period of 20 minutes. Thereafter, the reaction flask was taken out of the cooling bath and the mixture was stirred at room temperature for 6 hours. The reaction mixture during rapid stirring was poured into a 0.2M phosphate buffer solution (about 400 ml) to separate the methylene chloride layer, and the residue was washed with a 0.2M phosphate buffer solution (about 400 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an orange-colored oily material (12.07 g). This crude oily material was purified by silica gel column chromatography (LiChroprep Si60, 300 g, chloroform/methanol=30/1) to obtain the objective compound (IX-2) (4.45 g; yield: 39.3%) as a light-yellow oily material.