Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:22][CH:21]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:15]3)[C:6]=2[N:5](COCC[Si](C)(C)C)[C:4]1=[O:58])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:24][CH:25]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:15]3)[C:6]=2[NH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)[nH]c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21
Temperature: 25 °C

Procedure:
A solution of 0.310 g of benzyl 3-[1-ethyl-2-oxo-3-(2-trimethylsilanylethoxymethyl)-2,3-dihydro-1H-benzimidazol-4-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 4 ml of tetrahydofuran is admixed with 6 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran). The reaction solution is heated to reflux over 48 hours, subsequently cooled to room temperature and admixed with 40 ml of water. The mixture is extracted with tert-butyl methyl ether (2×40 ml) and the combined organic phases are washed with 40 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.18 (3:1 EtOAc-heptane); Rt=5.66.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.C[O-].[Na+]>C(O)C(C)C.CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2([C:9]3[NH:1][C:2]4=[N:3][C:4]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[O:27])[CH2:21]5)=[CH:5][CH:6]=[C:7]4[N:8]=3)[CH2:13][CH2:12]2)[CH:15]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5cccnc5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (35 mg, 0.081 mmol) in isobutanol (500 μL) was added sodium methoxide (18 mg, 0.335 mmol) in methanol (250 μL). The reaction mixture was shaken 110° C. for 18 h. The solvent was evaporated under a nitrogen stream. The residue was partitioned between water (0.5 mL) and ethyl acetate (1.5 mL×3). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via HPLC to afford (R)-(1-(2-(1-(pyridin-3-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (7.2 mg). MS (ESI+) (M+H) 417.3; HPLC retention time 1.59 min (Method A).
Reaction SMILES: O.NN.C1(=O)[N:8]([C@@H:9]2[C:15](=[O:16])[NH:14][C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][CH2:10]2)C(=O)C2=CC=CC=C12.C(N(CC)CC)C.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)Cl)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:32]1([C:38]([NH:8][C@@H:9]2[C:15](=[O:16])[NH:14][C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][CH2:10]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)CCC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Reaction time: 72 h

Procedure:
Hydrazine monohydrate (4.59 ml., 94.6 mmol.) was added to a solution of (S)-hexahydro-6-phthalimido-2,2-dimethyl-2H-azepine-7-one [preparred as described in Example 66(e), 19.98 g., 68.76 mmol.] in methanol (250 ml.) at room temperature under argon. The resulting mixture was stirred for 72 hours then filtered to remove the white precipitate. The volatiles were evaporated and the residue was dissolved in methylene chloride (560 ml.) and filtered to remove additional precipitate. To this filtrate was added triethylamine (13.3 ml., 96.21 mmol.) followed by triphenylchloromethane (20.65 g., 74.07 mmol.) and the resulting mixture was stirred for 1.5 hours. Additional triphenylchloromethane (958 mg., 3.44 mmol.) was added and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated to give a pale yellow foam. Following a crystallization from ethyl acetate and hexanes, 7.47 g. of title product was obtained as off-white crystals. The mother liquor was concentrated and crystallized from ethyl acetate and pentane to give a second crop (8.02 g.) of title product. The mother liquor was concentrated and the residue was flash chromatographed (E Merck silica gel) eluting with 4.5:5.5 ethyl acetate/hexanes to give 6.0 g of title compound as a white foam. The combined yield of title product was 21.49 g.; m.p. 139°-140° C.; [α]D =+43.4° (c=0.37, methylene chloride). TLC (2:3 hexane:ethyl acetate) Rf =0.63.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N)(=O)C.C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C.O>[Br:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10]2
Reactant: BrBr
Reactant: CC(=O)NC1Cc2ccccc2NC1=O
Agent: CC(=O)[O-]
Agent: CC(N)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC1Cc2cc(Br)ccc2NC1=O

Procedure:
Acetic acid (3,240 mL) was added to N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (405.8 g), and the acetamide was dissolved in acetic acid at an inside temperature of 51° C. The reactor was cooled to an inside temperature of 25° C., and sodium acetate was added thereto. To the mixture maintained at an inside temperature of 25° C., bromine was dropwise added over 30 minutes under stirring. The reaction mixture was added to water (35 L), and the reactor was washed with water (3.24 L). The thus-obtained mixture was stirred at 24° C. for one hour.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([O:8][CH:6]1[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC1CCC(C(C)C)C(OC(=O)c2ccccc2)C1

Procedure:
A solution of 1-menthol (1 gram) in benzoyl chloride (1 ml) was stirred at room temperature for 72 hours. This solution yielded menthyl benzoate of 89.5% purity. Further purification of this product through column chromatography resulted to increase in purity level to at least 98.8%. This fraction yielded colourless crystals and confirmed for purity by 1HNMR, 13CNMR, IR and Mass spectra.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].N1CCCC1>CO>[C:19]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:2][C:1](=[O:3])[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:11]4[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=4)[C:17]#[N:18])[CH:5]=3)[O:10]2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(-c2cccc(C#N)c2)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3′-acetyl-4′-hydroxybiphenyl-3-carbonitrile (0.802 g, 3.38 mmol) and 1-acetylpiperidin-4-one (0.477 g, 3.38 mmol) in MeOH (50 mL) was added pyrrolidine (0.4 mL). The resulting solution was heated to reflux for 1.5 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with aqueous 1 M HCl, aqueous 1 M NaOH, and brine successively. Solvent was removed under reduced pressure after dried over anhydrous Na2SO4, to yield 0.768 g of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile as a light brown solid. It was used for next step without further purification. MS ESI +ve m/z 361 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)=[O:4].C1COCC1.[OH-].[Li+].Cl>O.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N(C)C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(C(=O)O)cn1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a 5° C. mixture of methyl 6-[(dimethylamino)carbonyl]-3-pyridine carboxylate (52.5 g, 0.252 mol) and THF (390 mL) was added a solution of lithium hydroxide (trihydrate, 11.6 g, 0.277 mol) in water (60 mL) over 6 minutes. After stirring for 1 h, 2 N HCl (145 mL) was added over a 15-min period. Toluene (200 mL) was added and the organic solvents were removed in vacuo. The slurry was filtered, and the solids were washed with water (2×20 mL) and dried at 75° C. in vacuo to provide 47 g (96%) of 6-[(dimethylamino)carbonyl]-3-pyridine carboxylic acid.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]2[C:23]=1[CH:24]=[CH:25][C-:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+]>CCOCC>[CH3:31][C:28]1[CH:29]=[CH:30][C:22]([CH3:21])=[C:23]2[C:27]=1[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:25][CH:24]2[Si:7]([CH3:17])([CH3:18])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: Cc1ccc(C)c2c1cc[c-]2-c1ccccc1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3c(C)ccc(C)c32)C(C)=C1C
Reaction time: 25 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (4,7-dimethyl-1-phenylindenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 25 hours, and was then evaporated under vacuum. The residue was extracted with pentane (3×40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 9.07 g (100%). 1H NMR(C6D6): δ 7.41 (d, 2H), 7.19 (m, 2H), 6.97 (s, 3H), 6.45 (d, 1H), 3.78, (s, 1H), 2.86 (br s, 1H), 2.30 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H), 1.89 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), −0.04 (s, 3H), −0.32 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20](=[O:21])[C@@:19]([CH2:28][O:29][C:30](=[O:43])[C@@H:31]([NH:35]C(OC(C)(C)C)=O)[CH:32]([CH3:34])[CH3:33])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]([CH3:44])[C:17]2=[O:45])=[CH:12][C:11]=1[C:46]([F:49])([F:48])[F:47])#[N:9].C1(C)C=CC=CC=1.[Cl:57]CCl>>[Cl-:57].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20](=[O:21])[C:19]([CH2:28][O:29][C:30](=[O:43])[C@@H:31]([NH3+:35])[CH:32]([CH3:34])[CH3:33])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:18]([CH3:44])[C:17]2=[O:45])=[CH:12][C:11]=1[C:46]([F:48])([F:47])[F:49])#[N:9]
Reactant: ClCCl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@@]1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]([NH3+])C(=O)OCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3 mL of trifluoroacetic acid are added to a solution of 0.65 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid (S)-[1-(4-cyano-3-trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-phenylimidazolidin-4-yl]methyl ester in 30 mL of dichloromethane. The mixture is stirred at room temperature for 5 hours, 20 mL of toluene are added then the solvent is evaporated to dryness. The crude product is diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is dissolved in 120 mL of dichloromethane/ethyl ether mixture (10/90) and 0.75 mL of a 2M hydrogen chloride solution in ethyl ether is added. After filtration, the desired compound is obtained
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:11].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
(5-Bromopyridin-3-yl)methanol (1.41 g; 7.5 mmol) is dissolved in 20 mL DCM and the flask is flushed with argon and cooled to 0° C. Phosphorus tribromide (0.70 mL; 7.5 mmol) is added dropwise via a syringe and reaction mixture is stirred at RT for 2 h. NEt3 (1 mL) is added by syringe and the reaction mixture is stirred for 1 h. The mixture is cooled to 0° C. and quenched with the slow addition of 5 mL water, followed by the addition of 2M K2CO3 until mixture is neutral (pH=˜7). The mixture is partitioned between water and EtOAc, the aqueous phase is washed three times with EtOAc and the organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Purification by column chromatography on silica gel (pre-washed with 1% NEt3) using a solvent gradient of hexanes to EtOAc led to the isolation of the desired product as white crystals (1.29 g, 69% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31]O1.[C:32]([O-:35])([O-:34])=[O:33].[K+].[K+]>CN(C=O)C>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH:29]5[CH2:31][O:34][C:32](=[O:35])[O:33]5)=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][C:15]=2[O:19][C:18]=1[CH3:20])=[O:22]
Reactant: BrCC1CO1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5COC(=O)O5)ccc34)ccc12
Yield: 50.4 %

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 110-A13(500mg, 1.43 mmol), 2-(bromomethyl)oxirane (286mg, 2.1 mmol) and K2CO3 (386mg, 2.8 mmol) in DMF(15 mL) was stirred at 90° C. for 3h. The mixture was then extracted with EtOAc. The concentrated residue was purified by silica gel column chromatography using 0-5% MeOH/CH2Cl2 to give N,2-dimethyl-6-({7-[(2-oxo-1,3-dioxolan-4-yl)methoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide 110 (323 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Product: O=C(CCN1CCCC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (400 mg, 1.0 mmol) was treated with pyrrolidine (3 mL) according to the general aminolysis procedure to give the desired product BR-ACO-16 (348.mg, 74.4%) as a dark yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[CH:15]=[C:10]([OH:9])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: COc1cccc(B(O)O)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-bromopyridine, 3-methoxyphenylboronic acid (1.3 eq.), 2N sodium carbonate, and (PPh3)4Pd in toluene was stirred at 80° C. over night. The reaction mixture was taken up in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and then brine, dried, and concentrated. The residue was diluted in CDM and the solution was treated with boron tribromide at −78° C. (acetone-dry ice bath). The bath was allowed to warm up to room temperature over approximately 5 hr. Methanol was added to quench the reaction. The volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and the resultant solution was washed with saturated sodium bicarbonate. The organic phase was then extracted with 3 N hydrochloric acid, which was then basified with sodium bicarbonate The aqueous phase was extracted with ethyl acetate, which was washed with saturated brine, dried, and concentrated. The resultant white solid was pure by TLC, MS, and 1H-NMR and was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][CH:15]=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][CH2:15][OH:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=CC=Cc1nc(-c2ccc(F)cc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
692 mg (2.97 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)propenal and 224.5 mg (5.93 mmol) of sodium borohydride were stirred in 50 ml of ethanol at room temperature for 3 h. Water was added, and the mixture was concentrated. The residue was taken up with water and ethyl acetate. The organic phase was separated and evaporated. The residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA). Yield: 280 mg (40%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:38]2[S:42]/[C:41](=[N:43]\[C:44](=O)[O-:45])/[N:40]([C:47]3[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=3[CH:54]([CH3:56])[CH3:55])[C:39]2=[O:57])=CC=1)([O-])=O>>[CH2:22]([N:21]([CH2:20][CH2:19][C:18]1[CH:25]=[CH:26][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:44](/[N:43]=[C:41]1\[S:42][CH2:38][C:39](=[O:57])[N:40]\1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=1[CH:54]([CH3:55])[CH3:56])=[O:45])[CH:23]=[CH2:24]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: C=CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine (CB26) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.040 g, 43%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([O:22][CH2:23][C:24]=1[CH:25]=[CH:26]N(C)C)[CH:20]([NH:30][C:31](=[O:61])[C:32](=[N:58][O:59][CH3:60])[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:36][CH:37]=1)[C:19]2=[O:62])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=[O:66])C>>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([O:22][CH2:23][C:24]=1[CH2:25][CH:26]=[O:66])[CH:20]([NH:30][C:31](=[O:61])[C:32](=[N:58][O:59][CH3:60])[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[S:36][CH:37]=1)[C:19]2=[O:62])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CCOC(C)=O
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A solution of the E form of the syn isomer of 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.05 g) in ethyl acetate (10 cc) is stirred vigorously for 1 hour at 20° C., in the presence of a 1 N solution of hydrochloric acid (5 cc). The mixture is separated by decantation and the organic phase is washed with a saturated solution of sodium bicarbonate (10 cc), distilled water (10 cc) and a saturated solution of sodium chloride (10 cc). The ethyl acetate phase is dried over anhydrous magnesium sulphate and filtered and the filtrate is concentrated to dryness at 30° C. under reduced pressure (20 mm Hg; 2.7 kPa). This yields the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-8-oxo-3-(2-oxoethyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.00 g) in the form of a hard yellow foam.