Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH2:21])[CH2:16]1.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:21][CH2:33][C:30]2[CH:31]=[CH:32][C:26]3[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=3[N:29]=2)[CH2:16]1
Reactant: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(CCN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.22 g, 0.77 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24 h, at RT was added NaBH4 (0.03 g, 0.85 mmole). After 24 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.25 g, 70%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=4.5 Hz, 1H), 18.29 (d, J=9.1 Hz, 1H), 7.85 (m, 2H), 7.36 (d, J=9.1 Hz, 1H), 7.15 (d, J=5.8 Hz, 1H), 4.38 (s, 2H), 4.19 (s, 3H), 3.91 (m, 2H), 3.82 (m, 4H), 3.67 (s, 2H), 3.31 (m, 2H), 3.18 (m, 1H), 2.55 (m, 2H), 2.10 (m, 2H). LC-MS (ES) m/e 465 (M+H)+.
Reaction SMILES: CN(C=O)C.[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[OH:9].N1C=CN=C1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[O:9][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 15 h
Yield: 100.6 %

Procedure:
To a stirred DMF (65 mL) solution containing (R)-2-iodo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.7 g, 28 mmol), imidazole (5.25 g, 77 mmol), and 4-dimethylaminopyridine (0.30 g, 2.46 mmol) was added t-butyldimethylsilyl chloride (5.0 mL, 29.8 mmol). After 15 hours, the completed reaction was diluted with EtOAc (200 mL) and heptane (70 mL). The organic phase was washed 1×100 mL H2O, 2×100 mL aq. sat. CuSO4, 1×100 mL H2O, 1×100 mL sat'd brine, and dried over Na2SO4. The filtrate was concentrated in vacuo to give 15.81 g of a tan solid which was dissolved in ~125 mL CH2Cl2 and diluted with 650 mL heptane. The mixture was concentrated in vacuo at 40° C. to 42° C. until solids were seen (~105 mL distillate were collected), cooled to ~15° C. and filtered. The collected solids were washed with heptane and dried in vacuo at 45° C. to give 11.1 g (70%) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].Cl.[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][N:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=2)=[O:15])[N:23]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(Cl)=NN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(Cl)=NN1C(=O)c1cccc(F)c1
Temperature: 0 °C
Yield: 37 %

Procedure:
A 250 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with dry CH2Cl2 (100 mL), Hunigs base (7.8 mL, 45 mmol) DMAP (5 mg) and 3-fluorobenzoyl chloride (1.8 mL. 15 mmol). The mixture was cooled to 0° C. To this mixture was added portionwise, 3-chloro-5,5-dimethyl-4,5-dihydro-1H-pyrazole.Hydrochloride (1.68 g, 10 mmol) and the reaction was allowed to warm to RT overnight. LC-MS showed consumption of SM. The reaction was added to water (100 mL), the phases were separated and the organic phase was washed with NaHCO3 (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 20% EtOAc. Amount obtained: 0.9 g, 3.7 mmol, 37% yield. LC-MS (ESI) m/e 255 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H) 3.03 (s, 2 H) 7.14 (td, J=8.36, 1.98 Hz, 1H) 7.36 (td, J=7.96, 5.71 Hz, 1H) 7.43 (dd, J=9.57, 2.25 Hz, 1H) 7.51 (d, J=7.76 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:11]=[O:12]>>[OH:12][CH2:11][C:2]([F:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=O
Reactant: COC(=O)C(F)C(=O)OC
Product: COC(=O)C(F)(CO)C(=O)OC

Procedure:
The process according to the invention for preparing an α-fluoroacrylic acid ester is carried out in three stages. First dimethyl α-fluoromalonate is reacted with formaldehyde to give dimethyl α-hydroxymethyl-α-fluoromalonate, which is then hydrolyzed and the hydrolysis product is dicarboxylated and dehydrated, and finally the resulting α-fluoroacrylic acid is esterified with an alcohol of the formula (3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[C:6]=2[CH:21]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:12]1[CH2:13][CH:10]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cnc3ccc(Br)cc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2ncn(C3CNC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (crude) in DCM (9 mL) was added TFA (3 mL). After stirred for 2 h, the solution was concentrated to give desired product and used directly in the next step.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[O:11][CH:10]1[C@H:30]([OH:62])[C@@H:31]([C:55]([O:57]C(C)(C)C)=[O:56])[NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:54])[C@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>O>[O:29]=[C:23]1[NH:24][C:25](=[O:28])[CH:26]=[CH:27][N:22]1[C@@H:12]1[O:11][CH:10]([C@H:30]([OH:62])[C@@H:31]([C:55]([OH:57])=[O:56])[NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:54])[C@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:9]([OH:8])[C@H:13]1[OH:14]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)O)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 15.4 %

Procedure:
By using an analogous procedure to that described for Example 47, tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis[tert-butyl(dimethyl)silyl]oxy}-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (123 mg, 0.136 mmol, obtained from Example 6), trifluoroacetic acid (5 ml) and water (6 drops) were stirred for 10 hours at room temperature. The volatiles were removed and the residue was azeotroped with toluene. The resulting residue was purified by preparative HPLC (20×250 mm YMC-ODS column eluted with 10-70% acetonitrile in water containing 0.02% trifluoroacetic acid over 49 minutes) to provide (5S,12S)-12-[(R)-[(3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxy-tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oic acid (13 mg, 15%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=4)(=[O:29])=[O:28])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)c3)c2[nH]1
Yield: 72 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethyl)benzenesulfonyl chloride to afford the title compound as an off-white solid (42 mg, 72%). 1H-NMR (δ, ppm, DMSO-d6): 6.19 (d, 1H, HPy,5, J=5.5 Hz), 6.78 (s, 1H, Harom), 6.86 (d, 1H, Harom, J=8.0 Hz), 6.98 (d, 1H, Harom, J=7.5 Hz), 7.31-7.35 (m, 1H, Harom), 7.74 (d, 1H, HPy,6, J=5.5 Hz), 7.82-7.85 (m, 1H, Harom), 7.96-8.06 (m, 4H, Harom), 10.57 (s, 1H, NHSO2), 11.13 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.21, 110.98, 113.74, 115.45, 116.59, 123.09, 123.24, 129.88, 130.68, 131.02, 131.08, 138.71, 138.72, 140.20, 141.16, 144.09, 147.21, 154.15, 155.04. HRMS (EI): m/z [M+H] calcd for C19H14F3N4O4S: 451.0688; found: 451.0687.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH2:18][CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:33]([O:35][CH2:36][CH3:37])=[O:34])#N>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#N
Reactant: O=C1CCc2c1ccc1nn(Cc3ccccc3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Temperature: -70 °C

Procedure:
A stirred suspension of 2-benzyl-7,8-dihydrocyclopenta[e]indazol-6(2H)-one (10.3 g, 39.3 mmol) in 180 mL of THF was cooled to −70° C. and a 1.0M solution of lithium bis(trimethylsilyl)amide in THF (86 mL, 86 mmol) was added dropwise during 20 minutes. The reaction mixture was allowed to warm to −33° C. during approximately 1 hour giving a reddish brown solution. The solution was re-cooled to −65° C. and ethyl cyanoformate (5.9 mL, 60 mmol) was added during 1 minute. The reaction mixture was allowed to warm to 15° C. during 2¾ hours and was then partitioned between ethyl acetate and 1N aqueous HCl. The organic phase was washed successively with water, saturated NaHCO3 and brine. After drying over Na2SO4 the solution was filtered through a short column of silica gel and evaporated under vacuum to give ethyl 2-benzyl-6-oxo-2,6,7,8-tetrahydrocyclopenta[e]indazole-7-carboxylate as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=[N:3]1
Reactant: Cc1c(C=O)cnn1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnn(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (400 mg), sodium hydride (60% in oil, 155 mg), ethyl diethylphosphonoacetate (795 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3-(1,5-dimethyl-1H-pyrazol-4-yl)acrylate (304 mg, 49%) as colorless prism crystals. melting point: 82-83° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:24]([Cl:34])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:36]>O1CCOCC1.O>[Cl:34][C:24]1[CH:23]=[C:22]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:9])=[O:36])[CH:27]=[CH:26][C:25]=1[S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 105 °C

Procedure:
A solution of (R)-3-cyclopentyl-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (1.5 mmol) in dioxane (5 mL) is treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution is then heated at 105° C. for 16 h. The reaction is then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts and dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-3-cyclopentyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[NH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29]([NH:32][O:33][CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][O:35]5)=[O:30])[CH:22]=4)[O:17]3)[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: NOC1CCCCO1
Reactant: COc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.360 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the desired hydroxamic acid as a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([C@@H:26]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[N:28]([NH2:34])[C:27]1=[O:35])=[O:25])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=O)C1C=CC=CC=1.[H][H].C(N(CC)CC)C.[C:45]1(/[CH:51]=[CH:52]/[S:53](Cl)(=[O:55])=[O:54])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>[Pd].C(OCC)(=O)C.C1COCC1>[C:45]1(/[CH:51]=[CH:52]/[S:53]([NH:11][C@H:12]([C:24]([C@@H:26]2[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[N:28]([NH2:34])[C:27]2=[O:35])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:55])=[O:54])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: [H][H]
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OCc2ccccc2)C(=O)N1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NS(=O)(=O)/C=C/c2ccccc2)C(=O)N1N
Temperature: -15 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
(3S,4S)-3-{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (237 mg, 0.5 mmol) obtained in example 8, was hydrogenated with 400 mg of 10% palladium on activated carbon in ethyl acetate (20 ml) and THF (10 ml) at 50 psi hydrogen pressure at room temperature for 2 hrs. After removal of catalyst by filtration, the desubstituted (3S,4S)-3{β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one was cooled to -15° C. Then triethylamine (50 mg, 0.5 mmol) and trans-2-phenyl-eth-1-ene sulfonyl chloride (101 mg, 0.5 mmol) were added at -15° C. Stirring was continued at a bath temperature of -10 to 0° C. for 1 hr and 5° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with cold saturated NaHCO3 solution, water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1) as eluent and the title compound (30 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: COC(=O)C[C@@H](N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (3R)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.25 g, 0.91 mmol), sodium carbonate (0.10 g, 0.91 mmol) and N-carboethoxyphthalimide (0.20 g, 0.91 mmol) were allowed to react according to the procedure of Example 85. Methyl (3R)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.29 g (88%); 1H NMR (DMSO-d6, 250 MHz)δ 7.87 (br s, 4H, Ar), 6.80-7.10 (m, 3H, Ar), 5.64 (dd, 1H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.30-3.67 (m, 2H); 13C NMR (DMSO-d6)δ 170.8, 167.6, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.2, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19NO6.0.80 H2O. Theoretical C, 62.60; H, 4.99; N, 3.69. Found C, 62.60; H, 4.93; N, 3.69. HPLC 99.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([F:16])[CH:18]=1)=[CH:11]2
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.20 g, 0.71 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol) according to Method A to yield 0.14 (60%) of a yellow solid: mp 198–200° C.;1H NMR (DMSO-d6): δ 3.91 (3H, s), 7.27–7.33 (1H, m), 7.45 (1H, d, J=8.93 Hz), 7.71–7.74 (1H, m), 7.85 (1H, dd, J=2.23 Hz, J=13.09 Hz), 8.00 (1H, d, J×9.08 Hz), 8.48 (1H, d, J=1.97 Hz), 8.57 (1H, d, J=1.95 Hz), 11.18 (1H, s); MS (ESI) m/z 326/328 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[N:6]1([CH2:12][C:13](OCC)=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[NH2:19][NH2:20].Cl>C1(C)C=CC=CC=1.O1CCOCC1>[N:6]1([CH2:12][C:13]2[CH:4]=[C:3]([NH2:5])[NH:20][N:19]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC#N
Reactant: NN
Reactant: CCOC(=O)CN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1cc(CN2CCCCC2)n[nH]1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
NaH (0.234 g, 5.84 mmol) in dry toluene (5 ml) was heated to 80° C. A mixture of acetonitrile (0.229 ml, 4.38 mmol), ethyl 1-piperidineacetate (0.5 g, 2.92 mmol) and toluene (3 ml) was added dropwise to the hot reaction mixture. The mixture was stirred at 80° C. for 1.5 hours and after cooling to RT, quenched by the addition of water (6 ml). Hydrazine hydrate (0.142 ml, 2.92 mmol) was added and reaction mixture reheated to 80° C. for 3 hours. The reaction mixture was acidified with 2N HCl (aq.) to pH 2 and loaded onto a SCX-2 cartridge eluting with MeOH followed by 7M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford an oil. 4N HCl in dioxane (15 ml) was added to the yellow oil and the resulting suspension was filtered and washed with iso-hexane to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OCC)(=[O:16])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)n1)c1ccncc1
Temperature: 45 °C

Procedure:
To a cold (O ° C.) solution of 6-chloro-2-picoline (14.5 mL, 132.3 mmol) and ethyl isonicotinate (20.0 g, 132.3 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (280 mL 1.0 M in tetrahydrofuran, 278 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resulting solution was heated at 45° C. for 15 hours. The mixture was cooled to room temperature, methanol was added, and the solution was concentrated to give 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone as a syrup, that was used without further purification. This syrup (11.7 g, 50 mmol) was dissolved in methanol (200 mL). To this solution was added hydroxylamine hydrochloride (17.5 g, 250 mmol) followed by the addition of a sodium hydroxide solution (10 g, 250 mmol in 30 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone oxime (10.5 g, 850%) as a white solid. 1H NMR (CDCl3): δ 9.6 (broad s, 1H), 8.65 (d, 2H), 7.70 (d, 2H), 7.58 (t, 1H), 7.22 (m, 2H), 4.40 (s, 2H); MS m/248 (M+1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+].O>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]([OH:8])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1cccnc1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Nicotinaldehyde (0.500 mL, 4.83 mmol) was dissolved in THF (7.0 mL). n-Butyllithium (2.76 mol/L solution in n-hexane, 2.63 mL, 7.25 mmol) was added at −78° C. and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound A18 (597 mg, 75% yield).