Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=S.O[Li].O.OO>O1CCCC1>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20]2[O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[C:12]([F:11])[CH:17]=1
Reactant: Fc1cc(Br)ccc1N=C=S
Reactant: Cc1cc(C)c(O)c(N)c1
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-4,6-dimethylphenol (0.85 g, 6.2 mmol) and 2-fluoro-4-bromophenyl isothiocyanate (1.44 g, 6.20 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 335[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].CC(O)=O.[CH:15]([O-])([O-])[O:16][CH2:17][CH3:18]>>[CH2:17]([O:16][C:15]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1)[CH3:18]
Reactant: CCOC([O-])[O-]
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: CCOc1nc2ccc(C#N)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-diaminobenzonitrile (400 mg) in ethyl orthoformate (6.48 ml) was added AcOH (238 mg), followed by stirring at 80° C. for 2 hours. The reaction solution was cooled to room temperature, and partitioned between EtOAc and a 1M aqueous NaOH solution. The organic layer was washed with saturated brine, dried over anhydrous Na2SO3, and then collected by filtration, and the filtrate was concentrated, and purified by silica gel chromatography to obtain 2-ethoxy-1H-benzimidazole-6-carbonitrile (164 mg) as colorless powders.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>ClCCl>[CH:1]1[C:9]([NH:10][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: CCCCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Solvent: ClCCl
Product: CCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 19.8 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.13 g, 0.57 mmol), valeryl chloride (0.068 mL, 0.57 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloromethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylpentanamide (35 mg). MS (ESI) m/z 311; HPLC purity 100% at 210-370 nm, 10.6 min.; 100% at 250 nm, 10.6 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C20H26N2O+H+, 311.21179; found (ESI, [M+H]+), 311.2118.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(F)c1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cccc(F)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluoro-6-methoxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 517.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[O:32][CH2:31][CH2:30][O:29]1.CNN>C(Cl)Cl>[NH2:11][C@H:8]1[C:9](=[O:10])[N:6]([CH2:5][C:4]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=2[O:2][CH3:1])[C@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[O:32][CH2:31][CH2:30][O:29]1
Reactant: COc1ccc(CN2C(=O)[C@H](N3C(=O)c4ccccc4C3=O)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Agent: CNN
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@H](N)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.3 %

Procedure:
The product from Example 2 (5.8 g) was dissolved in methylene chloride (40 ml) and filtered to remove a trace of insoluble solids (0.15 g). The filtrate was cooled with an ice bath and treated under a nitrogen atmosphere with methylhydrazine (0.85 g, 18.7 mmol). The reaction was stirred 2 days under nitrogen at room temperature and then filtered to remove a solid, which was washed with a small amount of methylene chloride. The filtrate ws evaporated in vacuo to give 4.65 g of the title product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:36][S:37][S:38][C:39]([CH3:43])([CH3:42])[CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:40][C:39]([CH3:43])([S:38][S:37][CH3:36])[CH3:42])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CSSC(C)(C)C=O
Reactant: COCCOCCOCCNc1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCCl
Product: COCCOCCOCCN(CC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxyl)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8 g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8 g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxyl)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z): found 684.2 (M+Na)+. See FIG. 46.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29])(=O)=O.[CH3:32][NH2:33].C(Cl)Cl.C(Cl)Cl.CO>C1COCC1.CN1C(=O)CCC1.CO>[CH3:27][N:26]1[C:18]2[CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:33][CH3:32])=[C:11]([C:28]([F:31])([F:29])[F:30])[CH:12]=3)[N:21]=[C:20]([C:22]#[N:23])[C:19]=2[N:24]=[CH:25]1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: CN
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl methanesulfonate (1.5 g) and methylamine in THF (2M, 8.25 ml) in NMP (12 ml) was heated at 100° C. under microwave conditions for 30 minutes. The mixture was then columned on silica gel using DCM-DCM-MeOH (19:1) then MeOH-2M ammonia in MeOH as eluant to give the expected product (757 mg). 1H NMR (CD3OD) δ: 8.43 (s, 1H), 8.31-8.40 (m, 3H), 7.31 (d, 1H), 4.26 (t, 2H), 4.02 (s, 3H), 2.80 (t, 2H), 2.41 (s, 3H), 2.06 (quin, 2H). MS m/z 390 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][CH2:9][C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N[C@@H](CO)c1ccccc1)c1cccc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: -60 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a mixture of 2-(3-bromobenzamido)-2(R)-phenylethan-1-ol (18 g, 56 mmol) and triphenylphosphine (19.2 g, 73 mmol)) in dry tetrahydrofuran (350 ml) cooled to -60° C. was added dropwise diethyl azodicarboxylate (12 ml, 73 mmol). The reaction mixture was allowed to warm to ambient temperature, stirred for 18 h and volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:7) to afford 2-(3-bromophenyl)-4,5-dihydro-4(R)-phenyloxazole (10.9 g, 65%) as a pink liquid.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CN(C)C=O>[O:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCCCCBr
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCOc1ccccc1
Yield: 93.4 %

Procedure:
60% Sodium hydride (1.4 g) was suspended in dimethylformamide (40 ml), and phenol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane (5.9 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 5.9 g of 5-phenoxypentyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][O:38][CH3:39])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CON
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent Mass: 536.18 (M+H).
Reaction SMILES: [P:1]([O:19][C:20]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C@H:36]4[O:40]C(C)(C)[N:38]([C:43](=[O:47])[CH:44]([F:46])[F:45])[C@@H:37]4[CH2:48][F:49])=[CH:32][CH:31]=3)=[CH:26][N:25]=2)[CH2:23][O:22][CH2:21]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].FC(F)(F)C(O)=O>[Pd].C(O)C.O.C(Cl)Cl>[P:1]([OH:11])([OH:3])([O:19][C:20]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C@@H:36]([OH:40])[C@H:37]([NH:38][C:43](=[O:47])[CH:44]([F:46])[F:45])[CH2:48][F:49])=[CH:34][CH:35]=3)=[CH:26][N:25]=2)[CH2:21][O:22][CH2:23]1)=[O:2]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C4(OP(=O)(OCc5ccccc5)OCc5ccccc5)COC4)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3(OP(=O)(O)O)COC3)nc2)cc1)C(F)F
Temperature: 25 °C
Yield: 36.7 %

Procedure:
10% Palladium on carbon (45.1 mg, 0.042 mmol) is added to a degassed solution of the product of step 1, Example 24 (451.0 mg, 0.687 mmol) in ethanol (17.1 mL) and water (3.42 mL). After purging with nitrogen, 1 atm of hydrogen is bubbled through the reaction mixture for 5 min before being left under 1 atm of hydrogen. After 1 hour the reaction mixture is filtered through solka floc, and the cake washed with ethanol. The filtrate is concentrated and azeotroped with ethanol to afford a white foam. The crude intermediate is taken up in methylene chloride (4.51 mL) and cooled at 0° C. before trifluoroacetic acid (1.06 mL, 13.7 mmol) is added and the mixture warmed to room temperature. After 4 hours the mixture is concentrated and azeotroped with methylene chloride then purified by reverse phase CombiFlash (30 g column) eluting with 0-25% acetonitrile in water (with 0.1% trifluoroacetic acid) to afford the title compound (120 mg): 1H NMR (300 MHz, DMSO-6) δ 4.27-4.52 (m, 2.5H), 4.66-4.69 (m, 0.5H), 4.87-4.90 (m, 1H), 4.97 (d, 2H), 5.08 (d, 2H), 6.20 (t, 1H), 7.48 (d, 2H), 7.69 (d, 1H), 7.75 (d, 2H), 8.14-8.17 (dd, 1H), 8.83 (d, 1H), 8.96-8.97 (m, 1H). MS (ESI+) m/z 477.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:17][NH:18][O:19][CH3:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:17][N:18]([O:19][CH3:20])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CONCc1ccc(F)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 91 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-chloro-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (91% yield): mp 110–111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.75 (2H, s), 6.38 (1H, s), 7.09 (1H, t, J=8.8 Hz), 7.23 (1H, m), 7.41 (1H, dd, J=2.4 Hz and J=6.8 Hz). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C, 52.25, H, 4.36, N, 3.87.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1
Reactant: CCN(CC)CCNC(=O)c1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Yield: 106.4 %

Procedure:
5.7 g (19.3 mmol) of 4-nitro-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is dissolved in 120 ml of tetrahydrofuran:ethanol 1:1>mixed with 2 g of palladium on carbon (10%×50% water) and hydrogenated for 1 hour at room temperature and normal pressure. After being drawn off on diatomaceous earth and after concentration by evaporation, 5.45 g of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is obtained.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1>C(OCC)(=O)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([O:45][CH3:46])=[C:38]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:37]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
To a suspension of Example 3A (5 g, 14.79 mmol) in 2:1 1,2-dimethyoxyethane/ethanol (150 mL) was added 2M aqueous sodium carbonate (29.6 mL, 59.1 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (3.02 g, 17.74 mmol) and dichlorobis(triphenylphosphine) palladium(II) (1.038 g, 1.479 mmol). The mixture was heated at 100° C. for 1.5 hours, cooled and diluted with 100 mL ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with dichloromethane, filtered, and dried under vacuum. The filtrate was concentrated to ⅓ volume, and the solid filtered and rinsed with dichloromethane. The remainder of the filtrate was purified by flash chromatography on silica (Analogix 280) eluting with a gradient of 15 to 70% ethyl acetate/hexane. This was combined with the triturated material and dried over vacuum to give the title compound. MS (ESI+) m/z 383.5 (M+H)+.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[SH:50][C@@H:51]1[CH2:55][N:54]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=2)=[O:57])[C@H:53]([C:69]([N:71]2[CH2:74][CH:73]([N:75]3[CH:79]=[N:78][CH:77]=[N:76]3)[CH2:72]2)=[O:70])[CH2:52]1>C(#N)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([S:50][C@@H:51]3[CH2:55][N:54]([C:56]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=4)=[O:57])[C@H:53]([C:69]([N:71]4[CH2:72][CH:73]([N:75]5[CH:79]=[N:78][CH:77]=[N:76]5)[CH2:74]4)=[O:70])[CH2:52]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC(n2cncn2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 3 h
Yield: 54 %

Procedure:
886 mg of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) was dissolved in 10 ml of dry acetonitrile, and 0.26 ml of diisopropylethylamine and 873 mg of (2S,4S)-4-mercapto-2-[3-(1-1,2,4-triazolyl)-1-azetidinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 120) dissolved in 5 ml of acetonitrile were added dropwise at the same time to the resulting solution, whilst ice-cooling. The mixture was then stirred at the same temperature for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting mixture was washed with water, with an aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride. The aqueous layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a gradient solution method, with mixtures of ethyl acetate and methanol ranging from 6:1 to 4:1 by volume as the eluent, to obtain 661 mg of the title compound, as a powder.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.BrC(C(F)(F)F)=C.FF.C(N(CC)CC)C>CN(C)C=O.O>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=2)=[CH:12][CH:11]=1
Reactant: ON=Cc1ccc(Br)c2ccccc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: C=C(Br)C(F)(F)F
Agent: FF
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Chlorosuccinimide (1.70 g, 12.7 mmol) was added to a solution of 4-bromo-1-naphthalenecarboxaldehyde oxime (i.e. the product of Step A, 2.33 g, 9.3 mmol) in N,N-dimethylformamide (6.0 mL). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (2.70 g, 11.2 mmol, prepared from commercially available 2-bromo-3,3,3-trifluoropropene by the method described in J. Fluorine Chem. 1999, 95, 167-170) and triethylamine (4.5 mL, 32.0 mmol) in N,N-dimethylformamide (9.0 mL) was added. After stirring for an additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate/hexanes to afford the title compound as a white solid (2.9 g). 1H NMR (CDCl3): δ 8.87 (m, 1H), 8.32 (m, 1H), 7.77 (d, 1H), 7.66 (m, 2H), 7.55 (s, 1H), 7.46 (dd, 1H), 7.32 (d, 1H), 4.24 (d, 1H), 3.88 (d, 3H).