Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[C:17]([CH:18]=[O:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:13]2[C:17]([CH2:18][OH:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:23][CH3:24])([CH2:25][CH3:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC[Si](CC)(CC)c1occ(C=O)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane, 1.48 ml, 1.48 mmol) was added dropwise to a solution of 3-phenyl-2-triethylsilyl-4-furaldehyde (422 mg, 1.48 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon. This mixture was warmed to room temperature, quenched wtih ice-cold 5% (V/V) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. The dried extracts (magnesium sulfate) were concentrated to an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexanes to give the title compound. IR (neat): 3300 (broad); 2953 cm-1.
Reaction SMILES: C(OCC([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=O)C(=C)C.[CH2:16]([O:20]C1C=CC(N)=CC=1)[C:17](=[CH2:19])[CH3:18]>>[CH2:16]([O:20][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[NH2:9])[C:17](=[CH2:18])[CH3:19]
Reactant: C=C(C)COCC(=O)Nc1ccccc1
Reactant: C=C(C)COc1ccc(N)cc1
Product: C=C(C)COc1cccc(N)c1

Procedure:
The starting material was meta-methallyloxyacetamidobenzene, which was obtained under the same conditions as those described in Example 4, paragraph (4.1) for paramethallyloxyacetamidobenzene.
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][NH:21][C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([NH:7][CH:5]3[CH2:6][N:3]([C:23](=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27])[CH2:4]3)[C:13](=[O:14])[NH:12][CH:11]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CC/C=C/C(=O)O
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C/C(=O)N1CC(Nc2cc(-c3ccnc(NC)c3)c[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (Example 14, Step 4, 80 mg, 0.19 mmol), in DMF (1 mL) was added (E)-pent-2-enoic acid (28 mg 0.28 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.923 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep. HPLC to afford (E)-2′-(methylamino)-5-((1-(pent-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one (34 mg, 42%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (dt, J=15.3, 6.4 Hz, 1H), 6.62 (dd, J=5.3, 1.6 Hz, 1H), 6.38 (d, J=1.8 Hz, 2H), 5.85 (dt, J=15.3, 1.7 Hz, 1H), 5.48 (d, J=6.6 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 4.55-4.46 (m, 1H), 4.33 (dt, J=12.5, 6.3 Hz, 1H), 4.07 (m, 2H), 2.97 (d, J=4.9 Hz, 3H), 2.22 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); MS (ES) m/z 354 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:44][CH2:45][O:46]C(=O)C(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:44][CH2:45][OH:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: OCCOC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of benzene is cooled to 0° C. At 0° C., 31.4 g (150 mmol) of 2,2-dimethyl-propionic acid-bromoethylester is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 0° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/100 ml of water. 100 ml of 50% aqueous potassium hydroxide solution is added, and it is refluxed for eight hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 400 ml of ethyl acetate, and the pH of the aqueous phase is set at 5 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol=20:8:2). The product-containing fractions are concentrated by evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH2:10][CH2:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2]
Reactant: CCOC(=O)C1=C(N)N=C(N)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.5 %

Procedure:
To a solution of 2,6-diamino-4,5-dihydronicotinic acid ethyl ester described in Preparation Example A-13 (4.5 g, 24.6 mmol) in tetrahydrofuran (300 mL) was added 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.6 g, 24.7 mmol), which was then stirred for 40 minutes at room temperature. The residue obtained by concentrating the reaction solution was then purified by NH silica gel column chromatography (ethyl acetate) to obtain a solid of the target compound. This solid was washed with hexane and dried to obtain the title compound (3.1 g, 17.1 mmol, 69.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([O:45][C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:51]3[CH2:52][CH2:53][CH:48]([C:46]([O:45][CH2:43][CH3:44])=[O:47])[CH2:49][CH2:50]3)=[O:22])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCOC(=O)C1CCN(C(=O)C23CCC(N(CC(=O)N4C[C@@H](F)C[C@H]4C#N)C(=O)OCc4ccccc4)(CC2)CC3)CC1

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-ethoxycarbonylpiperidine (20.1 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-ethoxycarbonylpiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.1 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:15]2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38].N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:15]2)=[CH:11][CH:12]=1)[C:4]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[O:5]
Reactant: COC(=O)/C=C/c1ccccc1N
Reactant: CC(C)C(C(=O)O)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccccc1NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(C)C

Procedure:
A solution of 50 mg (0.14 mmol) of 3-methyl 2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoic acid (enantiomer 2; Example 79A), 20 mg (0.11 mmol) of methyl (2E)-3-(2-aminophenyl)prop-2-enoate, 1.5 ml of pyridine and 65 mg (0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 7 mg (0.01 mmol, 9.8% of theory) of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[S:30])[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)CCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2
Reaction time: 12 h
Yield: 94.5 %

Procedure:
A solution of (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 18.1 mmol) in THF (400 mL) was treated with Lawesson's Reagent (7.5 g, 18.5 mmol). After stirring for 12 hours, the precipitate was removed and the filtrate was concentrated. The residue was purified by silica gel chromatography with DCM to give (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 17.1 mmol, 94%): MS (m/e) 293 (M+1).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29])[CH:25]=1)[C:19]([O:21]C)=[O:20].[Li+].[OH-].Cl>C1COCC1.CO>[NH2:8][C:9]1([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29])[CH:25]=1)[C:19]([OH:21])=[O:20]
Reactant: CCCN(c1cc(COC2OCCC2(N)Cc2ccccc2)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(c1cc(COC2OCCC2(N)Cc2ccccc2)cc(C(=O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-{[(3-amino-3-benzyltetrahydrofuran-2-yl)oxy]methyl}-5-[(methylsulfonyl)(propyl)amino]benzoate TFA salt (40 mg, 0.07 mmol) in THF (0.5 mL) and MeOH (0.5 mL) is 1N LiOH (0.6 mL, 0.6 mmol) and the reaction mixture is stirred at RT for 3 h. 1N HCl (0.4 mL, 0.4 mmol) is added and the reaction mixture is concentrated in vacuo to give 3-{[(3-amino-3-benzyltetrahydrofuran-2-yl)oxy]methyl}-5-[(methylsulfonyl)(propyl)amino]benzoic acid as a white solid, used as is in the following coupling.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5]O)[CH2:3][CH2:2]1.CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Cl-].[Li+].C(OP([CH2:43][C:44]([O:46][CH3:47])=[O:45])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.C1(CC=O)CC1>C(#N)C.C(#N)C.C(Cl)Cl>[CH:1]1([CH2:4]/[CH:5]=[CH:43]/[C:44]([O:46][CH3:47])=[O:45])[CH2:2][CH2:3]1
Reactant: OCCC1CC1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=CCC1CC1
Agent: [Cl-]
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/CC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclopropylethanol (20.72 g, 240.6 mmol) (commercially available from Alfa Aesar) in 5:1 ACN/DCM (480 mL) were added TEMPO (1.879 g, 12.03 mmol) (commercially available from Aldrich) and iodobenzene diacetate (81.36 g, 252.6 mmol) (commercially available from Aldrich) as solids. The resulting slurry was stirred overnight at room temperature to afford a homogeneous solution. The reaction mixture was used directly in the next step. To a suspension of lithium chloride (15.30 g, 360.9 mmol) in ACN (400 mL) were added methyl 2-(diethoxyphosphoryl)acetate (48.04 mL, 288.7 mmol) (commercially available from Aldrich) and DBU (115.1 mL, 769.9 mmol) (commercially available from Aldrich) at room temperature. The mixture was cooled to 0° C., and to it was added 2-cyclopropylacetaldehyde (20.24 g, 240.6 mmol) solution dropwise. The resulting cloudy mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 89.A as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11]C)[CH:6]=[O:7].CNC>>[OH:11][C:10]1[C:9]([O:13][CH3:14])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CNC
Product: COc1cc(C=O)cc(OC)c1O
Temperature: 140 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A 100 ml glass autoclave is charged with 11.8 g (60.0 mmol) of 3,4,5-trimethoxybenzaldehyde and 47.2 g (420 mmol) of dimethylamine (40% solution in water). The autoclave is closed and the biphasic reaction mixture is stirred at 140° C. (autogenous pressure 10 bar) for 18 h. Excess dimethylamine and water are removed under reduced pressure, methyl tert-butyl ether is added and the mixture is acidified with 30% hydrochloric acid in water. After phase separation and removal of all volatile constituents of the organic phase, 4-hydroxy-3,5-dimethoxybenzaldehyde is obtained in a yield of 72%.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CO.[OH-].[Li+].Cl>C1COCC1>[CH:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:15])=[O:2])=[CH:7][CH:8]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)COc1ccc(C2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(C2CC2)cc1
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of (4-cyclopropyl-phenoxy)-acetic acid methyl ester (1.29 g, 6.27 mmol) in mixed solvent (10 mL, MeOH: THF=1:1) was added 1N lithium hydroxide solution (5 mL). After stirring for 6 hours, the reaction mixture was acidified with aqueous 2N HCl and subsequently extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil (1.18 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][O:9][C:8]1=[NH:12])([O-])=O.[H][H]>[Pd].CO>[NH:12]=[C:8]1[N:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:4]=2[NH2:1])[CH2:11][CH2:10][O:9]1
Reactant: [H][H]
Reactant: N=C1OCCN1Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: N=C1OCCN1Cc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
In a 100 mL round bottom flask, added palladium (110 mg, 0.10 mmol, 10% w/w on carbon), methanol (20 mL), and 3-(2-nitro-4-(trifluoromethyl)benzyl)oxazolidin-2-imine (Step 2, 600 mg, 2.07 mmol). Attached a balloon containing hydrogen, stirred at room temperature for 22 hours. Filtered through a pad of Celite, concentrated down to yield 2-((2-iminooxazolidin-3-yl)methyl)-5-(trifluoromethyl)benzenamine as a waxy orange-yellow solid. MS (M+H)+=260; Calc'd 259.22 for C11H12F3N3O.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCCC(=O)O)C1
Reaction time: 8 h

Procedure:
Stir a solution of (S)-2-(3-ethoxycarbonylpropyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.739 g, 1.84 mmol) in MeOH add 1.0 N NaOH (2.13 mL) and continue stirring overnight. Concentrate the mixture under reduced pressure, dilute with H2O (40 mL) and wash with Et2O (3×30 mL). Acidify the aqueous layer with 10% NaHSO4 (20 mL) and extract with EtOAc (3×50 mL). Dry the organic layer with Na2SO4 filter, concentrate under reduced pressure and place the residue under vacuum to give the title compound: white solid (0.618 g), mass spectrum (m/e):373.07 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][O:22][S:48]([CH3:47])(=[O:50])=[O:49])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Solvent: ClCCl
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(c3cn4cnc(SCCOS(C)(=O)=O)c4s3)[C@H](C)[C@H]12
Reaction time: 0.67 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (62.8 mg) was dissolved in 2 ml of dichloromethane. N,N-Diisopropylethylamine (0.040 ml) and 0.011 ml of methanesulfonyl chloride were added to the solution at −50° C. The mixture was stirred at that temperature for 40 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 40.9 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-methanesulfonyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[OH:4][C:5]1[CH:6]=[C:7]([C:24]2[CH:25]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:23]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: COCOc1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2cccc(O)c2)c1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 2 g (13.3 mmol) of 3-methoxymethoxyphenylboronic acid with 1.83 mL (11 mmol) of ethyl 3-iodobenzoate, 1.9 g (72%) of the expected ethyl ester are obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:14]#[N:15])=[CH:5]2)[CH2:3][CH2:2]1.C(OB(OC(C)C)OC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH:37]1([C@H:40]([O:42][C:43](=[O:52])[NH:44][C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)[CH3:41])[CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.Cl[Pd]Cl.CN(C=O)C>[CH:37]1([C@H:40]([O:42][C:43](=[O:52])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:5]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:12]4[C:7]([C:6]=3[C:14]#[N:15])=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=4)=[CH:47][CH:46]=2)[CH3:41])[CH2:39][CH2:38]1
Reactant: N#Cc1cn(C2CC2)c2cc(O)ccc12
Reactant: C[C@@H](OC(=O)Nc1ccc(I)cc1)C1CC1
Agent: Cl[Pd]Cl
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1)C1CC1
Temperature: -78 °C
Yield: 96.3 %

Procedure:
To a solution of 1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile (0.59 g, 3.0 mmol) and triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) with stirring. The mixture was stirred at −78° C. for 10 min and at room temperature for 30 min followed by the addition of (R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6 mmol) and PdCl2 (dppf) (0.11 g, 0.15 mmol). The reaction mixture was cooled to −78° C. and flushed with nitrogen whereupon DMF (30 mL) and aq. K2CO3 (2.0M, 4.5 mL, 9.0 mmol) was added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2/EtOAc, 9:1) to give (R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (1.16 g, 97%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 0.031 mL of oxalyl chloride were added to 69 mg of 3,4-dimethoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 57 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.7 mL of methylene chloride and 0.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-phenoxybenzoate.