Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][C:15]([O:17]CC)=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:20][CH2:21][C@@H:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][C@H:22]([OH:34])[CH2:21][NH:20][C:15](=[O:17])[CH2:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: CCOC(=O)COc1cccc2ccc(OC)nc12
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: COc1ccc2cccc(OCC(=O)NC[C@@H](O)CN3CCc4ccccc4C3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
Ethyl 2-((2-methoxyquinolin-8-yl)oxy)acetate (100 mg, 0.383 mmol), (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (79.0 mg, 0.383 mmol) and EtOH (1 mL) were combined in a sealed tube. The mixture was stirred at 120° C. for 30 min in a microwave. The EtOH was evaporated and the residue was purified by pre-HPLC to give the desired product (77 mg, yield 48%). 1H NMR (MeOD-d4, 400 MHz) δ: 8.36 (br. s., 1H), 8.16 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.28-7.15 (m, 4H), 7.12 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.82 (s, 2H), 4.23-4.16 (m, 3H), 4.10 (s, 3H), 3.54-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.33 (m, 2H), 3.13-2.98 (m, 4H). LCMS (m/z): 422.2 [M+H]+
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.BrC[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].P(OCC)(OCC)OCC>>[C:12]1(=[O:21])[N:11]([CH2:10][P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COP(OC)OC
Agent: CCOP(OCC)OCC
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC

Procedure:
Reaction of N-bromoethylphthalmide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].ClCC1[N:10]=[C:11]([C:14]2C=CC(C(O)=O)=CC=2)[S:12][CH:13]=1.CN(C=O)C.C(Cl)[Cl:29]>>[Cl:29][CH2:14][C:11]1[S:12][CH:13]=[C:1]([C:2]([Cl:4])=[O:3])[N:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1csc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (3.2 mL, 36.6 mmol, 5 eq.) was added dropwise to a suspension of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.30 g, 7.32 mmol, 1 eq.) in DCM (10 mL) followed by a catalytic amount of DMF at RT. The reaction mixture was allowed to stir at RT overnight and then evaporated to give the title compound as the crude product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][C@H:34]([CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[C:35]([NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12](=[O:14])[NH:33][C@@H:34]([C:35](=[O:36])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To the solution of (2S)-4-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-4-oxobutanoic acid VIII (430 mg, 1.33 mmol) in DCM (10 mL) was added DIPEA (0.65 mL, 3.75 mmol), (2R)-2-amino-N-(quinolin-6-yl)-4-[4-(trifluoromethyl)phenyl]butanamide VII (540 mg 1.21 mmol) and TBTU (428 mg, 1.33 mmol). The mixture was stirred at r.t. overnight. The reaction mixture was then washed with 1 M K2CO3, 1 M HCl, brine and dried over MgSO4. The residue was then purified on a silica gel column (50:1 CHCl3/methanol) to yield benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoate IX (680 mg, 1.00 mmol, 75% yield). 1H NMR (CDCl3) 1.46 (s, 9H), 1.88-2.20 (m, 2H), 2.40-2.64 (m, 1H), 2.66-2.88 (m, 1H), 2.92 (d, J=6 Hz, 1H), 3.27 (dd, J=5 Hz, J=17 Hz, 1H), 4.49-4.70 (m, 2H), 5.12 (d, J=5 Hz, 2H), 5.59 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.22-7.42 (m, 8H), 7.53 (s, 1H), 7.57 (s, 1H), 7.72 (dd, J=2 Hz, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 8.82 (d, J=4 Hz, 1H), 8.89 (s, 1H); 19F NMR (DMSO-d6) −61.73 (s, 3F); ESIMS found for C36H37F3N4O6 m/z 679 (M+H).
Reaction SMILES: [OH:1][C@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[C:10](Cl)(=[O:12])[CH3:11].S(Cl)(Cl)=O.C(N(CC)CC)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:35]=1[CH2:36][NH:37][C:38]([C@H:40]1[NH:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1)=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][N:45]([C:3](=[O:4])[C@H:2]([O:1][C:10](=[O:12])[CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:40]([C:38](=[O:39])[NH:37][CH2:36][C:35]2[CH:53]=[C:54]([Cl:57])[CH:55]=[CH:56][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:41]1)=[O:47])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[C@@H](O)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of (R)-2-hydroxy-3,3-dimethylbutanoic acid (86.2 mg, 0.65 mmol) in acetyl chloride (0.15 mL, 2.11 mmol) was heated to 60° C. for 15 min. Excess acetyl chloride was removed under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in thionyl chloride (0.15 mL, 2.06 mmol) and the mixture was heated at refluxed for 2 h. Volatile impurities were dissolved in THF (5 mL) and triethylamine (0.45 mL, 3.26 mmol) was added. A solution of (S)-tert-Butyl 3-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]piperazine-1carboxylate (0.30 g, 0.62 mmol) in THF (2 mL) at −5° C. was then added and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution (50 mL) then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.2 g) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)C2C=CC=C[C:45]=2N=N1.C(C1C=C(O)C=CC=1)#N.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][CH:45]=[C:31]([C:32]#[N:35])[CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc(C#N)c4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this 3-cyanophenyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and 3-cyanophenol (13.1 mg, 0.110 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at 85° C. over 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 47.5 mg (82% yield) of the title compound as a clear gum. Rf (50% EtOAc in hexanes)=0.58. 1H NMR (500 MHz, CDCl3): δ 8.49 (s, 1H, Ar—H), 8.45 (s, 1H, Ar—H), 7.62-7.54 (m, 4H, Ar—H), 6.54 (t, 1H, H-1′, J=6.4), 4.64 (m, 1H, H-3′), 4.05 (q, 1H, H-4′, J=3.4), 3.91 (dd, 1H, H-5′, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 3.9), 2.64 (app quint, 1H, H-2′, Japp˜6.3), 2.49 (ddd, 1H, H-2′, J=13.2, 6.3, 4.4), 0.92, 0.916 (2 s, 18H, tert-Bu), 0.11, 0.105 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 159.1, 153.0, 152.7, 151.6, 142.2, 130.4, 129.2, 126.7, 125.6, 122.1, 117.9, 113.6, 88.1, 84.8, 71.8, 62.7, 41.5, 25.9, 25.7, 18.4, 17.9, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C29H44N5O4Si2 (M++H) 582.2932. found 582.2927.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:23]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[N:24]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][C@@H:17]([CH3:22])[C:18]([F:21])([F:20])[F:19])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:38]1[C:39]([CH3:50])=[N:40][N:41](C(OC(C)(C)C)=O)[CH:42]=1.[C:51](=[O:54])([O-])[O-:52].[Na+].[Na+]>O1CCOCC1.O.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>[F:19][C:18]([F:21])([F:20])[C:51]([OH:52])=[O:54].[C:1]([CH2:3][C:4]1([N:23]2[CH:27]=[C:26]([C:38]3[C:39]([CH3:50])=[N:40][NH:41][CH:42]=3)[CH:25]=[N:24]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][C@@H:17]([CH3:22])[C:18]([F:19])([F:20])[F:21])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].[C:51]([OH:52])([C:18]([F:21])([F:20])[F:19])=[O:54]
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1Br
Reactant: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]cc1-c1cnn(C2(CC#N)CN(c3cnc(C(=O)N[C@@H](C)C(F)(F)F)cn3)C2)c1
Product: O=C(O)C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (27.0 mg, 0.0533 mmol), tert-butyl 4-bromo-3-methyl-1H-pyrazole-1-carboxylate (15 mg, 0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (3.1 mg, 0.0027 mmol) and sodium carbonate (17.0 mg, 0.160 mmol) in 1,4-dioxane (1.6 mL) and water (0.8 mL) under nitrogen was stirred at 100° C. overnight. The reaction mixture was filtered, and purified by RP-HPLC (pH=2 conditions) to afford the desired product as TFA salt. 1H NMR (300 MHz, CD3OD) δ 8.73 (d, J=1.4 Hz, 1H), 8.18 (d, J=0.6 Hz, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.91-7.79 (m, 2H), 4.84 (m, 1H), 4.81 (d, J=10.2 Hz, 2H), 4.60 (d, J=10.2 Hz, 2H), 3.59 (s, 2H), 2.44 (s, 3H), 1.43 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C20H21F3N9O (M+1)+: m/z=460.2. Found: 460.0.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C:13](=O)[C:12]=2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].[ClH:30].Cl.O>C(O)C>[ClH:30].[C:1]([N:9]1[C:17]2[CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C:13](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[C:12]=2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2c1ccn2C(=O)c1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2c1ccn2C(=O)c1ccccc1
Yield: 94.4 %

Procedure:
A mixture of 1-benzoyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.68 g), aminoguanidine hydrochloride (0.26 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water to give crystals, which were recrystallized from ethanol to give 1-benzoyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 11) (0.83 g) as colorless crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:53])=[C:9]([CH2:11][O:12][C:13]2[CH:52]=[CH:51][C:16]([CH2:17][N:18]3[CH:22]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:30]CC4C=CC(OCC5N=C(C6OC=CC=6)OC=5C)=CC=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.C(O)C>[C].[Pd].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:53])=[C:9]([CH2:11][O:12][C:13]2[CH:52]=[CH:51][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.9 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]propenoate (12.5 g), 5% palladium-carbon (20.0 g), ethanol (200 ml), and tetrahydrofuran (200 ml) was stirred under a hydrogen atmosphere at room temperature for 7 hours. After removal of the catalyst by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration, and ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (4.40 g, yield: 56%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 145–146° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31](F)[CH:32]=[C:33]([Cl:35])[CH:34]=1.Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[C:33]([Cl:35])[CH:32]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](O)c2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2cc(Cl)cc(Cl)c2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylate (164 mg, 0.303 mmol) in THF (2 mL) and MeOH (2.000 mL) was added pre-made solution of Lithium hydroxide monohydrate (25.5 mg, 0.607 mmol) in water (2 mL). The resulting cloudy solution was stirred at room temperature overnight. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (136 mg, 0.232 mmol, 77% yield) as a white foam. LC-MS (retention time: 3.25 min, method B), MS m/z 527 (M+H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C@H:20]([CH:40]([OH:42])[CH3:41])[C@:21]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)([O:28][Si](C)(C)C)[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1.O>O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@:21]([OH:28])([C@H:20]([CH3:19])[CH:40]([OH:42])[CH3:41])[CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:34][CH:35]=1
Reactant: CC(O)[C@@H](C)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
0.35 ml (0.35 mmole) of tetrabutylammonium fluoride (as a 1 molar tetrahydrofuran solution) was added to a solution of 85.4 mg (0.233 mmole) of (2R*,3R*)-3-methyl-2-(4-chlorophenyl)-2-(trimethylsilyloxy)-1-(1H-1,2,4-triazol -1-yl)-4-pentanol (prepared as described in Preparation 7) in 2.5 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 64 mg (93%) of the title compound. Judging from the NMR spectrum, this compound is thought to be about a 5:1 mixture of the (2R*,3R*,4S*) isomer and the (2R*,3R*,4R*) isomer.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)[CH3:2].[OH:16]O.O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)=[O:16])[CH3:2]
Reactant: CCCCS(=O)(=O)c1nnc(SCC)s1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)c1nnc(S(=O)CC)s1

Procedure:
A solution of 53.29 g of 2-Ethylthio-5-butylsulfonyl-1,3,4-thiadiazole in 500 ml acetic acid is mixed with 23 g of 30 percent hydrogen peroxide. The reaction takes place over night upon standing at room temperature. Then one liter water is added to the reaction solution, the separated oil is extracted with dichloromethane, the extract is freed from acetic acid by extraction with soda ash solution, the dichloromethane phase is dried with magnesium sulfate and the solvent is distilled off completely, finally in vacuo. The remaining residue is recrystallized from isopropylether/isopropanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:13]=[CH:12][C:5]2[CH2:6][C:7]([NH:9][C:10](=[O:11])[C:4]=2[CH2:3]1)=[O:8].[Cl:15][C:16]([Cl:22])([S:20]Cl)[CH:17]([Cl:19])[Cl:18]>C(N(CC)CC)C>[Cl:15][C:16]([Cl:22])([S:20][N:9]1[C:10](=[O:11])[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH:13]=[CH:12][C:5]=2[CH2:6][C:7]1=[O:8])[CH:17]([Cl:19])[Cl:18]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CC1(C)C=CC2=C(C1)C(=O)NC(=O)C2
Solvent: CCN(CC)CC
Product: CC1(C)C=CC2=C(C1)C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)C2
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a 200-ml methylene solution of 4,4-dimethylhomophthalimide (33.5 g) and 1,1,2,2-tetrachloroethyl sulfenyl chloride (42.2 g) at 0° C. was added dropwise 18.2 g triethylamine over 5 minutes. The mixture was stirred for 4 hours, washed with 200 ml water and dried (MgSO4). The solvent was evaporated and a brown oil was recovered, recrystallized in ethanol to yield 54 g (78%) tan solid, m.p. 112°-113° C.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[CH3:25][CH2:26][C:27](Cl)=[S:28].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:25][CH2:26][C:27]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[S:28]
Reactant: CCC(=S)Cl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 8.8 g (0.026 mol) of 7-amino-3-(5-carboxymethyl-1,3,4-oxadiazol-2-ylthiomethyl)3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml of acetone is added dropwise a solution of 3.66 g (0.029 mol) of methylthioacetyl chloride in 52 ml of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml of ethyl acetate is added and the slurry is acidified with 3n hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[S:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.32 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).