Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 95 °C
Reaction time: 19 h
Yield: 89.5 %

Procedure:
Methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 57% ee) was dissolved in dimethylacetamide (DMAc; 3 ml) and potassium carbonate (474.1 mg) was added thereto at room temperature. Then the liquid reaction mixture was stirred at 95° C. for 19 hours. After adding water to the liquid reaction mixture, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to thereby give the title compound (179 mg) as colorless crystals. The optical purity of this product was 0% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:43][O:44][CH2:45][CH2:46][NH2:47]>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), 2-methoxyethylamine (0.203 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (10–90% acetonitrile/water). The pure fractions were made basic with ammonium hydroxide, and the solution evaporated under reduced pressure, diluted with water and filtered to give the title compound (0.162 g, 66% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.70 (t, 1H), 8.56 (s, 1H), 8.08 (AB quartet, 2H), 7.92 (dd, 1H), 7.63 (d, 1H), 7.40 (t, 2H), 3.49 (s, 3H), 3.34 (m, 2H), 3.28 (s, 2H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
To a stirred suspension, under nitrogen, of 14.0 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1H-indazole in 180 ml of tetrahydrofuran was added, dropwise, 55 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The reaction mixture was stirred under reflux for 1 hr and then stirred at ambient temperature for 15 hrs. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the filtrate was concentrated. Recrystallization of the residue from toluene afforded 9.0 g (68%) of product Recrystallization of a 3.0 g sample from toluene yielded the analytical sample, mp 175-178° C.
Reaction SMILES: [C:1]1([C@@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using (S)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=N)=O)(C)(C)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]=[N:29]O)=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:8]=[N:9][C:10]([C:12]3[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=3[F:18])=[N:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: O=C(C=NO)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NNC(=N)c1c(F)cccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1ncc(-c2ccc(Br)cc2)nn1
Temperature: 10 °C

Procedure:
A mixture of 200 mg of N′-[(2,6-difluorophenyl)-iminomethyl]-hydrazinecarboxylic acid tert-butyl ester, 114 mg of (4-bromophenyl)-oxoacetaldehyde oxime and 123 mg of sodium acetate in 1.5 ml of glacial acetic acid is heated at 10° C. for 3 h. After cooling to room temperature, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed in succession with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography (1% methanol in dichloromethane). In this way the title compound having a melting point of 180-181° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([OH:28])=[O:27].Cl>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=2[C:26]([OH:28])=[O:27])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A slurry of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.250 g, 3.47 mmol) DIPEA (3.03 mL, 17.35 mmol) and 2-amino-6-fluorobenzoic acid (0.646 g, 4.16 mmol) in iPrOH (30 mL) was heated at 90° C. for 3 h. The resulting mixture was allowed to cool to rt and diluted with EtOAc (100 mL) and a 1N HCl solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL) and a saturated NaCl solution (100 mL). The organic layer was diluted with Et2O and the resulting slurry filtered. The solids were washed with Et2O and dried in vacuum to afford 2-({2-chloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (0.69 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 6.71-6.87 (m, 1H), 7.21-7.36 (m, 1H), 7.48 (d, J=8.06 Hz, 2H), 7.76 (s, 1H), 7.96 (d, J=8.42 Hz, 2H), 8.26 (d, J=8.61 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19](O)=[O:20])=[CH:14][C:13]=2[F:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:65]([C:69]1[CH:73]=[C:72]([CH2:74][NH2:75])[N:71]([C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([Cl:82])[CH:77]=2)[N:70]=1)([CH3:68])([CH3:67])[CH3:66]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:65]([C:69]1[CH:73]=[C:72]([CH2:74][NH:75][C:19](=[O:20])[CH:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][CH2:11]3)=[C:13]([F:23])[CH:14]=2)[CH3:22])[N:71]([C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([Cl:82])[CH:77]=2)[N:70]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: CC(C(=O)O)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanoic acid (135 mg, 0.400 mmol, 1 eq) in THF/DMF (3 mL/0.15 mL) was added DIPEA (0.271 mL, 1.6 mmol, 4 eq) followed by TBTU (131 mg, 0.400 mmol, leg) and HOBt (131 mg, 0.400 mmol, 1 eq) at RT and the mixture was stirred for 3 h, then (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (175 mg, 0.56 mmol) was added and the mixture stirred for another 36 h. After completion of the reaction the reaction EtOAc was added and the mixture was washed with H2O (15 mL), dried (Na2SO4) and the solvent evaporated. The crude product was purified by CC using EtOAc/cyclohexane (1:4) to get N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanamide (143 mg; 61%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:17][CH2:18][C:19](OC)=[O:20])[S:15][CH:16]=2)[N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[OH:20][CH2:19][CH2:18][CH2:17][C:14]1[S:15][CH:16]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)[CH:13]=1
Reactant: COC(=O)CCc1cc(CCc2csc(NC(C)=O)n2)cs1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2csc(CCCO)c2)cs1
Temperature: -45 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of methyl 3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)propionate (1.450 g, 4.284 mmol) in anhydrous tetrahydrofuran (28 ml) was added dropwise 1.5M diisobutylaluminum hydride (10.7 ml, 16.1 mmol) at −50° C. over 30 min. After stirring at −50 to −40° C. for 2 hr, saturated aqueous potassium sodium tartrate solution (60 ml) was added. The mixture was warmed to room temperature, and stirred for 1.5 hr. The mixture was extracted 3 times with ethyl acetate, and washed with 1M hydrochloric acid, saturated-aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=2:1) to give N-(4-{2-[5-(3-hydroxypropyl)thiophen-3-yl]ethyl}-1,3-thiazol-2-yl)acetamide (499.9 mg, 1.610 mmol, yield 37.6%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:17][C@H:18]([OH:37])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([C:13]([NH:15][CH:16]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:17][CH:18]([OH:37])[CH:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 135 mg (0.27 mmol) of (2S,3S,5S)-5-(N-(N-(t-butyloxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane was added 8 ml of 4M HCl in dioxane. The resulting mixture was stirred at ambient temperature for 1 h and concentrated in vacuo to provide the crude desired compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][O:36][C:37]1[C:38]([NH2:43])=[CH:39][CH:40]=[CH:41][CH:42]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][CH3:35])=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COc1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1NC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2-anisidine (0.109 ml, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the objective product as a solid material.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].OO.O.Cl>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 116.7 %

Procedure:
1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Aldrich, 700 mg, 2.46 mmol) was dissolved in THF (6 mL) and cooled to 0° C. NaOH 2.5 M (2 mL, 4.93 mmol) and H2O2 30% solution in water (503 μl, 4.93 mmol) were added and the reaction mixture was stirred at room temperature for 45 min. Then the pH was adjusted to 2 by the addition of aqueous HCl 2 M and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluant. The expected fractions were combined and evaporated under reduced pressure to give the title compound 1-benzyl-1H-pyrazol-4-ol (500 mg, quantitative yield). LCMS: (M+H)+=175; Rt=0.61 min.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][CH:16]3[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])[CH2:17]3)[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:55]2[C@H:56]([CH3:79])[C@H:57]3[C@@H:74]([C@H:75]([OH:77])[CH3:76])[C:73](=[O:78])[N:58]3[C:59]=2[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=2)=[O:61])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]([N:18]2[CH2:19][CH:16]([NH:15][C:14]([C:12]3[N:13]=[C:9]([N:7]4[CH2:8][CH:5]([S:4][C:55]5[C@H:56]([CH3:79])[C@@H:57]6[C@@H:74]([C@H:75]([OH:77])[CH3:76])[C:73](=[O:78])[N:58]6[C:59]=5[C:60]([O:62][CH2:63][C:64]5[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=5)=[O:61])[CH2:6]4)[S:10][CH:11]=3)=[O:33])[CH2:17]2)=[O:21])=[CH:25][CH:26]=1)([O-:32])=[O:31]
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
Reactant: CC(=O)SC1CN(c2nc(C(=O)NC3CN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NC5CN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 3-acetylthio-1-{4-[1-(p-nitrobenzyloxycarbonyl)-azetidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (400 mg, 0.814 mmol) (obtained as described in Reference Example 54) in dimethylformamide (20 ml) was added hydrazine acetate (90 mg, 0.977 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (484 mg, 0.814 mmol) in acetonitrile (25 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (568 μl, 3.26 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (9:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[1-(p-nitrobenzyloxycarbonyl)-azetidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (496 mg, yield 77%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].N1C=CN=C1.[CH3:16][CH:17]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH3:18].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:16]
Reactant: Cc1cc(O)c(F)cc1F
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirred solution of 2,4-difluoro-5-methylphenol (780 mg, 5.41 mmol, 1.0 eq) and imidazole (442 mg, 6.5 mmol, 1.2 eq) in DMF (10 mL) at 0° C. was added TIPSCl (1.15 g, 5.95 mmol, 1.1 eq) dropwise. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether: EtOAc, 100:1) to give the title compound as a colorless oil (1.2 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:6]=1[CH3:45])=[O:4].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25]([S:54]([CH3:53])(=[O:56])=[O:55])[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:6]=1[CH3:45])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)C(=O)OC(C)(C)C)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)S(C)(=O)=O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of Intermediate 18 (0.12 g, 0.19 mmol) in DCM (2.5 mL) and TFA (0.25 mL) was added. The resulting mixture was stirred at RT for 1 hour and then evaporated in vacuo. The resulting residue was taken up in DCM (4 mL), and then triethylamine (105 μL, 0.75 mmol) added, followed by methanesulfonyl chloride (28 μL, 0.36 mmol). The reaction mixture was stirred at RT for 30 mins and then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM as eluent to yield the title compound as a white solid (106 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (R)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).