Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Sulfur trioxide pyridine complex (847 mg, 5.36 mmol) was added to a solution of 619 mg (1.74 mmol) 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared according to step c of Example 1, 411 μL (3.23 mmol) of N,N-diisopropylethylamine, and 230 μL (3.0 mmol) of dimethylsulfoxide in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 h and then quenched with 10% citric acid (20 mL). The reaction mixture was extracted with diethyl ether (3×30 mL), dried (MgSO4), and purified by flash chromatography (diethyl ether/petroleum ether (2:1 to 4:1)) to afford 289 mg (47% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ9.83 (t, 1H, J=1.4 Hz), 7.97 (dd, 1H), 7.56-7.65 (m, 2H), 7.35-7.42 (m, 1H), 6.60 (br s, 1H), 6.57 (br s, 1H), 6.49 (br s, 1H), 4.19 (t, 2H, J=6.1 Hz), 2.86 (dt, 2H, J=6, 1.4 Hz), and 2.25 (s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[C:17]([S:18](=[O:21])(=[O:20])[CH2:19][C:10]=3[C:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:8]2)=[CH:16][CH:15]=[N+:14]([O-])[CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Fe]>[C:1]1([N:7]2[C:11]3[C:12]4[C:17]([S:18](=[O:20])(=[O:21])[CH2:19][C:10]=3[C:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:8]2)=[CH:16][CH:15]=[N:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1cc[n+]([O-])cc1-2
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccncc1-2
Temperature: 85 °C
Yield: 83.6 %

Procedure:
To a solution of ethyl 1-phenyl-1,4-dihydropyrazolo[3′,4′:4,5]thiopyrano[3,2-c]pyridine-3-carboxylate 5,5,8-trioxide (0.1 g, 0.259 mmol) in glacial acetic acid is added iron powder (58 mg, 1.038 mmol) under nitrogen and the reaction mass is heated to 85° C. for 1 h. The reaction mass is concentrated completely under reduced pressure and is partitioned between water and ethylacetate. The organic layer is separated, dried using sodium sulphate and is concentrated under reduced pressure to afford 80 mg, 83% yield of the title compound. 1H NMR (400 MHz, DMSO-d6) δ=8.85-8.84 (d, J=5.2 Hz, 1H), 8.00-7.98 (m, 2H), 7.68-7.66 (m, 3H), 7.61 (m,1H), 5.12 (s, 2H), 4.38-4.36 (q, 2H), 1.35-1.32 (t, J=7.12 Hz, 3H). MS (ESI+): 370.0.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CC#N>N1C=CC=CC=1>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[NH:21][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Nc1nccs1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(N1CCc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (8.4 g, 0.03 mol) was dissolved in pyridine (10 mL) and heated to 60° C. 2-Aminothiazole (2.5 g, 0.03 mol) was added slowly and the reaction mixture was stirred at 60° C. for 1 hour. Complete conversion to product was observed by LC/MS (10-99% CH3CN). The crude reaction mixture was then purified via column chromatography using 5% MeOH/CH2Cl2 to obtain the sulfonamide (7.0 g, 0.018 mmol, 70% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=392.0; tR=2.65 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](I)[C:16]([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:15][C:16]([CH3:19])([CH3:18])[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: CC(C)(C)CI
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Cn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1H-Indole-3-carboxylic acid (208 mg) was dissolved in N,N-dimethylformamide (10 ml), then sodium hydride (154 mg) was added thereto, and the mixture was stirred for 10 minutes at room temperature. Neopentyl iodide (0.25 ml) was added to the reaction solution and stirred for 15 hours at 80° C. Water was added to the reaction mixture which was then washed with ethyl acetate. The aqueous phase was adjusted to pH 6 by 1 N hydrochloric acid, extracted with ethylacetate, and the extract was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give the title compound (264 mg, Y.:89%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13]>CN(C)C=O>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: CNC(=O)NC
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 90 °C
Reaction time: 28 h
Yield: 81.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and 1,3-dimethylurea (441 mg; 5.0 mmoles) in dimethylformamide (DMF) (3 ml) was heated at 90° C. with stirring for 28 hours. DMF was evaporated under reduced pressure, and the residue was purified by a column chromatography on silicagel (chloroform) to give 861 mg (yield: 82%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)CSc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of Example 480A (5 g, 13.2 mmol) and Wilkinson's catalyst (1 g) in tolune (125 mL) was stirred under H2 at 60° C. for 18 hours, cooled, filtered through silica gel, and concentrated. The concentrate was dissolved in 3:1:1 THF/water/MeOH (150 mL), treated with with a 10-fold excess of LiOH, and stirred for 24 hrs. The mixture was poured into saturated NaH2PO4 (200 mL) and extracted three times with ethyl acetate (200 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324, 326 (M−H)−, (M+H)+.
Reaction SMILES: C([S:9][CH2:10][CH:11]([CH3:28])[C:12]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:25]([OH:27])=[O:26])=[O:13])(=O)C1C=CC=CC=1.N>>[SH:9][CH2:10][CH:11]([CH3:28])[C:12]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:25]([OH:27])=[O:26])=[O:13]
Reactant: COc1ccc2c(c1)CC(C(=O)O)N2C(=O)C(C)CSC(=O)c1ccccc1
Agent: N
Product: COc1ccc2c(c1)CC(C(=O)O)N2C(=O)C(C)CS

Procedure:
The title compound was prepared from 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-5-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid of Example 26 by treatment with methanolic ammonia as described in Example 5.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](OC1C=CC=CC=1)(=[O:25])[C:10]1[CH:24]=[CH:23][CH:22]=[C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=1>>[C:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:25])[C:10]1[CH:24]=[CH:23][CH:22]=[C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=1
Reactant: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccccc2)c1
Reactant: Oc1ccc(O)cc1
Product: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccc(O)cc2)c1
Temperature: 250 °C

Procedure:
330 g. (3 moles) of hydroquinone and 974 g. (3 moles) of diphenyl isophthalate are placed in a four-necked resin kettle equipped as in Example 3. The reaction mixture is stirred constantly under a nitrogen atmosphere throughout the run. The mixture is heated to 250°C, forming a melt, and the temperature is maintained at 250°C for 16 hours. During this period the hydroquinone and diphenyl isophthalate react to produce, as the principal product, p-hydroxyphenyl phenyl isophthalate, i.e., an ester of the formula ##SPC18##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(O)cc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 68.1 %

Procedure:
(S)-2-(1-((5-(4-Hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (48 mg, 0.08 mmol) was treated with trifluoroacetic acid (960 μl, 12.46 mmol) and a solution of ammonia (7N in methanol, 960 μl, 6.72 mmol) according to the method described in Example 27 to give 26 mg (69% yield) of the title compound. Purity 95%.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[S:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[S:37][C:36]([S:38]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:40])=[O:39])=[CH:35][CH:34]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-chlorothiophene-2-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH2:25][CH2:26][CH2:27]Cl)(=[O:24])=[O:23])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:27][CH2:26][CH2:25][S:22]3(=[O:24])=[O:23])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(NS(=O)(=O)CCCCl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N3CCCS3(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-3-chloro-1-propanesulfonamide (0.367 g, 0.82 mmol) in DMF (8 mL), cooled to 0° C., was added sodium hydride (60% dispersion in oil) (0.036 g, 0.9 mmol) and the mixture allowed to warm to room temperature. After 30 min, the reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The title compound, as an oil, was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1O>CO.ClCCl>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Cc1ccc(O)c(C)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c(C)c1
Yield: 71 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2,4-dimethylphenol (16 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 48 mg (71%) of the titled compound as a white solid. ESI-MS m/z 396 (MH+), 394 (M−H−).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([N+:15]([O-])=O)=[CH:13][N:12]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:11]=3)=[N:7][C:6]=2[CH:24]=1.[H][H]>CO.[Pd]>[NH2:15][C:14]1[C:10]([C:8]2[NH:9][C:5]3[CH:4]=[C:3]([NH:25][CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[C:2]([F:1])=[CH:24][C:6]=3[N:7]=2)=[N:11][N:12]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:13]=1
Reactant: [H][H]
Reactant: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3N)nc2cc1F
Yield: 92.3 %

Procedure:
350 mg of N1-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine in 15 mL of methanol and 40 mg of palladium-on-charcoal are hydrogenated under 1 bar of hydrogen pressure at 22° C. for 16 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 300 mg of N1-{2-[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine are obtained. The compound is used as it is for the subsequent stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1>>[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH:21]([C:13]([C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[C:19](=[O:20])[O:18]1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Yield: 89 %

Procedure:
A was prepared from (4R)-3-(tert-butoxycarbonyl)-1,3-thiazolidine-4-carboxylic acid (5.30 g, 22.7 mmol) and Meldrum's acid according to the previously described procedure used for Example 1C, giving the title compound as yellow solid (7.31 g, 89%). LCMS m/z 358 (M−H). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 5.88 (m, 1H), 4.80–4.51 (m, 3H), 369 (m, 1H), 3.05 (m, 1H), 2.0–1.8 (m, 3H), 1.8–1.7 (m, 6H), 1.44 (s, 5H), 1.38 (s, 4H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(C)(C)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(C)(C)N1CC(C)C

Procedure:
Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to method B1c, Step 1. The ester was reduced to 3-hydroxy-2-methyl-2-propylamine according to Method B1c, Step 2. The 2-hydroxyethylamine was treated with SOCl2 according to Method B7b, followed by 2-methyl-3-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: I.CO[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[CH2:22]([CH:18]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:4]=2[O:20][C:19]1=[O:21])[CH2:23][CH3:24]
Reactant: CCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Solvent: CC(=O)OC(C)=O
Product: CCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 63.2 %

Procedure:
Hydriodic acid (55-58%, 20 ml) was added portionwise to a solution of 2-[2-methoxy-3-(o-tolyloxy)phenyl]valeric acid (3.7 g) in acetic anhydride (10 ml) with stirring under ice-cooling, and the mixture was refluxed under heating for an hour. After cooling, the reaction mixture was evaporated. The oily residue was purified by column chromatography (silica gel, benzene) to give oily 3-n-propyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[CH2:15][C@@H:14]([C:18](O)=[O:19])[CH2:13]2)=[CH:8][CH:7]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:28][NH:29][C:18]([C@@H:14]1[CH2:15][C:16](=[O:17])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])=[CH:7][CH:8]=2)[CH2:13]1)=[O:19]
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=361 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)O1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27](OS(C(F)(F)F)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1

Procedure:
The title compound was prepared by Suzuki coupling of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)). Mass spectrum (ESI, m/z): Calcd. for C16H22N2O2, 275.2 (M+H), found 275.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][CH:3]=1.[OH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24].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>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:23](=[O:24])[C@@H:22]([OH:21])[CH3:26])[CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Brc1ccc2ncc3nnc(C4CCNCC4)n3c2c1
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: C[C@H](O)C(=O)N1CCC(c2nnc3cnc4ccc(Br)cc4n23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
A mixture of 8-bromo-1-(piperidin-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2-hydroxypropanoic acid (75 mg, 0.83 mmol), HATU (346 mg, 0.90 mmol), and DIEA (116 mg, 0.90 mmol) in DMF (5 mL) was stirred at r.t. for 6 h. Then the solvents was removed, and the residue was purified by ISCO (MeOH/H2O=20%-90%) to afford (S)-1-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as pale yellow solid (200 mg, yield 66.0%). MS (m/z): 404 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C@H:3]1[C:10]([S:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=3)=[O:18])[CH2:13]2)=[C:9]([C:29]([OH:31])=[O:30])[N:8]2[C@H:4]1[C@@H:5]([C@H:32]([OH:34])[CH3:33])[C:6]2=[O:7].C(=O)(O)[O-].[Na+:39].C(=O)=O>O.C(=O)(O)O.C1COCC1.CN(C=O)C.C(OCC)(=O)C.[Pd].[C]>[CH3:2][C@H:3]1[C:10]([S:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([C:26]([O-:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:13]2)=[C:9]([C:29]([O-:31])=[O:30])[N:8]2[C@H:4]1[C@@H:5]([C@H:32]([OH:34])[CH3:33])[C:6]2=[O:7].[Na+:39].[Na+:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)O)c4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=C(O)O
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)[O-])c4)C3)[C@H](C)[C@H]12

Procedure:
To the solution of sodium salt of di-protected Ertapenem (IV) (50 g) in carbonic acid water (500 ml), THF (100 ml), DMF (25 ml) and ethyl acetate (1000 mL) and sodium bicarbonate (6.5 gm) in autoclave, Pd/carbon charged and subjected to hydrogenation with 8 to 10 Kg pressure at 5-10° C. After completion of reaction CO2 gas was purged, the reaction mass was filtered. The aqueous layer was separated, washed with ethyl acetate and the residual solvents in aqueous layer removed using degassing technique. The pH of the aqueous layer was adjusted using acetic acid to about 5.5-7.0 and slowly added into mixture of methanol (400 ml) and absolute isopropyl alcohol (6 L) under stirring. The precipitated Ertapenem disodium was filtered, washed with IPA and dried to yield amorphous form of Ertapenem disodium of formula (I). The solid obtained was optionally treated with methanol/isopropyl ether mixture at about −20° C. to yield Ertapenem disodium with low residual solvent content.