Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[CH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21]>C(C(C)=O)C>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]#[N:21])[CH2:10][CH2:11]1)([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)N1CCNCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CC(C)(C)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a suspension (10 mL) of 1-(1,1-dimethyl-2-propynyl)piperazine (350 mg, 2.3 mmol) and potassium carbonate (480 mg, 3.45 mmol) in methyl ethyl ketone (MEK) was added bromoacetonitrile (0.176 mL, 2.53 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with MEK and filtered. The filtrate was concentrated to give the title compound (0.439 g, quantitative) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@H:26]5[CH2:29][C@H:28]([O:30]C(=O)C6C=CC([N+]([O-])=O)=CC=6)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1.O>[OH:30][C@H:28]1[CH2:27][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:49])[CH3:48])[CH:19]=2)=[O:22])[CH3:25])[CH2:29]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a suspension of 4-nitrobenzoic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (250 mg, 0.36 mmol) in THF (12 mL) was added 10% aqueous sodium hydroxide (0.44 mL, 1.09 mmol), water (1 mL), and MeOH (2 mL). The reaction mixture was stirred at room temperature for 30 min then diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 80% EtOAc/hexanes to afford 140 mg (72%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide as an off-white solid.
Reaction SMILES: [NH2:1][CH:2]([C@@:5]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][CH:8]2[OH:12])[CH2:3][CH3:4].[H-].[Na+].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][N:28]=[C:29]2[O:32][CH3:33])=[CH:24][C:23]=1F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][N:28]=[C:29]2[O:32][CH3:33])=[CH:24][C:23]=1[O:12][CH:8]1[CH2:7][C@@H:6]2[CH2:11][C@H:9]1[CH2:10][C@@:5]2([CH:2]([NH2:1])[CH2:3][CH3:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2ccnc(OC)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.5 %

Procedure:
200 mg (0.82 mmol) of (1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]heptan-2-ol (89) were dissolved in 5 mL anhydrous dimethylacetamide. Afterwards, 39 mg (1.63 mmol) of NaH were added, followed by the addition of 173 mg (0.82 mmol) of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10). The mixture was stirred at ambient temperature for 20 h. Afterwards, 50 mL of a saturated aqueous NaHCO3-solution were added and the mixture extracted three times using 30 mL ethyl acetate each. The organic layer was dried using MgSO4 and evaporated. The residue was purified using chromatography on reversed phase (acetonitrile/water). The product-containing fractions were evaporated to half of the original volume, 10 mL of a saturated aqueous Na2CO3-solution was added and the mixture extracted three times using 20 mL of ethyl acetate each. The organic layer was dried using MgSO4, filtered and evaporated yielding 34 mg of the desired product 90. Rt=0.86 min (Method 18). Detected mass: 437.3 (M+H+)
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-fluoro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 394 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C@H:20]1[CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:19][CH:20]1[CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:4](=[O:18])[CH:3]=2)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reactant: C[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 10.4 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridine-2(1H)-one (173 mg, 0.652 mmol), cis-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (191 mg, 0.652 mmol) and potassium carbonate (180 mg, 1.304 mmol) in DMF (3.0 mL) was heated at 140° C. for 6 hrs and 100° C. overnight. To the above mixture additional potassium carbonate (90 mg, 1 equiv.) was added and the reaction was heated at 120° C. for 3 hrs and then cooled to room temperature. The mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (4×). The combined organic layers were washed with brine/water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield trans-isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (31.4 mg, 10.4%) as an off-white solid. 1H NMR (500 MHz, CDCl3). δ 8.07 (d, J=8.25 Hz, 2H), 7.61 (d, J=8.25 Hz, 2H), 7.22 (d, J=7.70 Hz, 1H), 6.02 (dd, J=7.70, 2.20 Hz, 1H), 5.97 (d, J=2.20 Hz, 1H), 4.50-4.66 (m, 2H), 4.09-4.13 (m, 1H), 3.09 (s, 3H), 2.91-3.05 (m, 1H), 2.10-2.22 (m, 1H), 1.96-2.07 (m, 1H), 1.69-1.85 (m, 1H), 1.51-1.64 (m, 1H), 1.48 (s, 9H), 1.23 (d, J=7.15 Hz, 3H). MS (ESI) 463 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10][N:9]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl.O>CN(C)C=O>[CH3:23][N:24]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10][N:9]=1)[CH3:28]
Reactant: CN(C)CCCl
Reactant: Oc1ccccc1-c1cc(-c2ccccc2)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccccc1-c1cc(-c2ccccc2)ncn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.8 %

Procedure:
A solution of 4-(2-hydroxyphenyl)-6-phenyl-pyrimidine (0.5 g, example 1) and sodium hydride (0.12 g, 80% in oil) in anhydrous dimethylformamide (5 ml) was stirred 20 minutes at room temperature. Then 2-dimethylaminoethyl chloride hydrochloride (0.29 g) was added and the solution was heated at 100° C. under stirring for 6 hours. The reaction mixture was cooled, then poured into water, and the separated oil was extracted with ethyl acetate. The organic layer was dried, then evaporated to dryness to give 500 mg of the title compound as a crude residue, which was purified through its hydrochloride salt. This was obtained by dissolving the free base in acetone, adding a hydrochloric acid ethereal solution and filtering off the crystallized salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](I)=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([N+:18]([O-:20])=[O:19])=[CH:10][C:11]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[C:28]=2[F:29])=[C:12]([N:14]([CH3:16])[CH3:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1I
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-dimethylamino-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C2) and 2,3-difluorophenylboronic acid according to the general procedure D. Obtained as a yellow solid (3.096 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([CH2:14][O:15]C(=O)C)=[O:13])[CH:8]=2)[NH:3]1.[OH-].[Na+].Cl>CO>[OH:15][CH2:14][C:12]([NH:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:13]
Reactant: CC(=O)OCC(=O)Nc1ccc2c(c1)CC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CO)Nc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Yield: 19.5 %

Procedure:
Acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (2.43 g, 10 mmol) was dissolved in 60 ml of methanol under stirring, and sodium hydroxide solution (20 ml, 2 mol/L) was added to the solution and stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was neutralized with hydrochloric acid solution (6 mol/L) in ice-water bath, concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain the title compound 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 44b (402 mg, yield 19.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][O:126]C(=O)C3C=CC=CC=3)[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][O:114]C(=O)C4C=CC=CC=4)[C@@H:101]([O:102]C(=O)C4C=CC=CC=4)[C@H:91]([O:92]C(=O)C4C=CC=CC=4)[C@H:81]3[O:82]C(=O)C3C=CC=CC=3)[C@H:68]([O:69]C(=O)C3C=CC=CC=3)[C@H:58]2[O:59]C(=O)C2C=CC=CC=2)[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:143]=[CH:142][CH:141]=[CH:140][CH:139]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][OH:126])[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][OH:114])[C@@H:101]([OH:102])[C@H:91]([OH:92])[C@H:81]3[OH:82])[C@H:68]([OH:69])[C@H:58]2[OH:59])[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:139]=[CH:140][CH:141]=[CH:142][CH:143]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](O[C@@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H](O[C@@H]4[C@@H](COCc5ccccc5)N(C(=O)OCc5ccccc5)C[C@H]4OCc4ccccc4)O[C@@H]3COCc3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.8 %

Procedure:
The compound (390.8 mg, 0.20 mmol) synthesized in Example 20 (20c) was dissolved in methanol (8 mL) and potassium carbonate (27.6 mg, 0.20 mmol) was added thereto, followed by stirring of the mixture at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 30:1-20:1-10:1, V/V) to obtain the desired title compound (146.5 mg, 61%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (44.1 mg, 0.203 mmol) in DCM (2 mL) was added DMAP (41.4 mg, 0.339 mmol) and DCC (41.9 mg, 0.203 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give (S)-2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (110 mg, 82%).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:17]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([NH:6][C:7]3[O:11][N:10]=[C:9]([CH3:12])[C:8]=3[CH3:13])=[O:14])[CH2:27][CH2:28]2)[CH:18]=1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3cccc(-c4ccccc4)c3)CC2)c1C
Yield: 62.7 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (265 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and then recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound (198 mg, 62.6%) as solid product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:10]2[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:9]=2[C:8](=[O:19])[CH2:7]1)=[O:5])C>[OH-].[Na+].CCOCC>[CH3:18][O:17][C:13]1[C:10]2[CH2:11][CH2:12][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][C:8](=[O:19])[C:9]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCc2c(OC)cccc2C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1cccc2c1CCC(C(=O)O)CC2=O
Yield: 65.6 %

Procedure:
A suspension of 0.7 g of (±)-1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic acid ethyl ester (prepared as described in Bowman, Tetrahedron, 48, 4027, 1992) in 2 mL of 2N NaOH was refluxed for 2 h, then cooled and extracted with Et2O. The aqueous layer was brought to acidic pH with 10% HCl, the precipitate formed was redissolved in Et2O and the organic phase was washed with water and dried. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH 9:1 respectively, yielding 0.41 g of the title compound.
Reaction SMILES: CC(OCC1CS[C@@H]2CC(=O)N2C=1C(O)=O)=O.CC(O[CH2:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34])=O.C([SiH](CC)CC)C.B(F)(F)F>FC(F)(F)C(O)=O>[CH3:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1

Procedure:
7-Amino- and 7-(N,N-disubstituted)aminocephalosporanic acids are converted to the corresponding 3-methyl-3-cephem-4-carboxylic acids by reacting the cephalosporanic acid with a tri(C1 -C6 alkyl)silane in the presence of an organic acid having a pKa of <1.5 and a Lewis acid. For example, 7-aminocephalosporanic acid (7-ACA) is reacted with triethylsilane in trifluoroacetic acid in the presence of boron trifluoride to provide 7-aminodesacetoxycephalosporanic acid (7-ADCA).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]2[C:4]=1[C:5](=O)[CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].Cl.[CH3:21][O:22][NH2:23]>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[C:5]1[C:4]2[C:12](=[C:13]([CH3:18])[C:14]([CH3:17])=[C:15]([OH:16])[C:3]=2[CH2:1][CH3:2])[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: CON
Reactant: CCc1c(O)c(C)c(C)c2c1C(=O)CC1(CCC1)O2
Agent: Cl
Solvent: c1ccncc1
Product: CCc1c(O)c(C)c(C)c2c1C(=NOC)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (0.51 g) in 9 mL of pyridine was added methoxyamine hydrochloride (0.82 g). The reaction mixture was allowed to stir at room temperature overnight. The mixture was extracted with ethyl acetate, washed with 1N HCl, and concentrated in vacuo to give 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one O-methyloxime, 1H-NMR (300 MHz, CDCl3) δ=4.58 (s, 1H, 4.01 (s, 3H), 3.05 (m, 2H), 3.02 (s, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10-1.60 (m, 6H), 1.24 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=151.0, 147.4, 146.3, 125.8, 124.6, 124.3, 115.3, 76.9, 61.9, 33.9, 33.4, 21.2, 13.6, 12.7, 12.3, 12.1 ppm. MS: (m/z)=290.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH:16]([C:17]([O:19]C)=[O:18])[CH2:15][CH2:14][C:13]2=[O:21])=[CH:7][CH:6]=1>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:13](=[O:21])[CH2:14][CH2:15][CH:16]2[C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1
Reactant: COC(=O)C1CCC(=O)N1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CN2C(=O)CCC2C(=O)O)cc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A solution of 16.80 g of sodium hydroxide pellets in 175 ml of water was treated with 75 g of (±)-1-[(4-methoxyphenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and the mixture was heated for two hours with a steam bath. The solution was cooled to room temperature and extracted with diethyl ether (2×300 ml). The aqueous phase was acidified to about pH=1 with 50 ml of concentrated hydrochloric acid and extracted with dichloromethane (3×250 ml). The dried (Na2SO4) organic phase was vacuum filtered and concentrated to an oil which solidified on standing (80 g). The solid was recrystallized from toluene (300 ml) to give 34.18 g of crystals, m.p. 103°-104.5° C.
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][CH3:12])[CH:6]=[O:7].[CH2:15]([Li])[CH2:16][CH2:17][CH3:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: [Li]CCCC
Product: CCCCC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (3.92 g) and butyl lithium (1.56M hexane solution, 15 ml) to give 1-(3,4,5-trimethoxyphenyl)-1-pentanone (2.84 g).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])[CH:4]=1)#[N:2]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C#N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
0.19 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 88 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.16 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.