Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][Mg]Cl.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1.C[Si](Cl)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:18])[CH2:13]1
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 3-methoxybenzylmagnesium chloride (19.8 mole) in tetrahydrofuran (20 ml) was added a mixture of 2-cyclohexen-1-one (1.9 g) and trimethylsilyl chloride (5.8 ml) in tetrahydrofuran (30 ml) at -78° C. under N2. The mixture was stirred for 1 hour at 0° C. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give 3-(3-methoxybenzyl)cyclohexanone (2.12 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:47](=[O:71])[CH2:48][CH2:49][N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[C:51](=[O:60])[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[CH2:53]([O:52][C:51]([N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[CH2:49][CH2:48][C:47]([N:27]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:26][CH2:25][N:14]([CH2:13][CH2:12][C:5]1[C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[C:2]([OH:1])=[CH:3][CH:4]=1)[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:71])=[O:60])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)N(CCNC1CCOCC1)CCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(Cl)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCOCC1)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of benzyl 2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(tetrahydro-2H-pyran-4-ylamino)ethyl)carbamate (2.5 g), as prepared as in Example 23 step i), in dichloromethane (40 mL) was added triethylamine (2.95 mL) followed by chlorotrimethylsilane (2.69 mL). The reaction was allowed to stir for 30 min before a solution of the acid chloride of step i) (2.198 g) in dichloromethane (20 mL) was added. The reaction was stirred for 2 h before the mixture was diluted with dichloromethane (200 mL), washed with water (150 mL) and saturated sodium hydrogen carbonate (150 mL), and the organic layer was dried over sodium sulphate, filtered and evaporated to afford crude product. This was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (3.10 g) as a off-white foam.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].C1N=C[N:23](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:23])=[O:4]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CDI) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH4Cl and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d6-DMSO): δ □11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS (ES): 270 (M+1).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:49].O>O1CCCC1>[Si:3]([O:10][C@H:11]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[N:25]([CH3:49])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
NaH (8.38 mg of a 60 wt % dispersion in mineral oil, 0.210 mmol) was added to a stirred, room temperature mixture of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate (120 mg, 0.191 mmol) in tetrahydrofuran (1.9 mL), and the mixture was stirred for 30 minutes. After 30 minutes, iodomethane (0.014 mL, 0.23 mmol) was added and the mixture was stirred for 12 hours. Water was then added and the mixture was partitioned with EtOAc. The aqueous extracts were extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product as an orange oil that was used directly in the next step. LC-MS=644.3 (M+1)+.
Reaction SMILES: ClC(Cl)([O:4][C:5](=[O:11])[O:6]C(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][OH:21])[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][N:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][OH:21])[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][N:15]=1.[C:5](=[O:4])([O-:11])[O-:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: ClCCl
Product: O=C([O-])[O-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
mPEG21OH (0.21 mmol, 200 mg) and DMAP (1.0 mmol) were dissolved in anhydrous DCM (10 ml). Triphosgene (0.13 mmol, 39 mg) was added at room temperature. The solution was stirred at room temperature for 5 minutes. Metronidazole (1.0 mmol, 171 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was evaporated at reduced pressure. The residue was extracted with EtOAc/H2O (20 ml/20 ml) three times. The aqueous phases were combined and adjusted to PH 4.0 by adding 0.1N HCl solution. The solution was extracted with DCM (3×20 ml). The organic phases were combined and dried with anhydrous Na2SO4. The solid was filtered off and the solvent was evaporated to give compound 2d (220 mg, yield 90%). 1H NMR (CDCl3) δ 7.89 (s, 1H), 4.53 (t, 2H), 4.43 (t, 2H), 4.19 (t, 2H), 3.63-3.46 (m, 80H), 3.31 (s, 3H), 2.45 (s, 3H). LC/MS 1154 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C)(=O)=O.[CH3:24][NH2:25]>N1C=CC=CC=1.CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([NH:25][CH3:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-benzhydryl-azetidin-3-ol (15 g, 62.7 mmol) in pyridine (60 mL) was cooled to 0° C., treated with mesyl chloride (6.3 mL, 81 mmol) and stirred at room temperature for 3 hours. The mixture was partitioned between ether (300 mL) and H2O (150 mL). The ether layer was washed with H2O, washed with brine, dried (MgSO4), filtered and concentrated to provide a greenish solid. The solid (23.3 g) was mixed with methyl amine (40% in H2O, 90 mL) in DMF (60 mL), heated at 85° C. for 48 hours, cooled to room temperature, and partitioned between H2O (200 mL) and EtOAc (400 mL). The aqueous was extracted with additional EtOAc. The combined organics were extracted twice with 2 N HCl (200 mL). The combined 2M HCl layers were basified with NaOH (50%) and extracted with diethyl ether. The ether layer was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified on a silica gel column eluting with NH4OH/MeOH/CH2Cl2 (0.4/4/96) to provide the title compound. NMR (CDCl3): δ 2.26 (s, 3H), 2.83 (t, J=6 Hz, 2H), 3.33 (m, 1H), 3.46 (t, J=6 Hz, 2H), 7.15-7.20 (m, 2H), 7.24-7.29 (m, 4H), 7.36-7.4 (m, 4H). MS (DCI-NH3) m/z 254 (M+H)+.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7][CH3:8].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[S:7][CH3:8])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1Br
Reactant: CSc1ccsc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1ccsc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
A solution of 2-iodo-3-methylthiothiophene (18 g, 70.3 mmol, preparation 2), 4 bromobenzeneboronic acid (14.1 g, 70.3 mmol), potassium carbonate (21.4 g, 155 mmol), tetrakis(triphenylphosphine)-palladium (0) (8.1 g, 7.02 mmol) in a mixture of anhydrous dimethoxyethane (300 ml) and absolute ethanol (150 ml) is degassed with Ar or N2 for 15 min and stirred for 12 hours at 80° C. The reaction mixture is cooled to room temperature, water (100 ml) is then added and the crude product is extracted with methylene chloride (3×150 ml). The crude product is purified by column chromatography using hexane as eluent solvent yielding 12 g (60%) of title compound as a white solid. NOTE: This product is also light sensitive and should be used immediately.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[CH2:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C(=O)C>[CH2:21]([O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCO
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
In a 1 liter flask were charged 1-fluoro-2,4-dinitrobenzene (40.94 g, 0.22 mol), triethylamine (24.29 g, 0.24 mol), 1-decanol (34.82 g, 0.22 mol), 220 g of N,N-dimethylacetamide and stirred at room temperature for 24 hours under a nitrogen atmosphere. The resultant etherified product was extracted with 1 liter of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain crude product. Isolation and purification of the target product by silica gel chromatography afforded 57.80 g (yield: 81%) of 4-decyloxy-1,3-dinitrobenzene as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][CH:14]=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: [OH-]
Reactant: COc1ccc(C2CC2CC=O)cc1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CC2CC(=O)O)cc1F
Reaction time: 3 h
Yield: 79.6 %

Procedure:
[2-(3-Fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde (0.088 g, 0.42 mmol) obtained in Step C was dissolved in EtOH (2 mL). AgNO3(0.143 g, 0.84 mmol) dissolved in water (0.26 mL) and NaOH (0.067 g, 1.69 mmol) dissolved in water (0.26 mL) was added thereto in turn, and the mixture was stirred for 3 hours. After the termination of the reaction, the reactant was filtered by using celite to remove solid material, and 1N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with EtOAc was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.075 g, 79%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][S:31]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH3:21])=[CH:5][CH:4]=1)(=[O:33])=[O:32]
Reactant: CN(CCCC(=O)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCC(=O)c1ccc(COS(C)(=O)=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
The compound (651 mg, 2.12 mmol) obtained in Example 78a was dissolved in dichloromethane (20 mL), triethylamine (0.590 mL, 4.24 mmol) and methanesulfonyl chloride (0.245 mL, 3.18 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude 4-{4-[(tert-butoxycarbonyl)(methyl)amino]butanoyl}benzyl methanesulfonate (851 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[NH:24]N.Cl>C(O)C>[CH3:12][O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][C:9]=1[CH3:13])[C:6]1[NH:24][C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=3[C:5]=1[CH2:4]2
Reactant: Cc1ccc(NN)c(C)c1
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Agent: Cl
Solvent: CCO
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2c(C)cc(C)cc12
Reaction time: 2 h

Procedure:
4,6-Dimethyl-5-methoxy-1-indanone (2.2 g, 11.6 mmol) and 2,4-dimethylphenylhydrazine hydrochloride (2.00 g, 1 eq) were heated to reflux in ethanol (15 cm3) containing conc. HCl (1 cm3). After 2 hours, the precipitate was filtered and washed with ammonium hydroxide solution. All the collected material was extracted with ethyl acetate with the aid of salting out. The solvent was dried, and evaporated in vacuo and the product purified by column chromatography, eluting with 5% EtOAc/60°-80° petrol. The indole was recrystallised from dichloromethane/60°-80° petrol as pale beige needles. M.p. 210° C. 1H NMR (CDCl3)δ: 8.03 (1H, br), 7.25 (1H, s), 7.15 (1H, s), 6.81 (1H, s), 3.76 (3H, s), 3.53 (2H, s), 2.49 (3H, s), 2.43 (3H, s), 2.37 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[CH3:17][O:18][NH2:19].Cl>C(O)C>[CH3:17][O:18][N:19]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=NOC)c1ccc(OC)cc1
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (500 mg) and MeONH2.HCl (207 mg) in ethanol (4 mL) was heated at 80° C. for 2 h. Ethanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue. The aqueous solution was extrated with ethyl acetate (x4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a colorless oil, which was used directly in the Step B. HPLC retention time: 2.02 min (method A). MS (ESI) (M+H)+ 252.14.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][N:19]=[C:18](Br)[CH:17]=1)[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu](I)I.C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:17]=[CH:18][N:19]=[C:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[CH:2]2)[CH:21]=1)[CH3:13]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1ccnc(Br)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(-n2cc(C#N)c3ccccc32)c1
Temperature: 110 °C
Reaction time: 38 h
Yield: 30.1 %

Procedure:
A mixture of 1H-indole-3-carbonitrile (0.1 g), 2-bromoisonicotinic acid ethyl ester (0.16 g), potassium phosphate (0.27 g), (1R,2R)-(−)-N,N′-dimethylcyclohexane-1,2-diamine (0.017 g), copper iodide (0.006 g) and toluene (0.7 mL) was stirred at 110° C. for 38 hours. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90 to 66/34) to give the title compound (0.061 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[N+:47]([C:50]1[CH:61]=[CH:60][C:53]([CH2:54][O:55][C:56](=[O:59])[CH2:57][NH2:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[N+:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][O:55][C:56]([CH2:57][NH:58][C:1]([C:4]2[N:5]=[C:6]([N:9]3[CH2:10][CH:11]([S:13][C:14]4[C@H:15]([CH3:45])[C@@H:16]5[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:12]3)[S:7][CH:8]=2)=[O:3])=[O:59])=[CH:60][CH:61]=1)([O-:49])=[O:48]
Reactant: NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Subsequently, to a suspension of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (207.4 mg, 0.31 mmol) (obtained as described in Reference Example 41(7)) and glycine p-nitrobenzyl ester hydrochloride (116 mg, 0.47 mmol) (obtained as described above) in dimethylformamide (10.5 ml) were added diethylphosphoryl cyanide (0.072 ml, 0.47 mmol) and triethylamine (0.14 ml, 1.00 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with a 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(p-nitrobenzyloxycarbonylmethyl)carbamoyl-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (209.7 mg, yield 77%) as a pale yellow syrup.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:6]2[C:12]([CH3:13])=[N:11][N:10](CC3OC=CC=3)[C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2].P(=O)(O)(O)O>>[C:1]([C:4]1[C:5]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:6]2[C:12]([CH3:13])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2c(c(C)nn2Cc2ccco2)c1NC1CCCC1
Agent: O=P(O)(O)O
Product: CC(=O)c1cnc2[nH]nc(C)c2c1NC1CCCC1

Procedure:
5-Acetyl-4-cyclopentylamino-1-(2-furanyl)methyl-3-methyl-1H-pyrazolo[3,4-b]pyridine is treated with concentrated phosphoric acid according to the procedure of Example 2 to obtain 5-acetyl-4-cyclopentylamino-3-methyl-1H-pyrazolo[3,4-b]-pyridine.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH3:26])[CH:5]=1.CO.C(O)C.[OH-].[K+]>O>[CH3:26][O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:27])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OC
Yield: 83.1 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 40 g of the product from Example 46, 320 ml of methyl alcohol, 125 ml ethyl alcohol, 20 ml of water and 17.8 g of potassium hydroxide. The residue is recrystallized from chloroform/hexane to give 32 g of the desired product as white crystals.
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:4]([C:5]#[N:6])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1](=[O:3])[CH3:2])=[CH:16][CH:15]=1
Reactant: CC(=O)C(C#N)c1ccccc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C(C#N)(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (α-acetylphenylacetonitrile (1.0 g, 6.3 mmol) in acetonitrile (25 mL) was added 4-chlorobenzyl bromide (1.3 g, 6.3 mmol) and cesium carbonate (8.2 g, 25 mmol). After stirring at room temperature for 2 h, the reaction mixture was poured into ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, and the residue was purified on a silica gel column eluting with 1 to 5% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.5-6.9 (m, 9H), 3.56 (d, 1H), 3.37 (d, 1H), 2.22 (s, 3H). LC-MS: m/e 306 (M+Na)+ (3.0 min).