Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.Br.[NH2:12][C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:16]=2[O:15][C:14]=1[Br:36].C(N(CC)CC)C>C(Cl)Cl>[Br:36][C:14]1[O:15][C:16]2[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][C:17]=2[C:18](=[O:19])[C:13]=1[NH:12][CH:1]=[O:3]
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(N)c(=O)c2cc1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: O=CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
3.06 g of acetic anhydride and 2.76 g of formic acid were mixed and stirred for 1.5 hours at 40°-45° C. to prepare a mixed acid anhydride. Separately, 5.06 g of 3-amino-2-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one hydrobromide was suspended in 100 ml of methylene chloride. To the suspension being ice-cooled was added 1.06 g of triethylamine, and the mixture was stirred for 30 minutes at the same temperature. Thereto was added the above mixed acid anhydride, and the resulting mixture was stirred for 1 hour at 20°-25° C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 200 ml of water. The resulting crystal was collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 4.15 g (yield: 97.6%) of 2-bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 237°-238° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]=[C:9]1[N:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH:12]2[CH:11]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:10]1.CS(OS(C)(=O)=O)(=O)=O>C(Cl)Cl.CS(O)(=O)=O>[C:1]([C:17]1[CH:16]=[CH:15][C:14]2[N:13]3[C:9](=[O:8])[O:10][CH:11]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH:12]3[CH2:20][C:19]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(C(C)=O)cc3CC12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (53 μl) is slowly added to a mixture of (±) N-[(9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (X diastereomer A, EXAMPLE 18, 21 mg), methanesulfonic anhydride (33 mg) in methylene chloride (0.1 ml) and methane sulfonic acid (0.50 ml) at 0°. The temperature is kept below 15° for 3 hr, then allowed to warm slowly to 20°-25° overnight. Then the mixture is added to crushed ice (0.5 ml). After the ice has melted the mixture is extracted with ethyl acetate (4×3 ml). The combined organic layers are washed with saturated aqueous sodium bicarbonate (2 ml), saline (1 ml), dried over anhydrous potassium carbonate and concentrated to an oil. The oil is place on a silica prepratory plate (14 cm×17.5 cm, 250μ) and developed in methanol/methylene chloride (5/95, 3×). Extraction of the appropriate band and concentration give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(=O)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.9 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and triethylamine (2 mL) in chloroform (10 mL) was added isobutyryl chloride (173 μA, 1.64 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/1 to 1/2) to afford the title compound as a white solid (2 mg, 0.8%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]#[N:21]>CC(C)=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CCBr
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(OCC#N)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3-hydroxy-phenyl)-acetamide (5 g, 33.1 mmol) in acetone (50 ml) were added K2CO3 (5.49 g, 39.8 mmol) and bromo-acetonitrile (4.37 g, 36.4 mmol). The reaction mixture was heated to 100° C. for 3 h, filtered and the acetone layer evaporated in vacuo. This residue was dissolved in EtOAc (100 ml) and washed with 1M NaOH (10 ml×2). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo. The crude residue was purified by column chromatography eluting with 80% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:4][C:5]([O:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][C:7]=1[NH2:8].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=O)[CH:26]=1>C1COCC1>[N:19]1([C:3]2[N:4]=[C:5]([O:9][CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:6]=[C:7]3[C:2]=2[N:1]=[C:32]([NH:31][C:27]2[CH:26]=[C:25]([CH3:34])[CH:30]=[CH:29][CH:28]=2)[NH:8]3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(OCCOc2ccccn2)nc(N2CCOCC2)c1N
Solvent: C1CCOC1
Product: Cc1cccc(Nc2nc3c(N4CCOCC4)nc(OCCOc4ccccn4)nc3[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.2 %

Procedure:
5,6-Diamino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (0.332 g, 1.00 mmol, 1.00 equiv.) and m-tolyl isocyanate (0.133 g, 1.00 mmol, 1.00 equiv.) were mixed in 10 mL THF and stirred at room temperature for 15 hours. THF was removed, and the residue was treated with POCl3 in 2 mL CH3NO2 at 100° C. for 30 minutes. The reaction mixture was neutralized with 2N NaOH solution at 0° C., and subjected to EtOAc extraction. The organic solution was dried over MgSO4, filtered through a plug of silica gel, concentrated to around 2 mL, and cooled to 0° C., resulting in formation of the titled compound as off-white crystal which was collected by filtration, washed with EtOAc, and dried (0.095 g, 0.212 mmol, 21.2% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#[N:7])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][NH2:7])[CH3:21]
Reactant: CCN(CC)CC(C#N)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
A solution of 3-(diethylamino)-2,2-diphenylpropanenitrile (0.627 g, 2.25 mmol) in diethyl ether (5 mL) was slowly added to a suspension of lithium aluminum hydride (0.171 g, 4.50 mmol) in diethyl ether (5 mL) at 0° C. The resulting slurry was stirred at 0° C. for 1.5 hours. The reaction was then quenched by adding sodium sulphate decahydrate and stirring for 30 minutes. The reaction was then diluted with ethyl acetate and celite was added. The suspension was filtered and the filtrate was concentrated to dryness to give the title material (0.511 g, 80%) as an oil. LC/MS (M+H)+: 283. HPLC ret. time (Condition B): 1.602 min. 1H NMR (400 MHz, CDCl3) δ ppm: 0.81 (6H, t, J=7.07 Hz), 2.19 (4H, q, J=7.07 Hz), 3.18 (2H, s), 3.51 (2H, s) 7.16-7.20 (6H, m) 7.24-7.32 (4H, m).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH:6]2[O:13][CH3:14].[Li]CCCC.[CH2:21]1[O:23][CH2:22]1.O>C1COCC1>[CH3:14][O:13][CH:6]1[C:7]2[C:3](=[C:2]([CH2:21][CH2:22][OH:23])[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=2)[CH2:4][CH:5]1[CH3:15]
Reactant: COC1c2cc(C)c(C)c(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC1c2cc(C)c(C)c(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 52.77 g (196.0 mmol) of 4-bromo-1-methoxy-2,5,6-trimethylindane in 300 ml of THF 156.8 ml of 2.5 M (392.1 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 17.27 g (392.1 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, l 90 mm; eluent: hexanes/ether=20/1). Yield 36.66 g (80%) of a ca. 1 to 1.7 mixture of two diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=O)=[C:4]([CH3:14])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:8][CH:9]2[CH2:10][CH2:11]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CNC1CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH3·SMe2 (1.08 g, 14.24 mmols) The solution was heated to 60° C. for 6 hours, cooled to room temperature and carefully treated with saturated aqueous Na2CO3 (30 mL) and stirred for 17 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with H2O, saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-15% EtOAc-hexanes).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH2:27][CH3:28]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][CH3:28])[CH:18]=2)=[CH:4][N:3]=1
Reactant: CCCI
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Temperature: 50 °C
Reaction time: 17 h
Yield: 41.2 %

Procedure:
In a reaction vessel, 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (100 mg, 0.393 mmol) and potassium carbonate (109 mg, 0.787 mmol) were suspended in methanol (2 ml). Then, propyl iodide (134 mg, 0.787 mmol) was added thereto, followed by stirring at 50° C. for 17 hours. After the reaction was terminated, the mixture was concentrated and suspended in dimethylsulfoxide. The insoluble matters were removed by filtration and the resulting filtrate was purified by HPLC, to give the title compound (48 mg, 41%) as a pale yellow solid.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:30]([C:33]1[CH:46]=[CH:45][C:36]([C:37]([O:39][C@H:40]2[CH2:44][CH2:43][NH:42][CH2:41]2)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(#N)C>[N+:30]([C:33]1[CH:46]=[CH:45][C:36]([C:37]([O:39][C@H:40]2[CH2:44][CH2:43][N:42]([CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:41]2)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 90 °C

Procedure:
4-Methoxyphenethyl tosylate (1.24 g, 4.05 mmol), sodium carbonate (430 mg, 4.06 mmol) and sodium iodide (40 mg, 0.26 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (799 mg, 3.38 mmol) in acetonitrile (40 ml), and they were heated under reflux at 90° C. for 3 hours. The insoluble material was removed by the filtration. The insoluble material was washed with ethyl acetate, and the wash solution was combined with the filtrate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-(4-nitrobenzoyloxy)-1-(4-methoxy-phenethyl)pyrrolidine in the form of a light yellow oil (1.00 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][CH2:6][C@H:7](O)[C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][CH2:6][C@@H:7]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[NH:15]1)=[O:23]
Reactant: COC(=O)[C@H](CC[C@H](O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H]1CC[C@@H](C#C[Si](C)(C)C)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A 100-L, flask equipped with an overhead stirrer, a thermocouple and an addition funnel was charge with the product from Example 18 (2.1 kg, 6.08 mol), CH2Cl2 (32 L) and triethylamine (0.92 kg, 9.12 mol) and the solution was cooled to 0° C. Methanesulfonyl chloride (0.77 kg, 6.69 mol) was added through the addition funnel such that the internal temperature of the reaction remained below 5° C. The reaction was followed by HPLC until the starting material was consumed. 4 M HCl in dioxane (23 L, 91.2 mol) was added through the addition funnel such that the temperature remained below 10° C. The ice bath was removed and the solution was allowed to stir at room temperature for 2 hours. The reaction was concentrated to about 5 L. Dioxane (4 L) was added and the solution was concentrated to about 4 L. Tetrahydrofuran (27 L) was added followed by solid K2CO3 (2.1 kg, 15.2 mol). After stirring for 30 minutes, the reaction was cooled to 0° C. and water (18 L) was added such that the temperature remained below 15° C. After 20 minutes, the layers were separated. The aqueous layer was extracted with tert-butyl methyl ether (12 L). The combined organic layers contained 1.37 kg of product (99.9% yield) and were used directly in the next reaction.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:8]([N:10]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[N:12]=[N:11]3)[CH2:9][C@H:5]12)[CH3:3].C(=O)(O)[O-].[Na+:37]>O1CCCC1.C(O)C.O.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([N:10]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[N:12]=[N:11]3)[CH2:9][C@H:5]12)[CH3:3].[Na+:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(n3cc(CCO)nn3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(n3cc(CCO)nn3)C[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4-(2-hydroxyethyl)-1,2,3-triazol-1-yl]carbapen-2-em-3-carboxylate (35 mg, 0.08 mmol) in tetrahydrofuran (5.5 ml) is diluted with ethanol (2.8 ml) and DI water (4.2 ml) containing sodium bicarbonate (6.8 mg, 0.08 mmol). The resulting solution is added to a prereduced mixture of 10% palladium on carbon (37 mg) in ethanol (2.7 ml), and the mixture is stirred under an atmosphere of hydrogen for 2 hours at ambient temperature. The mixture is filtered through a celite pad which is washed with water. The filtrate and wash are extracted with methylene chloride and diethyl ether, concentrated under vacuum, and lyophilized to afford sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4-(2-hydroxyethyl)-1,2,3-triazol-1-yl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:19][C:18](=[O:20])[CH2:17][CH:16]3[N:12]2[C:13](=[O:21])[CH2:14][CH2:15]3)[CH:7]=[CH:8][C:9]=1[F:10]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:19][CH:18]([OH:20])[CH2:17][CH:16]3[N:12]2[C:13](=[O:21])[CH2:14][CH2:15]3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C1CC2CCC(=O)N2C(c2ccc(F)c(F)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2CC(O)CC(c3ccc(F)c(F)c3)N12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (644 mg) was added to a solution of 5-(3,4-difluorophenyl)hexahydroindolizine-3,7-dione obtained above (1.4 g) in ethanol (20 mL) at room temperature, and the reaction solution was stirred for one hour. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.5 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][O:16]C(=O)C2C=CC=CC=2)[C:10](=[O:25])[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CO>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][OH:16])[C:10](=[O:25])[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCn1c(=O)sn(Cc2ccccc2)c1=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1sn(Cc2ccccc2)c(=O)n1CCO
Temperature: 50 °C
Reaction time: 84 h
Yield: 81.1 %

Procedure:
To a suspension of benzoic acid 2-(2-benzyl-3,5-dioxo-[1,2,4]thiadiazolidin-4-yl)ethyl ester (74.0 g, 207.6 mmol) in methanol (740 mL) 12N HCl (740 mL) was added at room temperature. The mixture was heated at 50° C. for 18 h, then additional 12N HCl (250 mL) was added and the mixture was stirred for 84 hours at 40° C. until hydrolysis was completed. The mixture was concentrated at reduced pressure to remove the methanol, and the resulting mixture was extracted with methylene chloride (3×500 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to yield an oil that was treated with hot ethyl acetate (200 mL) and precipitated by the addition of n-heptane (200 mL) to yield the pure desired product as a white solid (42.5 g, 81%)
Reaction SMILES: I[CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:24]([CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1)#[N:25]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CI)c3ccccc32)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC#N)c3ccccc32)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of (5S)-5-iodomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.41 g), potassium cyanide (0.42 g), a catalytic amount of 18-crown-6 and dimethylformamide (16 ml) is heated with stirring at 85° C. for one hour. To the mixture is added potassium cyanide (0.42 g), and the mixture is further stirred at 85° C. for totally 6 hours. To the reaction solution is added ice, and the mixture is extracted with ethyl acetate--toluene. The extract is dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1), and recrystallized from ethyl acetate--n-hexane to give (5R)-5-cyanomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.41 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([N:7]1[CH:11]=[N:10][C:9]([S:12][CH2:13][CH2:14][CH3:15])=[N:8]1)=[O:6])[CH2:2][CH3:3].[OH:19]O>C(O)(=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([N:7]1[CH:11]=[N:10][C:9]([S:12]([CH2:13][CH2:14][CH3:15])=[O:19])=[N:8]1)=[O:6])[CH2:17][CH3:18]
Reactant: CCCSc1ncn(C(=O)N(CCC)CCC)n1
Reactant: OO
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A solution of 13.5 g. 1-dipropylcarbamoyl-3-propylthio-1,2,4-triazole and 100 vol. hydrogen peroxide solution (5.7 ml., 1.0 molecular proportion) in 450 ml. glacial acetic acid was kept at room temperature for 14 days. The resulting solution was evaporated to dryness under reduced pressure and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, and 0.5N hydrochloric acid. Solvent was removed from the solution by distillation under reduced pressure to give a residual oil which solidified on cooling. The solid product was recrystallized from benzene/petroleum ether, b.p. 40° - 60° C. to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 51° - 52.5° C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](OC)=[O:14])=[C:6]2[S:17][CH:18]([CH3:20])[CH3:19].[NH2-:21].[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([NH2:21])=[O:14])=[C:6]2[S:17][CH:18]([CH3:20])[CH3:19]
Reactant: [NH2-]
Reactant: COC(=O)c1c(SC(C)C)c2cc(OC)ccc2n1C
Agent: [Li+]
Product: COc1ccc2c(c1)c(SC(C)C)c(C(N)=O)n2C
Yield: 68 %

Procedure:
Prepared from methyl 5-methoxy-1-methyl-3-[(1-methylethyl)thio]-1H-indole-2-carboxylate and lithium amide as described in Example 23. Yield 68% after recrystallization from ethyl acetate-hexane; mp 122°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[C:9](=[O:17])[CH2:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:4]1[C:3]([O:2][CH3:1])=[CH:18][C:7]2[CH2:8][C:9](=[O:17])[N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CC(=O)N(CCCCl)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CCCCl)C(=O)C2

Procedure:
Here, 1-(8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)3chloro-propane (28.5 g, 0.016 mol) is stirred into concentrated nitric acid (350 ml) for half an hour at 20°-25° C. The solution is poured onto ice water, neutralized with potassium carbonate and extracted twice with methylene chloride. The extract is dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([O:18][CH3:19])(=[O:17])[C:15]#[CH:16].O>CC(N(C)C)=O>[CH3:19][O:18][C:14]([C:15]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:16]=1)=[O:17]
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#CC(=O)OC
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cc(C(=O)O)ccc2C)nn1
Yield: 62.3 %

Procedure:
A mixture of 1.11 g (6.27 mmol) of 3-azido-4-methyl benzoic acid (Compound 2) and 1.12 mL (12.5 mmol) of methyl propiolate, was stirred in 4.2 mL of DMA at 110° C. in a sealed tube overnight. The resulting brown solution was poured into water, and the resulting precipitate was filtered, and then recrystallized from EtOH/water to provide 1.02 g (62.3%) of 1-(5-carboxy-2-methyl-phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester as tan crystals. ESI MS (m/z 262, 100, M+1)