Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:25])[NH:17][C@@H:18]3[C:22](=[O:23])[CH2:21][O:20][C@@H:19]3[CH3:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].N(C(NCC1CCC(C(O)=O)CC1)=O)N.FC(F)(F)C([O-])=O>C(O)C.O.C(Cl)(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:25])[NH:17][CH:18]3[C:22](=[O:23])[CH2:21][O:20][CH:19]3[CH3:24])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H]1OCC(=O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)[O-]
Agent: NNC(=O)NCC1CCC(C(=O)O)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1OCC(=O)C1NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
(2R, 3S) (2-methyl-4-oxo-tetrahydrofuran-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6b) (354 mg, 1.05 mmol, 1 eq) was dissolved in a mixture of ethanol (9.6 mL) and water (1.4 mL) containing sodium acetate.trihydrate (218 mg, 1.6 mmol, 1.5 eq). 4-[[(hydrazinocarbonyl)amino] methyl]cyclohexanecarboxylic acid. trifluoroacetate (346 mg, 1.05 mmol, 1 eq, Murphy, A. M. et al, J. Am. Chem. Soc., 114, 3156–3157, 1992) was added and the mixture refluxed for 2 hr. Chloroform (100 mL) was added and the organics washed with dilute aqueous hydrochloric acid (0.1 M, 1×100 mL). The acidic layer was backwashed with chloroform (3×100 mL) and the combined organics washed with brine (100 mL), dried (Na2SO4) and evaporated under reduced pressure to afford linker construct (8b) as a white solid (660 mg). Analytical HPLC indicated one main peak at Rt=17.011 min, HPLC-MS (main UV peak with Rt=7.96 min, 535.3 [M+H]+. Crude (8b) was used directly for construct loading.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]1[C:16](=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[O:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([N:7]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1Cc2ccccc2CN1C(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccccc2CN1C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 915.9 %

Procedure:
To a stirred solution of the product of step 1 (10.0 g, 2.50 mmol), in 1:1 ethanol/tetrahydrofuran (110 mL) was added 1.0 N aqueous sodium hydroxide solution (55 (mL). The mixture was stirred for 1 hour, concentrated and redissolved in water (150 (mL). While stirring, the solution was acidified with the addition of 1.0 N aqueous hydrochloric acid (55 mL). The resulting white precipitate was collected by filtration, rinsed with water and vacuum oven dried to afford 8.55 g (89%) of product as a white solid. In chloroform-d solvent, the proton NMR spectra of this compound appears as a 6:4 mixture of rotamers: 1H NMR (CDCl3) δ 7.44-6.78 (m, 13H), 5.29 (t, J=5.7 Hz, 0.6H), 5.18 (d, J=17.9 Hz, 0.4H), 4.81-4.73 (m, 0.4H), 4.62-4.47 (m, 1.6H), 3.30-3.15 (m, 1.6H), 3.13-3.01 (m, 0.4H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][C:3]=1[C:24](OC)=[O:25].[Li+].[BH4-]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][C:3]=1[CH2:24][OH:25]
Reactant: COC(=O)c1cc(-n2c(CCC(=O)O)ccc2-c2ccccc2)ccc1O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(-c2ccccc2)n1-c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.9 %

Procedure:
To a solution of 3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid (40 mg, 0.109 mmol) in 2 ml anhydrous THF was added LiBH4 (2M in THF, 0.14 ml, 2.5 eq.) via a syringe at 0° C. The reaction mixture was stirred at rt for 4 hours. Mixture was quenched with saturated sol. NH4Cl, then acidified to pH=2 using 10% HCl solution. This was extracted several times using ethyl acetate. Combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude was purified by preparative TLC using 1:1 ethyl acetate/hexane. 18 mg of 3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid was obtained, 47% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1)#[N:2].[H-].[Na+].Br[CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]([CH3:16])=[N:15][C:11]=2[CH:10]=1)#[N:2]
Reactant: Cc1nc2ccc(-c3ccccc3C#N)cc2[nH]1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(C(=O)OCC)n1c(C)nc2cc(-c3ccccc3C#N)ccc21
Reaction time: 0.5 h

Procedure:
5-(2-Cyanophenyl)-2-methylbenzimidazole (3.43 mmoles, 0.8 g) was dissolved in DMF. Sodium hydride (3.75 mmoles, 0.15 g.) was added. The solution was stirred for 30 minutes. Ethyl 2-bromooctanoate was added. The solution was stirred for 1 hour. Water and ethyl acetate were added; and the layers separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The intermediate was chromatographed on silica gel eluted with 50% ethyl acetate in hexane to yield 1.0 g of ethyl 2-[5-[2-cyanophenyl]-2-methyl-1H-benzimidazol-1-yl]octanoate. The nitrile was dissolved in 10 ml of tributyltinazide and heated at 70° C. for 3 days. The solution was stirred in a mixture of acetonitrile, water, and acetic acid (100 ml of 8:1:1) for 3 hours, washed with hexane (4×250 ml), and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. The intermediate was triturated with hexane, filtered and chromatographed over silica gel eluted with 10% ethanol in ethyl acetate with 1% acetic acid. The isomers were separated by reverse phase HPLC eluted with a gradient of 30-50% acetonitrile in water with 1% ammonium acetate. The intermediate was dissolved in ethanol (20 ml) and 5N NaOH (5 ml) and heated on a steam bath for 1 hour. The solution was concentrated to 75 ml. The pH was adjusted to 3.0 using 5N HCl. The precipitate was collected and dried. The reaction yielded 110 mg of 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-2-methyl-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[C:20]([CH3:23])([CH3:22])[CH3:21].Cl.O.[H][H]>CO.[C].[Pd]>[OH:1][C:2]1[C:15]([C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:14][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: Cc1cn(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cn(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1

Procedure:
6.1 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-4-methylimidazole are hydrogenated at normal pressure and room temperature in 100 ml of methanol, 21 ml of 1N hydrochloric acid and 30 ml of water in the presence of palladium-carbon. After 500 ml of hydrogen have been taken up, the mixture is filtered. The filtrate is evaporated to a volume of 50 ml. Then, 50 ml of water are added and the mixture is treated with saturated sodium bicarbonate solution up to a neutral reaction (pH=7). The separated crystals are removed by filtration, and taken up with methylene chloride. The methylene chloride solution is washed once with water, dried and evaporated. The residue is triturated with cold ether. Thereafter the solid is removed by filtration, washed with ether and n-hexane and dried at 60° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-4-methylimidazole of m.p. 150°-151°.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11](CC([O-])=O)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH:28]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=4)[OH:29])[CH:22]=3)[O:20][C@@:6]1([CH:39]([O:41]C(=O)C)[CH3:40])[CH2:7][O:8]2)(=O)C.C(=O)([O-])[O-:46].[K+].[K+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:9]23[O:20][C@@:6]([CH:39]([OH:41])[CH3:40])([CH2:7][O:8]2)[C@@H:5]([OH:4])[C@H:11]([OH:46])[C@H:10]3[OH:16])=[CH:22][C:23]=1[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1)[OH:29]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc(C(O)c2cc([C@]34OC[C@](C(C)OC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](CC(=O)[O-])[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [K+]
Solvent: CO
Product: CCOc1ccc(C(O)c2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
To a solution of [(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-ethoxyphenyl)-hydroxy-methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate 29d (316 mg, 0.5 mmol) in methanol (20 mL) was added potassium carbonate (344 mg, 2.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Part of the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL×2) and then saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 29 as a white solid (47 mg, 20.0%, HPLC: 99.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84 (s, 1H), 7.32 (d, 2H), 7.19 (d, 2H), 6.84 (d, 2H), 5.93 (d, 1H), 5.90 (d, 1H), 5.31 (d, 1H), 5.02 (d, 1H), 4.91 (d, 1H), 4.65 (d, 1H), 4.04 (m, 1H), 4.01-3.96 (m, 2H), 3.88-3.82 (m, 1H), 3.79 (d, 1H), 3.61-3.55 (m, 1H), 3.46 (d, 1H), 3.44-3.39 (m, 1H), 1.30 (t, 3H), 1.17 (d, 3H); and MS (ESI, pos. ion) m/z: 5112[M+HCOO]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15](OC)=[O:16])[C:11]([C:19](OC)=[O:20])=[C:10]2[CH3:23])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>ClCCl.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH2:15][OH:16])[C:11]([CH2:19][OH:20])=[C:10]2[CH3:23])=[CH:5][CH:4]=1
Reactant: COC(=O)c1c(C(=O)OC)c(C)n(-c2ccc(OC)cc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-n2c(C)c(CO)c(CO)c2C)cc1
Yield: 91 %

Procedure:
A solution of dimethyl N-(4-methoxyphenyl)-2,5-dimethylpyrrole-3,4-dicarboxylate (0.04 mol) in dry dichloromethane (50 mL) was added dropwise over a 15-min period to a mechanically stirred mixture of lithium aluminum hydride (3.4 g, 0.08 mol) in anhydrous ether (100 mL) heated under reflux (50°-55° C. bath). The stirred mixture was heated under reflux for 1 h after the addition was complete and then cooled in an ice bath. The excess hydride was carefully decomposed with small additions of wet ether and then with water until the salts were white. The mixture was filtered (medium-porosity sintered-glass funnel) and the inorganic residue was washed with several portions of hot dichloromethane (about 30 mL) until the total filtrate volume was about 400 mL. The filtrate was concentrated in vacuo to a volume of about 125 mL, warmed to boiling, and diluted with slow portionwise addition of petroleum ether (about 100 mL) to yield 91% of N-(4-methoxyphenyl)-2,5-dimethyl-3,4-bis(hydroxymethyl)pyrrole: mp 143°-145° C. (dec).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:9]1[C:10](=[O:20])[O:11][C:12]([OH:19])=[C:13]([C:16](=[O:18])[CH3:17])[C:14]=1[OH:15])(=O)[CH3:7]>>[C:16]([C:13]1[C:12](=[O:19])[O:11][C:10](=[O:20])[C:9](=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:7])[C:14]=1[OH:15])(=[O:18])[CH3:17]
Reactant: CCCCN
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Product: CCCCNC(C)=C1C(=O)OC(=O)C(C(C)=O)=C1O

Procedure:
Similarly, 1.8 g. (0.025 m.) of n-butylamine and 5.3 g. (0.025 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed overnight in 50 ml. of benzene and the resulting solid filtered to give 5-acetyl-3-[1-(n-butylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 112°-114° C.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].[C:25]([C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([CH:52]=3)[C:49](O)=[O:50])=[O:42])[CH2:37][CH2:36]2)[CH:30]=[CH:31][CH:32]=1)#[N:26].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:25]([C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]3[CH:45]=[N:46][CH:47]=[C:48]([C:49]([NH2:3])=[O:50])[CH:52]=3)=[O:42])[CH2:39][CH2:40]2)[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1cccc(CCC2CCN(C(=O)Oc3cncc(C(=O)O)c3)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1cccc(CCC2CCN(C(=O)Oc3cncc(C(N)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (62 mg), 1-hydroxybenzotriazole (43 mg), ammonium chloride (43 mg) and TEA (0.038 ml) were added to a DMF (3.0 ml) solution of 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (102 mg), followed by stirring overnight at room temperature. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and the crystal precipitated was collected by filtration and dried. The resulting crystal was recrystallized from EtOAc/hexane to give 5-(aminocarbonyl)-3-pyridyl 4-[2-(3-cyanophenyl)ethyl]-1-piperidinecarboxylate (81 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15].[NH3:17]>C1COCC1>[NH2:17][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: N
Reactant: Cn1c(=O)c([N+](=O)[O-])c(Cl)c2cccnc21
Solvent: C1CCOC1
Product: Cn1c(=O)c([N+](=O)[O-])c(N)c2cccnc21
Temperature: 20 °C
Yield: 95.4 %

Procedure:
A solution of 4-chloro-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.54 g, 6.43 mmol) (J. Med. Chem. 1992, 35, 2863–2870) in 40 mL of THF was treated with 7.2 mL of 28% aqueous ammonia (6.4 g, 51 mmol). After stirring at 20° C. 17 h, the solvent was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was filtered and washed with water to give to give 4-amino-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.35 g, 96% yield). 1H-NMR (DMSO): δ 8.74 (m, 2H), 8.35 (s, 2H), 7.38 (dd, 1H, J=8.0, 4.8 Hz), 3.58 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[C:18]2[CH:19]=[C:20](B(O)O)[S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[S:21][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[C:18]=3[CH:19]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COc1cccc2sc(B(O)O)cc12
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc2sc(-c3ccc([N+](=O)[O-])cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a suspension of anhydrous 1,2-dimethoxyethane (DME, 20 mL) containing a palladium tetrakis catalyst (Pd(PPh3)4 (49.7 mg, 0.043 mmol) was added 4-iodonitrobenzene (535.8 mg, 2.15 mmol), stirred at room temperature for 10 minutes, followed by adding 4-methoxybenzothiophene-2-boronic acid (95a, 470 mg, 2.26 mmol) and 2.0 M sodium carbonate aqueous solution (43 mL, 0.086 mmol). The reaction mixture was heated to reflux for 10 hours and cooled to room temperature, and ice water was added. The resulting product was extracted with ethyl acetate, evaporated after a treatment with, and purified by column chromatograph to give the target compound 2-(4-nitrophenyl)-4-methoxybenzothiophene (1-1, 560 mg, 87%).
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:25])[N:15]2[O:20][S:21]([O-:24])(=[O:23])=[O:22])=[O:11])=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:25])[N:15]2[O:20][S:21]([OH:24])(=[O:23])=[O:22])=[O:11]
Reactant: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-])C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 2 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-{[2-(tert-butoxycarbonyl)-2-methylhydrazinyl]carbonyl}-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 180 (0.31 g, 0.49 mmol) in DCM (20 mL) was added trifluoroacetic acid (1.2 mL, 15.55 mmol) dropwise at 0° C. The reaction mixture was stirred for 2 h, than evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)—N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide Compound 1 (Table 2) (0.01 g, 6.9%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@H:4]([CH2:7][CH2:8][CH3:9])[N:3]1[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1)=[O:12].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:31][C:28]1[CH:27]=[N:26][C:25]([N:6]2[CH2:5][C@H:4]([CH2:7][CH2:8][CH3:9])[N:3]([CH2:10][C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)=[O:12])[C:2]2=[O:1])=[N:30][CH:29]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: CCC[C@H]1CNC(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCC[C@H]1CN(c2ncc(F)cn2)C(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Yield: 29.9 %

Procedure:
A solution of 2-[(5S)-2-oxo-5-propylimidazolidin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (70 mg), 2-chloro-5-fluoropyrimidine (33 mg), Pd2(dba)3 (22 mg), Xantphos (24 mg), and sodium tert-butoxide (30 mg) in toluene was stirred at 80° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to afford the title compound (27 mg).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>O>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Our efforts in an attempt to solve the above problem led to the discovery that by using an aqueous medium such as water or a mixture of water and an organic solvent, the nitro group or 1-nitroanthraquinone is reduced while the 1-nitroanthraquinone is in the suspended state, and 1-aminoanthraquinone of better quality with lesser amounts of impurities than in the case of using an organic solvent can be obtained. According to this method, however, when the particles of 1-nitroanthraquinone have a large size, it sometimes happens that only the surfaces of the particles are hydrogenated, but their insides remain unreacted or become a reaction intermediate. The unreacted matter and the reaction intermediate adversely affect the quality and yield of 1-aminoanthraquinone as a final product. Furthermore, since 1-aminoanthraquinone is scarcely soluble in water, it must be collected together with the catalyst, and the mixture is dissolved in a solvent such as sulfuric acid to separate the catalyst. In addition, since the resulting 1-aminoanthraquinone contains a 2-amino isomer and 1,5-, 1,8-, 1,6- and 1,7-diamino isomers ascribable to a 2-nitro isomer and 1,5-, 1,8 -, 1,6- and 1,7-dinitro isomers formed as by-products in the nitration of anthraquinone, it is necessary to remove these isomers. Separation of the 1,5- and 1,8-diamino isomers is not easy, however.
Reaction SMILES: [OH-].[Li+].[C:3]([CH2:11][NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:32][C:33]([CH3:43])=[CH:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.C1COCC1>[C:3]([CH2:11][NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:32][C:33]([CH3:43])=[CH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CC(=O)c1ccccc1)N[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)O
Reaction time: 16 h
Yield: 16.6 %

Procedure:
1.7 ml (1.70 mmol) of an aqueous 1M lithium hydroxide solution are added to a solution containing 620 mg (1.13 mmol) of methyl (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(1-methyl-3-oxo-3-phenylpropenylamino)propionate in 10 ml of a methanol/THF mixture (3/1). After stirring for 16 h, the medium is acidified with 1N hydrochloric acid until pH=4, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on a column of silica and eluted with a heptane/ethyl acetate mixture. 100 mg of (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(1-methyl-3-oxo-3-phenylpropenylamino)propionic acid are isolated with a 17% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2[N:15]3[CH2:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][C:12]3[CH:21]=[N:22][CH:23]=[N:24][C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>CCO>[CH3:20][C:19]1[C:14]2=[CH:13][C:12]3[CH:21]=[N:22][CH:23]=[N:24][C:11]=3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:16]=3[N:15]2[CH2:17][N:18]=1
Reactant: CCOC(=O)c1cccc2c1N1CN=C(C)C1=Cc1cncnc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=NCN2C1=Cc1cncnc1-c1cccc(C(=O)O)c12
Temperature: 0 °C
Yield: 75.3 %

Procedure:
To a solution of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester (1.6 g, 5 mmol) in EtOH (20 mL) was added sodium hydroxide (0.22 g, 5.5 mmol) and water (3.5 mL) and the resulting mixture was heated under reflux for 20 min. The mixture was then cooled to 0° C. and then hydrochloric acid (4 N, 1.32 mL) was added and the mixture was cooled in an ice-bath for 1 h. A solid formed and was filtered off and then dried under vacuum to leave the product (1.1 g, 77%) as off-white crystals, mp 285-287° C., m/z 292 (M).