Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=O)[N:8]3[CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:19][OH:20].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=[N:19][OH:20])[N:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: NO
Reactant: O=C1c2cc(Cl)c(Cl)cc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1c2cc(Cl)c(Cl)cc2CN2C(=NO)CCC12
Yield: 78.7 %

Procedure:
A stirred suspension of 6.37 g of 7,8-dichloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (40 ml) was treated with a premixed solution of 3.28 g of hydroxylamine hydrochloride in water (25 ml) and 6.42 g of sodium acetate trihydrate in water (25 ml). The solution was heated at reflux for 2.5 hours. The solution was then cooled with an ice-water bath as a precipitate began to separate from the reaction mixture. The solid was collected by vacuum filtration and recrystallized from 95% ethanol (250 ml) to afford 5.29 g of crystals, m.p. 245°-246° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:19]=2)=[CH:14][CH:13]=1.CN1CC[O:38][CH2:37][CH2:36]1.CC[C:43]([C:45](Cl)=[O:46])=[O:44]>C(Cl)Cl>[CH2:37]([O:38][C:43](=[O:44])[C:45]([N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:19]=2)=[CH:14][CH:13]=1)=[O:46])[CH3:36]
Reactant: CCC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccccc3F)cc2)n1
Reactant: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(CCc3ccccc3F)C(=O)C(=O)OCC)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-(2-fluorophenyl)ethyl]-N-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzyl]amine (45.1 mg, 0.1 mmol) in anhydrous DCM (0.6 mL) was added the morpholinomethyl polystyrene resin (Novabiochem, HL, 39.5 mg, 0.15 mmol, 3.8 mmol/g) and the resulting mixture was cooled at 0° C. Ethyloxalyl chloride (4.7 mg, 0.13 mmol) in anhydrous DCM (0.4 mL) was added. The reaction mixture was stirred for 2 h at rt, then the PL-AMS-Resin (Polymer Laboratories, 52 mg, 0.1 mmol, 1.93 mmol/g) was added and the mixture stirred for 1.5 h. The resins were filtered off, washed with DCM, and the filtrates were concentrated under vacuum to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][NH:7][CH2:8][C:9]1[C:10]([N:20]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:21][CH3:22])=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19].[Br:37][C:38]1[CH:39]=[N:40][C:41](Cl)=[N:42][CH:43]=1.[F-].[K+].O>CN(C)C=O.CCOC(C)=O>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:8][C:9]1[C:10]([N:20]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:21][CH3:22])=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[C:41]1[N:42]=[CH:43][C:38]([Br:37])=[CH:39][N:40]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCN(CC1CCC1)c1nc2c(C)cccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC1CCC1)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A mixture of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-methyl-quinolin-2-yl}-cyclobutylmethyl-ethyl-amine (0.23 g, 0.46 mmol), 5-bromo-2-chloropyrimidine (0.09 g, 0.46 mmol), and potassium fluoride (0.11 g, 1.8 mmol) in dimethyl formamide (10 ml) was heated at 80° C. overnight. After cooling the reaction to ambient temperature water (10 mL) and EtOAc (20 mL) were added and stirred for 0.5 h. Thereafter, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and solvent evaporated in vacuo. The crude was purified by chromatography using silica gel to afford the title compound as a colorless liquid (0.14 g, 47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:21]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>CO.ClCCl>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[C:31]2[CH2:32][CH2:33][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH:30]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: C1=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CCN(Cc2ccccc2)C1

Procedure:
A slurry of 5-benzyloxyindole (6.85 g, 30.7 mmol) in methanol (50 mL) was added to a 25 wgt % solution of sodium methoxide in methanol (115 mL) at 5° C. under argon. 1-Benzyl-4-piperidone (5.8 g, 30.7 mmol) was added in one portion and the suspension heated at reflux for 16 h, cooled and diluted with a mixture of dichloromethane (100 mL) and methanol (150 mL). The solution was acidified to pH 5 with glacial acetic acid, concentrated to 100 mL, diluted with water (750 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and dried (Na2SO4). Filtration and concentration in vacuo gave the title compound as a yellowrange solid (10.6 g, 87%). MS(ES) m/e 395.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To the suspension of 4-(4-bromo-phenyl)-1H-indole (1.20 g, 4.41 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (54 mL) was added pyridinium tribromide (4.23 g, 13.23 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (300 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.12 g, 88%) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]5[CH3:43])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]5[CH3:43])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:54]([CH3:53])(=[O:56])=[O:55])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 139 (54 mg, 0.092 mmol) in DCM (2.0 mL) was added DIPEA (65 μL, 0.37 mmol) followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.04 min, m/z 667 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:24]I.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH3:24])[CH2:15][CH2:16]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)CC1
Reaction time: 24 h

Procedure:
2-Chloro-3-(4-hydroxypiperidin-1-yl)-4-methylsulfonylbenzoic acid (0.70 g, 2.1 mmol) was added with stirring to a suspension of 0.25 g (6.3 mmol) of sodium hydride in a mixture of 0.40 mL (6.4 mmol) of methyl iodide and 10 mL of dry tetrahydrofuran. The mixture was heated to reflux and stirred for 24 hr. The resulting mixture was treated with water, acidified with 1N aqueous hydrochloric acid and extracted several times with dichloromethane. The organic layers were combined and dried over magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was rinsed with petroleum ether to obtain 0.70 g (96 percent of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:23]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)ccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
Ethyl 6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.185 g, 0.500 mmol), phenylboronic acid (0.76 g, 0.625 mmol, 1.2 equiv.) and potassium phosphate trihydrate (0.200 g, 0.750 mmol, 1.5 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.0105 g, 0.015 mmol, 3 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 70-80%. 1H-NMR (DMSO-d6) δ 1.11, 1.35 (each t, 3H, 3J=7.1 Hz, CH3); 2.60 (m, 2H, 2′-H); 3.31 (m, 2H, 1′-H); 3.99, 4.35 (each q, 2H, 4J=7.1 Hz, CH2); 7.35 (m, 2H, 4-H, 5-H); 7.46 (m, 2H, 2″-H, 6″-H); 7.62 (dd, 1H, 4″-H); 7.65 (m, 2H, 3″-H, 5″-H); 7.75 (dd, 1H, 7-H); 11.63 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.9, 15.1 (2CH3, each C═OOCH2CH3); 20.90 (C-2′); 35.9 (C-1′); 60.7, 61.2 (2CH2, each C═OOCH2CH3); 111.0 (C-7); 120.1 (C-4); 121.8 (C-3); 122.3 (C-3a), 124.8 (C-5) 127.2 (C-2″, C-6″); 127.7 (C-4″); 128.0 (C-3″, C-5″); 129.8 (C-2); 137.7 (C-7a); 138.2 (C-6); 141.9 (C-1″); 162.3 (2′-CO2Et); 173.1 (2-CO2Et). LC-MS (m/z): 383 [M-NH4+]+, 366 [M]+, 364 [M]−. Purity LC-MS: 96%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[F:14][C:15]1[C:20]2[CH2:21][CH2:22][O:23][C:19]=2[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH:26]=O.C[Si]([C:32]#[N:33])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C1COCC1>[F:14][C:15]1[C:20]2[CH2:21][CH2:22][O:23][C:19]=2[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH:26]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][CH:9]=1)[C:32]#[N:33]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)c(F)c2c1OCC2
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c(F)c2c1OCC2

Procedure:
After adding 287 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine [CAS No. 10185-68-9], 321 mg of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde, 300 mg of MS3A and 0.44 ml of trimethylsilyl cyanide to a solution of 102 mg of Yb(OTf)3 in 5 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give (4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).
Reaction SMILES: [C:1]([N:20]1[C:24](=[O:25])[CH2:23][O:22][C:21]1=[O:26])([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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].Cl[CH2:33][C:34]1[CH:57]=[CH:56][C:37]([O:38][CH2:39][C@H:40]2[CH2:45][CH2:44][C@H:43]([CH2:46][O:47][C:48]3[CH:53]=[CH:52][C:51]([CH2:54]Cl)=[CH:50][CH:49]=3)[CH2:42][CH2:41]2)=[CH:36][CH:35]=1>O1CCCC1.[Cl-].[NH4+]>[C:1]([N:20]1[C:24](=[O:25])[CH:23]([CH2:33][C:34]2[CH:57]=[CH:56][C:37]([O:38][CH2:39][C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][O:47][C:48]4[CH:53]=[CH:52][C:51]([CH2:54][CH:23]5[O:22][C:21](=[O:26])[N:20]([C:30]([C:4]6[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=6)([C:8]6[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=6)[C:29]6[CH:1]=[CH:14][CH:15]=[CH:27][CH:28]=6)[C:24]5=[O:25])=[CH:50][CH:49]=4)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[O:22][C:21]1=[O:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClCc1ccc(OC[C@H]2CC[C@H](COc3ccc(CCl)cc3)CC2)cc1
Reactant: O=C1COC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1OC(Cc2ccc(OC[C@H]3CC[C@H](COc4ccc(CC5OC(=O)N(C(c6ccccc6)(c6ccccc6)c6ccccc6)C5=O)cc4)CC3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 6.8 g of 3-trityl-2,4-oxazolidinedione dissolved in 200 ml of tetrahydrofuran were added 13.6 ml of n-butyllithium and, after 15 minutes of stirring at -78° C., 3.9 g of trans-1,4-bis[(4-chloromethylphenoxy)methyl]cyclohexane which has been dissolved in 20 ml of tetrahydrofuran, followed by additional 2 hours of stirring at -78° C. After completion of the reaction, the reaction mixture was dispersed in saturated ammonium chloride aqueous solution and ice layers and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then evaporated to dryness, thereby obtaining crude trans-1,4-bis[[4-[(3-trityl-2,4-dioxo-5-oxazolidinyl)methyl]phenoxy]methyl]cyclohexane.
Reaction SMILES: O[Li].O.O.C[O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:11]=2[CH:10]=1)=[O:8].C(OCC)(=O)C>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:11]2[CH:10]=[C:9]([C:7]([OH:8])=[O:6])[S:13][C:12]=2[CH:14]=1
Reactant: COC(=O)c1cc2ccc(Br)cc2s1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
LiOH.H2O (1.85 g, 44 mmol) and water (20 mL) were added to a stirred solution of 6-bromo-benzo[b]thiophene-2-carboxylic acid methyl ester (I-25a: 2.4 g, 8.85 mmol) in THF (25 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was concentrated, acidified with 2N HCl, filtered and the residue was washed with n-hexane to afford 1.9 g of the product (84% yield).
Reaction SMILES: O.[CH2:2]([O:9][NH:10][C@H:11]1[CH2:16][N:15](C(=O)C(F)(F)F)[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[CH2:2]([O:9][NH:10][C@H:11]1[CH2:16][NH:15][C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Yield: 90.1 %

Procedure:
Water (9.2 mL) was added to a solution of 6.91 g (17.17 mmol) of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in 1,4-dioxane (34 mL), and, under ice cooling, 2.5M NaOH (13.7 mL) was added dropwise, followed by allowing to react at the same temperature for 0.5 hours. Acetic acid (ca. 1 mL) was added to the reaction mixture, followed by concentration under reduced pressure, and subsequently the resulting concentrated residue was extracted with ethyl acetate (58 mL, 29 mL). After the organic layers were washed respectively with 50% aqueous potassium carbonate solution, they were combined, followed by drying with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=19/1) to afford 4.74 g of the title compound as a colorless oil (yield 90%). Enantiomeric excess: 98.9% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 mL/min., retention time 5.5 min.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:10]#[N:11]>O>[NH:8]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][N:1]=[C:10]1[NH2:11]
Reactant: N#CBr
Reactant: NCC1(N)CCCC1
Solvent: O
Product: NC1=NCC2(CCCC2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 138.8 %

Procedure:
3.35 g of 1-(aminomethyl)cyclopentanamine are solubilized in 20 mL of water, cooled beforehand in an ice bath. 3.52 g of BrCN are added and the mixture is then stirred for 3 h at RT. The solvent is evaporated. 5.67 g (yield=88%) of 1,3-diazaspiro[4.4]non-2-en-2-amine are obtained as a brown oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17][N:18]([CH2:29][C:30]([O:32][CH3:33])=[O:31])S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+].CO.Cl>CS(C)=O.O>[CH3:33][O:32][C:30]([C:29]1[N:18]=[CH:17][C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][CH:8]=[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]=2)=[O:31]
Reactant: COC(=O)CN(Cc1cc(Oc2ccccc2)ccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 0 °C
Yield: 73 %

Procedure:
To a mixture of 2-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-4-phenoxy-benzoic acid methyl ester (14.0 g, 28.1 mmol) in DMSO (56 mL) was slowly added 30% NaOMe in MeOH (15.3 mL, 84.3 mmol). The resultant mixture was stirred at room temperature for 30 min and poured into 200 mL of ice and water. It was slowly acidified by conc. HCl aq. solution (10 mL) and then extracted with EtOAc. Organic layer was washed with 3% NaHCO3 solution, water and brine, and was dried over Na2SO4, filtered and concentrated. Crude produce was purified by silica gel chromatography to provide the title compound 6.05 g (20.5 mmol) in 72.9% yield. 1H NMR in CDCl3, δ in ppm: 11.7 (s, 1H), 8.59 (s, 1H), 8.36 (d, 1H, J=9.2 Hz), 7.55-7.1 (m, 7H), 4.07 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=1.ON1[C:29](=[O:30])[CH2:28]CC1=O.C1([N:38]=C=NC2CCCCC2)CCCCC1.CO>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:38][CH2:28][CH2:29][OH:30])=[O:22])[CH:15]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(C(=O)O)c2)c(=O)n1C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(C(=O)NCCO)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a mixed solution of 1.57 g of 4-hydroxy-3-[3-(3-carboxyphenyl)-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, 50 ml of dimethylformamide and 0.58 g of N-hydroxysuccinimide was added a solution of 1.03 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide, and this was stirred at room temperature overnight. Insolubles were filtered, 0.33 ml of ethanolamine was added to the filtrate, and this was stirred at room temperature for 2.5 hours. To the residue obtained by concentration under reduced pressure was added 30 ml of methanol, and this was heated under reflux. After ice-cooling, crystals were filtered, washed with methanol, and dried to obtain 0.61 g of 4-hydroxy-3-[3-[3-[(2-hydroxyethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (96a)] as a yellow crystal.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[CH2:26][NH2:27])[C:6]([NH:8][C@H:9]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=2[O:11][B:10]1[OH:22])=[O:7].CC(O)=O.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=3[O:11][B:10]2[OH:22])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:1][CH:33]([CH3:35])[CH3:32]
Reactant: NCc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CN
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCc1cc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)ccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 14 (44.1 mg) in methanol (2 mL) was added TEA (0.042 mL), AcOH (0.050 mL), acetone (0.030 mL), and sodium triacetoxyborohydride (70 mg). The resulting reaction mixture was stirred at room temperature for overnight. After removal of the solvents, the product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 412 (MH)+.