Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C@@H:29]2[CH2:31][O:30]2)[CH:26]=[CH:27][CH:28]=1>C(O)C>[CH2:1]([N:8]([C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH2:10][OH:11])[CH2:31][C@@H:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a suspension of (25)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (6.0 g) in ethanol (60 ml) was added (2R)-2-(3-chlorophenyl)oxirane (4.86 g) and the mixture was refluxed for 23 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate=2/1) to give the (2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nitrophenyl)-1-propanol (5.46 g) as a yellow crystalline solid.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.N([O-])=O.[Na+].[I-:19].[K+]>O>[I:19][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 2.5 °C

Procedure:
45 g (0.25 mol) 4-Amino-3-nitrobenzoic acid, 400 ml water and 100 ml concentrated hydrochloric acid were added into a reaction flask. Started to stir, and the mixture was cooled to 0 to 5° C., then 50 ml aqueous solution of 25.9 g sodium nitrite (0.38 mol) was added dropwise. The solid was dissolved gradually. After completing the dropwise addition, the mixture was reacted at 0 to 5° C. for 1 hour, and 200 ml aqueous solution of 88 g (0.5 mol) potassium iodide was added dropwise at this temperature. The mixture was stirred at room temperature for 2 h after completing the dropwise addition, and solid was precipitated. The solid was filtered, washed with water, and dried to obtain 4-iodo-3-nitrobenzoic acid (compound V) as a solid, 65 g (0.22 mol), yield 89.7%.
Reaction SMILES: [Br:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH3:10]O>>[CH3:10][O:8][C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[Br:1])=[O:9]
Reactant: CO
Reactant: O=C(O)c1ccoc1Br
Product: COC(=O)c1ccoc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Bromofuran-3-carboxylic acid (5.0 g, 26 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2×). SO2Cl2 (15 mL, 0.2 mol, 7.7 eq.) was added dropwise and the resulting mixture was stirred for two days at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield 2-bromofuran-3-carboxylic acid methyl ester (5.0 g) as a brown solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].CC(C[AlH]CC(C)C)C>O1CCCC1.CCCCCCC>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([CH:4]=[O:5])[N:7]=1
Reactant: CON(C)C(=O)c1cc2ccccc2cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=Cc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.35 g (6.24 mmol) of isoquinoline-3-carboxylic acid methoxy-methyl-amide was dissolved in 50 ml tetrahydrofuran, 7.49 mL of 1.0 M DIBAL solution in heptane was added at −78° C. The reaction was warmed to room temperature and stirred for 1 hour at r.t., and then quenched by addition of 10 mL saturated sodium bicarbonate. 100 mL of water was added followed by extraction with 100 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuum to give colorless oil. The crude was used to next step without further purification. LC-MSD, m/z for C10H7NO [M+H]+: 158.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 min: 0.221 min.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Br:8][CH2:9][CH2:10]Br>>[Br:8][CH2:9][CH2:10][N:3]1[C:2](=[O:1])[CH:6]=[C:5]([CH3:7])[O:4]1
Reactant: Cc1cc(O)no1
Reactant: BrCCBr
Product: Cc1cc(=O)n(CCBr)o1

Procedure:
A mixture of 10 g of 3-hydroxy-5-methylisoxazole and 56 g of 1,2-dibromoethane was refluxed for 6 hours. After cooling, the reaction mixture was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of benzene and acetone. A yellow liquid separated, and this was crystallized with n-hexane, affording 2-(2-bromoethyl)-5-methyl-3-oxo-4-isoxazoline, melting at 39°-40° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][N:34](C)[CH2:35][CH2:36][CH2:37]N=C=NCC.CNCCC>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([C:8](=[O:9])[N:34]([CH3:33])[CH2:35][CH2:36][CH3:37])[CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N(C)CCC)c1
Yield: 90.1 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol), N-methylpropylamine (51 μL, 0.5 mmol) in dichloromethane (2.5 mL) at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 90%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][C:20]([C:23](OCC)=[O:24])=[CH:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H].[Cl-].[NH4+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:31][CH:30]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(-c4ncc(CO)s4)cc3c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a solution of ethyl 2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (242 mg) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (50 mg) at 0° C. After the mixture was stirred at 0° C. for 30 min, ethanol was added dropwise until hydrogen did not generate. A saturated aqueous ammonium chloride solution was added to the mixture and the resulting yellow suspension was filtered through celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 100/0, volume ratio) to give yellow crystals. The crystals were recrystallized from ethanol-ethyl acetate to give yellow crystals. The crystals were purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 90/10, volume ratio) to give yellow crystals. The crystals were recrystallized from ethanol-hexane to give the title compound (52 mg, 23%) as yellow crystals. MS 507 (MH+). mp 125-126° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:29])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:29])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2cccc(Cl)c2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A solution of the compound (0.040 g, 0.098 mmol) of Example 9 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0075 g, y. 23%).
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:10][NH:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[O:18])(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[F:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[C:16]2[CH:29]=[CH:30][CH:31]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)([CH3:33])[CH3:32])[CH:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(Cc1cccc(C(=O)NCCc2cccc(F)c2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(Cc1cccc(C(=O)NCCc2cccc(F)c2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Yield: 52 %

Procedure:
3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxylmethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-fluorophenyl)ethyl]benzamide (preparation 157), (343 mg, 0.58 mmol) and ammonium fluoride (213 mg, 5.76 mmol) in methanol (12 mL) and water (2 mL) were stirred at room temperature for 42 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were concentrated in vacuo and the residue was azeotroped (×2) in ethanol to give a white solid. This solid was then re-crystallised with ethanol/water and dried under vacuum to afford the title compound as very pale yellow crystals in 52% yield, 144 mg. 1H NMR (400 MHz, CD3OD) δ: 7.63 (2H, m) 7.38-7.23 (4H, m), 7.13 (1H, m), 7.05 (1H, m), 7.00 (1H, m), 6.91 (1H, m), 6.85 (1H, d), 4.65 (3H, m), 3.59 (2H, m), 2.96-2.84 (2H, m), 2.78-2.68 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm. LRMS ESI m/z 481 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([CH3:26])([CH3:25])[NH:5][C:6](=[O:24])[C:7]([CH3:23])([CH3:22])[NH:8][C:9](=[O:21])[C:10]([CH3:20])([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O[Li].O>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C:10]([CH3:20])([CH3:19])[C:9]([NH:8][C:7]([CH3:23])([CH3:22])[C:6]([NH:5][C:4]([CH3:26])([CH3:25])[C:3]([OH:27])=[O:2])=[O:24])=[O:21])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 6 (2.14 g, 5.52 mmol) was dissolved in THF (60 mL) and a solution of LiOH.H2O (0.695 g, 16.6 mmol) in de-ionized H2O (30 mL) added. The reaction mixture was stirred for 3 h at room temperature before the bulk of solvent was evaporated and the solution diluted with H2O (100 mL). The solution was washed with Et2O (2×40 mL) and acidified to pH 2 by addition of 5 M HCl. A white solid precipitated and was collected by filtration. The residue was washed with icecold H2O (30 mL) and dried under high vacuum affording the title compound as a white solid (1.84 g, 89%). The compound has been prepared before,6 but as far as we have been able to establish has not been appropriately characterised; 1H NMR (200 MHz, DMSO-d6) δ 11.84 (br s, 1H, COOH), 7.59 (s, 1H, NH(Aib)), 7.48 (s, 1H, NH(Aib)), 7.18 (s, 1H, NH(Aib1)), 1.40 (s, 9H, (CH3)3), 1.32 (s, 6H, CH3), 1.28 (s, 6H, CH3), 1.25 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 175.5, 173.5, 173.4, 155.1, 78.7, 55.8, 55.5, 54.8, 28.1, 24.8, 24.7, 24.6; HRMS (m/z): [M+Na]+ calcd. for C17H31N3O6Na, 396.2110. found, 396.2115; Anal. Calcd. for C17H31N3O6: C, 54.68; H, 8.37; N, 11.25. Found: C, 55.0; H, 8.4; N, 11.1.
Reaction SMILES: [CH2:1]([N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:20])[CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7](C)([CH3:10])[CH:8]=C)[CH:2]=[CH2:3]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCCl>[CH3:8][C:7]1([CH3:10])[CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:5](=[O:20])[N:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:1][CH:2]=[CH:3]1
Reactant: C=CCN(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CC=CC1(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 26.5 %

Procedure:
To a round bottom flask was added tert-butyl 1-(allyl(phenyl)amino)-3,3-dimethyl-1-oxopent-4-en-2-ylcarbamate (60 mg, 0.17 mmol) and 1,2-dichloroethane (2 mL). The reaction was charged with argon and brought to 60° C. Then, the Grubbs II catalyst (21 mg, 0.025 mmol) was added and the reaction was stirred at 60° C. for 4 hr and then at rt overnight. The reaction was concentrated and the residue was purified by RP prep-HPLC (Method A) to give (Z)-tert-butyl 4,4-dimethyl-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (15 mg, 0.045 mmol, 27% yield) as a clear oil. Anal. Calcd. for C19H26N2O3 m/z 330.2. found: 331.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (t, J=7.69 Hz, 2H), 7.30-7.25 (m, 1H), 7.21 (d, J=7.03 Hz, 2H), 5.82-5.71 (m, 2H), 5.71-5.64 (m, 1H), 5.10 (d, J=8.35 Hz, 1H), 4.82 (d, J=17.58 Hz, 1H), 3.76 (dd, J=17.58, 7.91 Hz, 1H), 1.50-1.44 (m, 9H), 1.20-1.16 (m, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2ccc3ccccc3n2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(CC(=O)O)c(OCc2cc(OCc3ccc4ccccc4n3)no2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of methyl [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (674 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetic acid (532 mg, yield 82%), which was then recrystallized from tetrahydrofuran-hexane. melting point: 124–125° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][N:15]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])[CH2:14][CH2:13][C:12]=2[N:11]=1>CN(C=O)C>[CH:1]1([O:6][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][N:15]([CH2:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH:29]5[CH2:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCc2nc(Cl)ccc2C1)N1CCN(C2CCC2)CC1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCc2nc(OC3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopentanol (99 mg, 1.15 mmol) in DMF (5 mL) is added NaH (60% in mineral oil, 18.4 mg, 0.46 mmol), and the mixture is stirred at rt for 30 min. 2-Chloro-6-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (80 mg, 0.23 mmol) is added and the mixture is heated at 100° C. for 2 hr. Solvent is removed and the residue is partitioned between water (10 mL) and DCM (10 mL). The layers are separated and the aqueous layer is extracted with DCM (10 ml). The combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil MS (M+1): 399.3; 1H NMR (δ, CDCl3): 7.17 (d, 1H), 6.46 (d, 1H), 5.28 (m, 1H), 3.64 (q, 4H), 3.58 (s, 2H), 3.36 (s, 2H), 2.80-2.88 (m, 4H), 2.63-2.73 (m, 1H), 2.28 (q, 4H), 1.58-2.08 (m, 14H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]#[N:13])=[C:7]2[NH:6][CH2:5][CH2:4]1.CS(C)=[O:29].[OH-].[Na+].OO>CCO>[NH2:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:11]([C:12]([NH2:13])=[O:29])=[C:7]2[NH:6][CH2:5][CH2:4]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2CN
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 60 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (15 mg, 0.043 mmol) in 2 mL of EtOH was added 1 mL of DMSO, 0.5 mL of NaOH (5N) and 0.5 mL of H2O2 (30% aqueous solution). After stirring at 60° C. for 2 hr, the mixture was concentrated to remove EtOH. The residue was partitioned between water (30 mL) and EA (20 mL). The organic phase was concentrated and purified by pre-HPLC eluting from 20% to 40% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to give the product as a TFA salt (10 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (br s, 3H), 7.62 (d, J=8.8 Hz, 2H), 7.43-7.35 (m, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.15-7.12 (m, 4H), 6.77 (br s, 1H), 4.38-4.30 (m, 1H), 3.40-3.20 (m, 4H), 2.16-2.06 (m, 1H), 2.00-1.80 (m, 1H). MS (ESI) m/e [M+1]+364.0.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH2:26]([O:28][CH2:29][CH2:30][NH2:31])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:26]([O:28][CH2:29][CH2:30][NH:31][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[CH3:27]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (31 mg) was prepared by following General Procedure F using 2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (36 mg), 2-ethoxy-ethyl amine (0.1 ml), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 433; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (m, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.76 (m, 1H), 7.65 (d, 1H), 7.48 (m, 2H), 3.66 (s, 3H), 3.47 (t, 2H), 2.88 (m, 4H), and 1.09 (t, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1([CH3:29])[CH2:7][N:6]1[C:8]1[CH2:9][C@@H:10]2[CH2:27][C:26](=[O:28])[N:11]2[C:12]=1[C:13]([O:15]CC1C=CC([N+]([O-])=O)=CC=1)=[O:14])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:34]>O1CCOCC1.O.C(O)C.[Pd]>[C:1]([O:4][C:5]1([CH3:29])[CH2:7][N:6]1[C:8]1[CH2:9][C@@H:10]2[CH2:27][C:26](=[O:28])[N:11]2[C:12]=1[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2].[Na+:34]
Reactant: CC(=O)OC1(C)CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)CN1C1=C(C(=O)[O-])N2C(=O)C[C@H]2C1

Procedure:
A solution of p-nitrobenzyl 2-(2-acetoxy-2-methyl-aziridin-1-yl)-carbapen-2-em-3-carboxylate (0.9 mg, 2.3 micromol) in dioxane (100 microliter), deionized water (60 microliter), absolute ethanol (8 microliter), and 0.5M aqueous sodium bicarbonate (5 microliter) was shaken with 10% (w/w) palladium on charcoal (1.1 mg) under hydrogen (50 psig) for 30 min. The mixture was centrifuged and the pellet washed with deionized water (3×100 microliter). The combined supernate and washes were extracted with ethyl acetate (3×0.5 ml) and concentrated under vacuum to provide 420 microliter of a solution of sodium 2-(2-acetoxy-2-methylaziridin-1-yl)-carbapen-2-em-3-carboxylate.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:12]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[ClH:38].[F:21][C:17]1[CH:16]=[C:15]([C:13]2[N:12]([S:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:24])[CH:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-hexane=1:1→9:1) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate, a 4 mol/L hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane, and recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 84 mg, 35%).