Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=4[N:26]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.N1CCCCC1CCOC1C=CC(C2NC3C=CC(C(N)=O)=CC=3N=2)=CC=1>>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=4[N:26]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCNCC4)cc3)nc2c1
Agent: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCN(Cc5ccccc5)CC4)cc3)nc2c1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting benzaldehyde for p-tolualdehyde and 2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. HPLC (Method C): Rt=4.41. MS (ESI+): mass calcd. for C28H30N4O2, 454.24; m/z found, 455.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.15 (s, 1H), 8.00 (d, J=8.9 Hz, 2H), 7.91 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.40 (br m, 5H), 7.12 (d, J=8.8 Hz, 2H), 4.21 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.43-3.40 (m, 2H), 2.95-2.89 (m, 2H), 2.00-1.97 (m, 2H), 1.87-1.78 (m, 1H), 1.78-1.72 (m, 2H), 1.48-1.37 (m, 2H).
Reaction SMILES: CN(C)C=O.[C:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+]([O-])=O)[CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N+:19]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:17][CH:16]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccccc3)cc2)c1
Temperature: 140 °C
Reaction time: 15 h
Yield: 70.1 %

Procedure:
To a four necked flask equipped with a thermometer, reflux condenser and stirrer, 400 g of N,N-dimethylformamide (DMF), 40 g of toluene, 80 g (0.47 mol) of p-phenylphenol, 86.9 g (0.517 mol) of m-dinitrobenzene, and 35.9 g (0.26 mol) of potassium carbonate were charged. The mixture was heated to 140° C. with stirring and aged at 140° C. for 15 hours. After finishing the reaction, the reaction mixture was cooled to 100° C. and filtered to remove inorganic salts. The filtrate was incorporated with 300 g of water and cooled to room temperature to crystallize the desired product. The precipitated crystals were filtered and recrystallized from a mixture of 380 g of DMF and 100 g of water to obtain 96 g (70% yield) of 4-(3-nitrophenoxy)-1,1'-biphenyl (NPBP).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11])(C)(C)C.[ClH:20].[O:21]1CCOCC1>>[ClH:20].[NH2:7][C@@H:8]([CH2:16][CH2:17][CH3:18])[CH:9]([OH:21])[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11]
Reactant: C1COCCO1
Reactant: CCC[C@@H](CC(=O)NC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CCC[C@H](N)C(O)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl-(3S)-1-(cyclopropylamino)-1-oxohexan-3-ylcarbamate (75 mg, 0.26 mmol) was added 4.0 M HCl in dioxane (6.0 mL). After 1 hour, the reaction mixture was concentrated and dried to give the (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide HCl salt as a white solid. To this salt in dichloromethane/N,N-dimethylformamide (10:3, 13 mL) was added (2S,4R)-1-(tert-butoxycarbonyl)-4-(6-ethoxyisoquinolin-1-yloxy)-pyrrolidine-2-carboxylic acid (106 mgs, 0.26 mmol), O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (119 mg, 0.31 mmol) and diisopropylethylamine (0.15 mL, 0.78 mmol). After 1 hour at room temperature reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), sodium bicarbonate (1×), and brine (1×). The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give (2S,4R)-1-(tert-butyl-2-((3S)-1-cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1-carboxylate.
Reaction SMILES: [OH-].[K+].[SH:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:20]([S:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CS
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CSCc1ccccc1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a solution of 71 mg of potassium hydroxide in 6 ml of ethanol were added 253 mg of α-mercaptomethyl-β-(p-nitrophenyl)-γ-butyrolactone and 239 mg of benzyl bromide and the resulting mixture was kept at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with 60 ml of ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The resulting crude product was purified by a silica gel column chromatography to give 218 mg (yield 50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reaction time: 24 h
Yield: 50 %

Procedure:
11.4 g (0.09 mol) of 1,2-dimethoxybenzene are mixed with 3 g (0.03 mol) of succinic anhydride, and then, under stirring, the semisolid mass is added with 7.8 g (0.06 mol) of AlCl3 under a light nitrogen flow. After 24 hours at room temperature under a nitrogen atmosphere, 300 ml of ethyl ether are added. A precipitate is formed which is filtered and treated by cooling with 100 ml of HCl 6N, extracting several times with CH2Cl2 and washing with water. The organic solution, anhydrified with anhydrous sodium sulphate, is concentrated to dryness, obtaining a yellow solid which is crystallised by n-hexane/EtOAc giving 3 g of product. Yield 50%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][C:15]([OH:17])=O)=[CH:4]1)[CH3:2].CN(C(ON1N=[N:33][C:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N(C)[CH3:43].Cl.CCN(C(C)C)C(C)C>C1COCC1>[NH2:32][C:27]1[CH:43]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:15](=[O:17])[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[OH:13])[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCn1cc(CC(=O)O)c2c(O)cc(F)cc21
Reactant: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(CC(=O)Nc2ccccc2N)c2c(O)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
The solution of 11-3 (440 mg, 1.85 mmol), HATU (850 g, 2.23 mmol), HNMe2.HCl (150 g, 1.84 mmol) in THF (5 mL) was added DIPEA (600 mg, 4.63 mmol) dropwise at 0° C. The reaction temperature was allowed to raise room temperature and stirred overnight. The volatile was removed by evaporation. A white residue was obtained, which was quenched with 100 mL of water and extracted with DCM (50 mL×4). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography (elution with petroleum:ethyl acetate: 1:1) to get 12-2 (324 mg, 53.5%) as a white solid. LCMS: calc 327.4 and found 328.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[O:10])[CH2:8]Br.C(N(CC)C(C)C)(C)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH2:33])[CH3:32])=[CH:26][CH:25]=1)([O:22][CH3:23])=[O:21].NC(N)=O.[BH4-].[Na+].C(Cl)[Cl:41]>CO>[ClH:41].[ClH:41].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH:33][CH2:8][CH:7]([OH:10])[C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])[CH3:32])=[CH:26][CH:25]=1)([O:22][CH3:23])=[O:21]
Reactant: Cc1ncoc1C(=O)CBr
Reactant: ClCCl
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: NC(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ocnc2C)cc1
Product: Cl
Temperature: 35 °C
Reaction time: 1 h

Procedure:
2.6 g (0.009 mol) of 4-Methyl-5-bromoacetyl-oxazole and 1.16 g (0.009 mol) of N,N-diisopropyl-ethylamine are dissolved in 50 ml of methylene chloride. This solution is added dropwise, within 20 minutes to 3.47 g (0.018 mol) of 2-(4-carbomethoxyphenyl)-1-methylethylamine in 100 ml of methylene chloride, and the mixture is stirred at room temperature for 2 hours and at 35° C. for 1 hour. The reaction solution is cooled in an ice bath, and 150 ml of methanol are added. Then, for the reduction of the resulting amino-ketone, 1 g of sodium borohydride is added in portions over 30 minutes, and the mixture is stirred at room temperature for 20 hours and then evaporated. Ice-water is then added to the residue, and the mixture is acidified with hydrochloric acid, made alkaline with concentrated aqueous ammonia and extracted with chloroform. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =9:1 as eluant. The hydrochloride is then precipitated with ethereal hydrochloric acid.
Reaction SMILES: [OH-].[Na+].C[C:4]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:5]([O-:7])=[O:6].O.Cl>C1COCC1.CO>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([OH:7])=[O:6])=[CH:18][CH:17]=1)#[N:20]
Reactant: CC(C(=O)[O-])(c1ccc(C#N)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
316.5 mg (7.9 mmol) of sodium hydroxide were added to a solution of 192.5 mg (0.79 mmol) of (+/−)-methyl(4-cyanophenyl)(cyclopentyl)acetate in 1.7 ml of THF/methanol (1:1), and the mixture was stirred at RT for 3 h. The reaction mixture was then poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated. This gave 125.6 mg (69% of theory) of the title compound.
Reaction SMILES: [ClH:1].[N:2]([O:4]CCC(C)C)=O.[CH2:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH3:11]>>[CH2:10]([O:12][CH2:13][CH:14]([N:2]=[O:4])[C:15]([Cl:1])([CH3:17])[CH3:16])[CH3:11]
Reactant: CCOCC=C(C)C
Reactant: CC(C)CCON=O
Reactant: Cl
Product: CCOCC(N=O)C(C)(C)Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Concentrated HCl was added to a cooled (0°-5° C.) solution of isoamyl nitrite (14.0 g, 120 mmol) and 1-ethoxy-3-methyl-2-butene (6.84 g, 60 mmol). The temperature was maintained below 5° C. during the addition and the reaction mixture was stirred at 5° C. for an additional 30 min. The product was filtered and washed with a cold (-20° C.) 1:1 mixture of ethanol and ether. The solid was further washed with ether to afford a white solid. Yield: 6.9 g (64%); mp 84°-85° C. 1H NMR (CDCl3) ε 1.12 (t, 3H, CH2CH3), 1.65 (d, 6H, CH3), 3.49 and 3.95 (m, 2H, CH2OCH2CH3), 4.15 (m, 2H,CH2CH3), 6.12 (dd, 1H, [CH3)2C=CH--]. MS: (M+H)+ =180.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[CH2:22][CH2:21][C:20]([F:26])([C:23]([OH:25])=O)[CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:20]1([C:23](=[O:25])[NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18][N:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:11][CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)N
Reactant: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)O)CC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N1CCCC(N2CCC(F)(C(=O)NC(C)(C)C)CC2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
Thionyl chloride (4 mL) was added to a solution of 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid (1.24 g, assume 3.92 mmol) and the reaction was stirred at 90° C. for 3 h. The reaction mixture was cooled to rt and concentrated in vacuo. DCM (4 mL) was added to a portion of the residue (0.65 mmol) followed by tert-butylamine (0.14 mL, 1.31 mmol) and DIPEA (0.57 ml, 3.27 mmol), the reaction mixture was stirred at rt for 48 h. The solvents were removed in vacuo, and the residue was partitioned between DCM (50 mL) and sat. NaHCO3 sol. (25 mL), organic layer washed with sat. NaCl sol. (25 mL) and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 7% MeOH in DCM]) to give ethyl 4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (0.11 g, 46.8%) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([OH:21])=O.[N:22]1([CH2:28][CH2:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C@H:36]([NH2:40])[CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[C@@H:3]1[CH2:18][C:19]([NH:40][C@H:36]1[C:37]2[C:32](=[CH:31][C:30]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:39][CH:38]=2)[CH2:33][CH2:34][CH2:35]1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Reactant: N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(CCN4CCCCC4)ccc32)cc1

Procedure:
A solution of (R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (310 mg, 1.0 mmol), crude (R)-6-(2-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (310 mg, 1.2 mmol), HOBt (135 mg, 1.0 mmol) and EDCI (191 mg, 1.0 mmol) in 1 mL of DMF was stirred overnight at room temperature. After quenching with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, EtOAc/MeOH=100:15 to 100:20 to EtOAc/2.0M NH3 in MeOH=100:10 to 100:15 to 100:20 ) gave the desired product as a white solid. MS: 551.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([OH:8])=[N:6][CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1O
Temperature: 50 °C
Yield: 66.7 %

Procedure:
A mixture of 5-bromo-3-nitropyridin-2-ol (1.26 g, 4.6 mmol) and tin chloride dihydrate (3.91 g, 17.3 mmol) in ethyl acetate (19.3 mL) was heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with brine. The aqueous layer was separated and extracted with ethyl acetate (5×50 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to give a black solid 580 mg (53%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16]([CH2:20][CH2:21][C:22](Cl)=[O:23])([O:18][CH3:19])=[O:17]>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To an ice cold solution of 3-aminophenol (21.8 g, 0.2 mol) and triethylamine (21.3 g, 0.2 mol) in tetrahydrofuran (250 ml) is added a solution of 3-carbomethoxypropanoyl chloride (30.1 g, 0.2 mol) in tetrahydrofuran. The reaction is allowed to warm to room temperature and is filtered through a pad of Celite and silica gel. The solvent is removed in vacuo to give a solid. Recrystallization from ethyl acetate gives 39.3 g (88% yield) of product, m.p. 144.5°-146° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.CN1CCOCC1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:34][C@H:35]([C:39]([N:41]1[CH2:61][CH2:60][CH2:59][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([C:52]([C:55]([F:58])([F:57])[F:56])([F:54])[F:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])=[O:40])[CH:36]([CH3:38])[CH3:37].Cl>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([NH:34][C@H:35]([C:39]([N:41]2[CH2:61][CH2:60][CH2:59][C@H:42]2[C:43]([NH:45][CH:46]([CH:47]([CH3:48])[CH3:49])[C:50](=[O:51])[C:52]([F:53])([F:54])[C:55]([F:56])([F:57])[F:58])=[O:44])=[O:40])[CH:36]([CH3:37])[CH3:38])=[O:11])[CH:2]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
Suspend 3-(3-pyridyl)propionic acid (174 mg, 1.15 mmol, Walker, F. A. et al., J. Amer. Chem. Soc., 102, 5530-5538 (1980)) in methylene chloride (15 mL). Add N-methylmorpholine (0.38 mL, 3.45 mmol) and triethylamine (0.32 mL, 2.30 mmol), and cool the resulting clear, colorless solution to -18° C. Add isobutylchloroformate (0.15 mL, 1.15 mmol) and stir for 20 minutes. Subsequently add N-methylmorpholine (0.13 mL, 1.15 mmol) and H-Val-Pro-Val-CF2CF3.hydrochloride (520 mg, 1.15 mmol) and stir at -20° C. for 1 hour. Allow reaction mixture to warm to room temperature, dilute the reaction mixture with additional methylene chloride (35 mL) and successively wash with 1N HCl (3×20 mL), saturated NaHCO3 (2×20 mL), and brine (1×20 mL). Dry and concentrate the crude product. Purify the crude product by flash chromatography (75:25::acetone:EtOAc) to give the title compound as a white solid foam. (Yield: 470 mg, 74%, 3:1::LLL:LLD).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.[CH:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:25]2[CH:30]=[CH:29][C:28]([N+]([O-])=O)=[CH:27][CH:26]=2)=[N:23]/O)=[CH:18][CH:17]=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(N)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:22]([NH:23][C:13]([CH:9]1[N:8]([S:40]([C:37]2[CH:36]=[CH:35][C:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)(=[O:42])=[O:41])[CH2:12][CH2:11][S:10]1)=[O:15])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Agent: NC(c1ccccc1)c1ccccc1
Product: O=C(NC(c1ccccc1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxy-carbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and benzhydrylamine, the title compound was obtained in 98.5% purity by HPLC.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.I[Si](C)(C)C>C(#N)C>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][C:4]1([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[CH2:12][C:3]1=[O:2]
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)C1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To a solution of Example 2B (0.18g, 6 mmol) in acetonitrile (2 mL) was added iodotrimethylsilane (TMSI) (0.13 mL, 0.9 mmol). The reaction solution was stirred at room temperature for 3 h. Afterwhich, additional 1.5 equivalents of TMSI (0.13 mL) were added and stirring was continued for 2 h. The solution was quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (40% →80% ethyl acetate/hexane) afforded the title compound as a white solid (0.11 g, 65%). 1H NMR (300 MHz, CDCl3) δ ppm 0.46 (m, 1H), 0.79 (m, 7H), 1.41 (m, 1H), 2.29 (m, 1H), 2.53 (m, 1H), 3.60 (s, 3H), 3.83 (m, 1H), 6.11 (s, 1H), 7.52 (m, 3H), 8.12 (d, J=7.72 Hz, 1H); MS m/z 289.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>CO.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]-oxaborol-3-yl]-acetic acid ethyl ester (0.250 g, 0.762 mmol) in methanol (5 mL) was added a solution of LiOH (0.091 g, 3.81 mmol) in water (4 mL) at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was acidified to pH 2 using 6M HCl and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.150 g, 65.6%). mp 156-157° C. 1HNMR (400 MHz, DMSO-d6 δ 9.20 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.19 (dd, J=2.63, 1.46 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.51 (dd, J=9.51, 2.20 Hz, 1H), 3.07 (dd, J=15.52, 2.63 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([BH3-])#N.[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 7.3 %

Procedure:
To a mixture of D-serine (25.0 g, 0.237 mol) and 200 mL anhydrous methanol was added sodium cyanoborohydride (11.95 g, 0.190 mol), while maintaining the temperature at 0° C. with an ice bath. Then, benzaldehyde (26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at 30° C. The mixture was stirred for 60 hr at room temperature. Then, the mixture was filtered and rinsed with methanol (50 mL). The white solid was dried in a vacuum oven at 40° C and 10 mmHg over 2 nights: 24.5 g. The filtrate was retained and the solvent was evaporated. This oil was passed through a silica gel column (10% MeOH/CH2Cl2) and 3.4 g of the desired compound was isolated. The total amount of the product was 27.9 g (60.0% yield). 1H NMR (DMSO-d6) δ3.25 (m, 1H, CH), 3.85 (m, 2H, CH2), 4.11 (d, 2H, benzylic CH2), 7.45-7.53 (m, 5H, ArH).