Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2.CN1CCCC1=O.O.Cl.[NH2:29][C@H:30]([CH2:32][OH:33])[CH3:31]>>[OH:33][CH2:32][C@H:30]([NH:29][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2)[CH3:31]
Reactant: C[C@H](N)CO
Reactant: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)[nH]c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
A solution of the product from example 2, step (f) (0.1 g) in a mixture of alaninol (0.128 g), disopropylethylamine (0.35 ml) and N-methylpyrrolidinone (3 ml) was stirred at 100° C. for 48 h before pouring into H2O (75 ml). 2M HCl solution was then added to pH=2 and the light brown solid formed filtered and recrystallised from EtOH to afford the subtitle compound (22 mg, 19%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=O)[CH3:2].[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1OCC

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-diethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 93.7% yield as a solid. m.p. 57.9° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(O)CC1
Temperature: -78 °C
Yield: 79.1 %

Procedure:
4-hydroxypiperidine (0.534 g, 5.3 mmol) was dissolved in methylene chloride (50 mL). The solution was cooled to −78° C. and triethylamine (1.10 mL, 7.95 mmol) was added. Acetyl chloride (0.33 mL, 4.77 mmol) was added dropwise to the mixture. The mixture was warmed to r.t., concentrated under reduced pressure and purified using silica gel chromatography (50% ethyl acetate in hexanes) to give the title compound (0.540 g, 80%) as an oil.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[C:12]([Br:16])[C:13]([OH:15])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=1>>[C:1]([N:4]1[C:10]2[CH:11]=[C:12]([Br:16])[C:13]([O:15][CH2:18][C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=3)=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN1CC=C(CO)CC1
Reactant: CC(=O)N1CCCCc2cc(O)c(Br)cc21
Product: CC(=O)N1CCCCc2cc(OCC3=CCN(C)CC3)c(Br)cc21

Procedure:
The title compound was prepared from 1-acetyl-8-bromo-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine (D25) and 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1) following the procedure of Description 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[O:10][CH3:11])[CH2:5][NH:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1c(Cl)cc(CN)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(CNc2ccccc2[N+](=O)[O-])cc1Cl
Yield: 86.1 %

Procedure:
A mixture of 3,5-dichloro-4-methoxybenzylamine (6 g, 29.2 mmole), 2-fluoronitrobenzene (2 g, 14.2 mmole) and ammonium acetate (1.0 g) was heated at 80° for 1 hour. The cooled mixture was taken up into ethyl acetate and washed sequentially with aqueous 3N HCl, water, aqueous 5% sodium bicarbonate, brine, dried (Na2SO4), and concentrated to give the title compound 4.0 g (78%) as orange crystals, mp 128°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[CH2:6]2.[Br:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:18][CH2:19][CH2:20][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=2[CH3:14])[CH2:6][C:7]2([CH2:15][CH2:16][CH2:17]2)[CH2:8]1
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(c(C)c1C)N(CCBr)CC1(CCC1)C2

Procedure:
A solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.12 g), 1,2-dibromoethane (2 mL) and Cs2CO3 (3.16 9) in DMF (7 mL) was heated in a bath of 110° C. for 6 hours. The mixture was cooled, water was added, and extracted with dichloromethane. The organic phase was then washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.6) to give 1′-(2-bromoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] which was then added NaN3 (1.1 g) and dissolved in dichloromethane (7 mL). After heating the solution in a bath of 90° C. for 1 hour, the mixture was cooled, mixed with water and extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.5-10:0.6) to give 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) as an oil. 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) was dissolved in methanol (7 mL) and ethylacetate to which 50 mg Pd/C (10%) was added. The flask was then flushed evacuated and flushed with hydrogen. Under a balloon of hydrogen for 1 hour, the mixture was filtered and evaporated to give 2-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)ethanamine (278 mg) as an oil. 1H-NMR (300 MHz, C2D6O) δ=6.414 (s, 1H); 3.77 (s, 3H); 3.52 (s, 2H); 3.16-2.92 (m, 4H); 2.81 (s, 2H); 2.18 (s, 3H); 2.12 (s, 3H); 2.03-1.86 (m, 4H); 1.84-1.64 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1cccnc1F
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCc1ccccc1)c1cccnc1F
Reaction time: 16 h
Yield: 14.3 %

Procedure:
2-Fluoro-nicotinic acid (0.793 g, 5.59 mmol) and phenethylamine (0.705 mL, 5.59 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (1.56 mL, 11.2 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.97 g, 7.83 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.196 g, 0.802 mmol, 14.3%). ESI-MS m/z calc. 244.1, found 245.2 (M+1)+. Retention time of 2.76 minutes.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:33]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:12]1[C:10]([OH:33])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above compound (6) (88 mg) was dissolved in methanol (12 mL) and 10% Pd—C (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure, the resulting residue was freeze-dried to obtain the titled compound (60 mg) as a colorless amorphous.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11](O)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11]([O:4][CH:1]2[CH2:3][CH2:2]2)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
0.9 ml of cyclopropanol were added to a mixture of 5.5 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 26 ml of methylene chloride and 1 g of 4-dimethylamino-pyridine and 3 g of dicyclohexylcarbodiimide were added thereto at 0° C. The mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 85-15 cyclohexane-ethyl acetate mixture yielded 3.6 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclopropyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 62° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(I)cc1
Yield: 90 %

Procedure:
4-Iodophenylacetic acid (3 g), ethanol (20 mL) and conc. H2SO4 (5 mL) were refluxed overnight. Ca. 15 mL ethanol was then evaporated, the residue was extracted with dichloromethane (3×100 mL), the combined organic extracts were washed with sat. aq. NaHCO3, dried over Na2SO4 and evaporated in vacuo to afford 2.97 g (90%) of 121JP58 as a yellow oil.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]4[CH2:44][CH2:43][CH2:42][C@H:41]4[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47]([NH:49][C@H:50]([C:58]4[S:59][CH:60]=[CH:61][N:62]=4)[CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[S:48])=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[NH2:18][C:19]1([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47]([NH:49][C@H:50]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCC1)C(C)C
Yield: 61.3 %

Procedure:
According to general procedure A, from #29 (54 mg, 0.054 mmol) in dichloromethane (6 mL, 0.9 mM) and diethylamine (4 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give example #30 (26 mg, 61%) as a solid. HPLC (Protocol A): retention time=7.233 minutes, m/z 785.4 [M+H+], (purity >72%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.82 (br d, J=8 Hz), total 1H], 8.19-8.27 (m, 1H), [7.80 (d, J=3.2 Hz) and 7.83 (d, J=3.2 Hz), total 1H], [7.65 (d, J=3.3 Hz) and 7.69 (d, J=3.3 Hz), total 1H], 7.28-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.14-7.19 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.44 (ddd, J=11, 8, 4 Hz), total 1H], [4.53 (dd, J=9, 8 Hz) and 4.60 (dd, J=9, 7.5 Hz), total 1H], 3.24 and 3.25 (2 s, total 3H), 3.17 and 3.21 (2 s, total 3H), 2.93 and 3.00 (2 br s, total 3H), [1.14 (d, J=6.5 Hz) and 1.17 (d, J=6.5 Hz), total 3H].
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].CO>C1C=CC=CC=1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([Br:11])=[CH:8][CH:7]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
In a 1-liter three neck round bottom flask, 43 g (0.2 mol) methyl 4-bromobenzoic acid and 17.6 g (0.4 mol) sodium hydride were dissolved in 200 ml dried benzene and heated to 60° C. Next, 39.8 g (0.2 mol) 4-bromoacetophenone in 100 ml dry benzene was slowly added through a dropping funnel, and 1 ml methanol was added to the flask to initiate the reaction. After the mixture was refluxed overnight, the reaction was quenched by adding methanol and pouring it into ice water. The pH of the mixture was brought down to 7.0 using 5 N sulfuric acid. A solid was collected, washed with water, and recrystallized from benzene to give a light yellow product. Characterization. Yield: 30.3 g (40%). 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.84 (d, 4H, ArH); 7.62 (d, 4H, ArH); 6.77 (s, 2H, CH2). EI-MS: 382 (M+), 301, 225, 183, 157.
Reaction SMILES: [CH3:1][C@H:2]([C:7](=O)[C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=1)[CH2:3][C:4](O)=[O:5].O.[NH2:25][NH2:26]>C(O)C>[CH3:1][C@@H:2]1[C:7]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:14][C:10]=3[CH:9]=2)=[N:26][NH:25][C:4](=[O:5])[CH2:3]1
Reactant: NN
Reactant: C[C@@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Solvent: O
Solvent: CCO
Product: C[C@H]1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
177 mg (572 μmol) (S)-3-methyl-4-oxo-4-(2-phenyl-benzoxazol-6-yl)-butyric acid are combined with 10 ml of ethanol and 350 μl (7050 μmol) hydrazine hydrate. The reaction mixture is refluxed for 3 h. The solvent is eliminated by rotary evaporation in vacuo and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:9]1[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@H:41]([OH:45])C(O)=O)=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@H:41]([OH:45])[C:6]([N:8]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:9]1[C:10]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 65.4 %

Procedure:
Following a procedure similar to that described in Example 11, 28 mg (0.10 mmol) of (3S)-1-t-butoxycarbonyl-N-t-butyl-3-hydroxy-L-prolinamide (prepared as described in Preparation 13) was deprotected to remove the t-butoxycarbonyl group. The resulting (3S)-N-t-butyl-3-hydroxy-L-prolinamide was then condensed with 52 mg (0.12 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1), to give 40 mg of the title compound as a white powder, melting at 111°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a solution of 4-fluorobenzaldehyde (3.0 g, 24.1 mmol) in MeOH (15 mL) was added NH2OH.HCl (2.0 g, 29.1 mmol) and Na2CO3 (1.53 g, 14.4 mmol) and the reaction stirred for 4 hours at room temperature. The reaction was concentrated under reduced pressure, extracted with DCM (2×100 mL), and the organic layer washed with water (2×50 mL) followed by brine solution (2×25 mL). The organic layer was concentrated under reduced pressure to obtain 4-fluorobenzaldehyde oxime [Brain, J. Am. Chem. Soc., 133:949-957 (2011)] as white solid (2 g, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.55 (dd, 2H), 7.06 (t, 2H).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:19][O:18][C@H:17]2[C@@H:12]([O:13][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:15][CH2:16]2)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CO.C1COCC1>[C:20]1([CH:14]2[O:13][C@H:12]3[CH2:11][C@H:10]([OH:9])[CH2:19][O:18][C@@H:17]3[CH2:16][O:15]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl benzoate (650 mg, 1.910 mmol) in methanol (10 mL) and THF (5 mL) was added 5N aqueous NaOH (4.0 mL, 20.0 mmol). After 18 hours the mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (2×120 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant white solid was chromatographed using a Biotage™ 25 g silica gel cartridge eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C13H16O4 236.10, observed m/e: 237.15 (M+H)+ (Rt 1.13/4 min).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:34])[C:6]([CH3:33])=[C:7]([CH3:32])[C:8](=[O:31])[C:9]=1[CH2:10][CH2:11][C@@:12]([OH:30])([CH3:29])[CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:2]=[CH2:3].CCOC(C)=O>C(Cl)Cl.O=[Pt]=O>[OH:30][C@:12]([CH3:29])([CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][CH2:10][C:9]1[C:8](=[O:31])[C:7]([CH3:32])=[C:6]([CH3:33])[C:5](=[O:34])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=C(C)C1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=C(C)C1=O
Reaction time: 120 h
Yield: 80 %

Procedure:
(R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5,6-dimethyl-[1,4]benzoquinone (Ex-1D-4) (50 mg, 0.1 mmol) was hydrogenated using PtO2 (5 mg) at 50 psi for 2 h in a solution of EtOAc (5 mL). The suspension was filtered through celite, which was rinsed with DCM (2×2 mL). The pale yellow solution was concentrated by rotary evaporation to yield a pale yellow oil (Ex-1D-5). The oil was dissolved in DCM (5 mL) and stirred with silica (˜20 mg) for 5 days. The bright yellow suspension was filtered through a cotton plug and concentrated by rotary evaporation to yield (R,R,R)-2-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5,6-dimethyl-3-propyl-[1,4]benzoquinone (Ex-1D-6) as a bright yellow oil (38 mg, 76%). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.57-2.52 (m, 2H), 2.48-2.44 (m, 2H), 2.02 (s, 6H), 1.57-1.04 (m, 26H), 0.99 (t, J=7.4 Hz, 3H), 0.89-0.85 (m, 15H).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)C1CCCCN1
Reactant: O=C(CCCl)c1ccc(F)cc1
Product: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Yield: 92 %

Procedure:
N-[3-(4-Fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester was prepared in 92% yield by alkylation of methyl pipecolinate with 3chloro-4′-fluoropropiophenone (Aldrich) as described in Example 20A (Step 1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[S:9](Cl)([Cl:12])(=[O:11])=[O:10]>O1CCOCC1.C(#N)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:9]([Cl:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)Cl)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of N-methylpiperazine (1.48 mL, 13.3 mmol) in dioxane (6.7 mL) cooled to 0° C. was added 4N hydrochloric acid in dioxane (10 mL). The reaction was very exothermic, and the mixture was stirred until the reaction cooled to room temperature. The solvent was removed under reduced pressure and chased with ether (2×). The solid obtained was taken up in acetonitrile (7 mL) and sulfuryl chloride (3.53 mL, 3.3 equiv) was added. The mixture was warmed at relux for 24 hours and the product removed by filtration and washed with 1:1 acetonitrile/ether (100 mL). This crude material was recrystallized from hot methanol and acetonitrile to afford 4-methylpiperazin-1-ylsulfonyl chloride (1.36 g, 44%) as a white crystalline solid.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[S:25][C:26]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Cc1ccc2nc(Cl)sc2c1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1ccc2nc(N3CC4CN(C(=O)c5ccccc5-c5ccccc5)CC4C3)sc2c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-methyl-benzothiazole. MS (ESI): mass calculated for C27H26N3OS, 439.57; m/z found 440.2 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[NH2:13]>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:17][C:15]1[CH:14]=[C:12]([NH:13][C:1](=[O:3])[CH3:2])[CH:11]=[C:10]([O:9][CH3:8])[CH:16]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (13 ml, 137 mmol, 1.05 equiv) is added (in 15 min) to a suspension of 3,5-dimethoxyaniline (20 g, 131 mmol) in toluene (110 mL), keeping the internal temperature in the range of 35-45° C. The reaction mixture is allowed to stir for 20 h at RT. The resulting thick, grey suspension is diluted with hexane (55 mL) and filtered. The residue in the filter is washed with toluene/Hex (2:1, 70 mL) and Hex, and dried to provide the title compound as a white solid. API-ES-MS: 196.1 [MH]+, tR=3.03 min (purity: 100%, system 1).