Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1>O1CCOCC1>[C:10]1([O:9][C:8](=[O:16])[NH:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[CH:28]=[CH:29][C:19]([F:18])=[CH:20][C:21]=2[N+:30]([O-:32])=[O:31])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Triethylamine (2.90 ml, 21.4 mmol) and phenyl chlorocarbonate (2.52 ml, 20.0 mmol) were added to a dioxane solution (43 ml) of 3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while being cooled with ice, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=30:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 5.92 g of powdery yellow phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[NH:9][C:10](=[O:25])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1CCCN1NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CCCN1NC(=O)c1ccc(O)cc1
Reaction time: 5 h

Procedure:
The above amide (10.0 g, 29.4 mmol) dissolved in 75 mL of absolute ethanol. To this solution was added 3 g of 10% Pd/C. The mixture was hydrogenated at 1 atm for 5 hours The catalyst was then removed by passing the reaction through a pad of celite. Concentration of the filtrate provided crude N-(4-hydroxybenzamido)-L-proline methyl ester that was purified by chromatography (SiO2, 30% ethyl acetate/hexanes) to provide 6.3 g (86%) as a white solid. MS.
Reaction SMILES: [CH2:1]([O:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:27]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:27]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:19])=[CH:21][CH:22]=2)=[O:41])=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCOC(C)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCCCCCCCCCOC(C)c1ccc(OC(=O)c2ccc(OCCCCCCCC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (+)-4-(1-hexadecyloxyethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (+)-4-(1-hexadecyloxyethyl)phenyl 4-octyloxy-benzoate. [α]D20 =+35.9° (c=1, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.B.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A solution of tert-butyl 4-[(3-bromophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (2.12 g, 4.40 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 13.2 mL, 13.2 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath, treated dropwise with methanol (15 mL) and concentrated. The resulting viscous, colorless oil was re-dissolved in ethyl acetate (25 mL), washed with a saturated aqueous solution of sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated to give a white solid, which was purified via flash column chromatography (silica, gradient from 10% ethyl acetate/hexane to 20% ethyl acetate/hexane) to yield 2.02 g (98%) tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a white powder. MS (ESI) m/z 467/469 ([M+H]+); HRMS: calcd for C23H35BrN2O3, 466.1831; found (ESI), 467.1899; Anal. Calcd for C23H35BrN2O3: C, 59.10; H, 7.55; N, 5.99. Found: C, 59.14; H, 7.72; N, 5.77.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C@H:16]([CH3:22])[CH2:17][C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:52]=[N+:53]=[N-:54])(=O)=O)(C)C.C(O)(=O)C.C([O-])(=O)C.[K+]>C1COCC1.CCOC(C)=O>[N:52]([C@@H:15]([C@H:16]([CH3:22])[CH2:17][C:18]([F:19])([F:20])[F:21])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:23])=[N+:53]=[N-:54]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)CC(F)(F)F
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of (4S)-4-benzyl-3-[(3S)-5,5,5-trifluoro-3-methylpentanoyl]-1,3-oxazolidin-2-one (8.2 g, 24.90 mmol) in THF (100 mL) was cooled to −78° C. and KHMDS (potassium hexamethyldisilazane—59.7 mL, 29.88 mmol) was added dropwise over a period of 10 min. After stirring at −78° C. for 1 h, a pre-cooled (−78° C., 50 min) solution of 2,4,6-triisopropylbenzenesulfonyl azide (10.1 g, 32.37 mmol) was added via cannula over a period of 10 min. After an additional 10 min at −78° C., glacial acetic acid (6.7 mL, 112.05 mmol) was added all at once through a funnel. After 5 min at −78° C. anhydrous potassium acetate (9.77 g, 99.6 mmol) was added. The −78° C. bath was lowered and the reaction mixture was allowed to warm to 25° C. overnight (19 h). The reaction mixture was diluted with EtOAc (200 mL) and the organic phase washed with saturated aqueous potassium phosphate monobasic (2×100 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a yellow oil (9.5 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish (S)-3-[(2S,3R)-2-azido-5,5,5-trifluoro-3-methylpentanol]-4-benzyl-1,3-oxazolidin-2-one as a colorless oil (7.2 g, 73.7%). Mass Spectrum (−ESI): 342 (M−N2)−.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].Br[CH2:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:2]([O:3][C:4](=[O:5])[CH:6]([C:7](=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH3:1]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C(CBr)C1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(=O)C1CCCCC1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred slurry of 1.44 g (36 mmol) sodium hydride, obtained as a 60% dispersion in mineral oil, in 45 mL anhydrous THF, at 0° C., was added dropwise 6.48 g (33.75 mmol) ethyl benzoyl acetate. The resulting slurry was stirred at 0° C. for 0.5 hr, upon which time was added dropwise the entire sample of 2-bromo-1-cyclohexyl-ethanone obtained in Step 1. The reaction was stirred at room temperature for 24 hr and poured into 0.4 L brine. The brine was shaken with ethyl acetate twice and the combined organic extracts were dried over MgSO4 and concentrated to afford 14.37 g (45.4 mmol, >100% yield) of 2-benzoyl-4-cyclohexyl-4-oxo-butyric acid ethyl ester. The product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:8]=2[CH2:9][NH:10]C(=O)OC(C)(C)C)=[O:6])[CH2:3][CH2:2]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:10][CH2:9][C:8]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(F)cc1C(=O)NC1CC1
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(cyclopropylcarbamoyl)-4-fluorobenzylcarbamate (130 mg, 0.42 mmol) prepared according to literature methods, in CH2Cl2 (5 mL) was stirred with trifluoroacetic acid (3 mL) at room temperature for 10 min, then concentrated in vacuo to give 140 mg (Yield 100%) of the title compound as a foam: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 0.62 (2H, m, CH2), 0.73 (2H, m, CH2), 2.86 (1H, m, CH), 4.02–4.07 (2H, ABq, NCH2), 7.46 (2H, m, Ar-Hs), 7.58 (1H, m, Ar—H), 8.11 (3H, br, NH3), 8.81 (1H, d, J=4.4 Hz, NH); LC/MS m/z 209 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3C[CH2:22][C@@H:21]([NH:24][C:25]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:26])[CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:45])[CH2:42][CH2:43]O)[C@@H:37]([OH:46])[C@H:36]2[OH:47])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:54][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CCO)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:1]1([CH:7]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:26])[CH:22]=[N:54]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:45])[CH2:42][CH3:43])[C@@H:37]([OH:46])[C@H:36]2[OH:47])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCO)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(NC(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-((1S,2R,3S,4R)-4-{6-(2,2-Diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-2-ylmethyl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-3-hydroxy-propionamide (Example 184), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate ZR) for N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([C:15]1([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].I[CH3:41].[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:19]([CH3:41])[C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: CI
Reactant: COC(=O)C1(COCc2ccc(OC)cc2)CC(=O)N(c2c(C)cccc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCc2ccc(OC)cc2)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
LHMDS (1 M solution in THF, 2.32 mL, 2.32 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-3-(4-methoxybenzyloxymethyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 767 mg, 1.93 mmol) in THF (7 mL). After 5 min, iodomethane (602 μL, 9.65 mmol) was added at −50° C. and the resulting reaction mixture was warmed to room temperature and stirred further for 2 h. Saturated aqueous NH4Cl solution (25 mL) was added, and the solution was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (75 mL), brine (75 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 20→70% EtOAc/hexanes) to give 1-(2,6-dimethylphenyl)-3-(4-methoxybenzyloxymethyl)-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (736 mg, 93% yield). LC-MS: Rt (retention time): 2.39 min, MS: (ES) m/z 412.4 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][C:10]=1[C:11]#[N:12].CS(C)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH:25]1[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O.C(OCC)(=O)C>[C:44]([O:43][C:41]([NH:40][CH:25]1[CH:24]([NH:23][C:15]2[C:14]([F:18])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:8])[N:16]=2)[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Triethylamine (0.22 ml) and 2,6-dichloro-5-fluoronicotinonitrile (470 mg) were added to a DMSO (2.4 ml) solution containing benzyl 4-amino-3-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (470 mg) obtained in the 2nd step, followed by stirring at room temperature for 0.5 hours. Ethyl acetate and water were added to the reaction solution for extraction. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 15:3) and a white solid of benzyl 3-((tert-butoxycarbonyl)amino)-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)piperidin-1-carboxylate (500 mg) was thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CN1CCOCC1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH2:33]([O:32][C:30]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:31])[CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)NCCO
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCCCCCC(=O)NCCOC(=O)OCC

Procedure:
3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was dissolved in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 moles) and 1.19 g of ethyl chloroformate (11 moles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried under a high degree of vacuum. The yield of the reaction was 93%.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=2)O1.[OH-].[K+].[C:16](O)(=[O:18])[CH3:17]>C(O)C>[CH2:16]([O:18][C:6]1[NH:2][N:1]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=2)[N:5]=1)[CH3:17]
Reactant: NN1CN=C(c2cccc(I)c2)O1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc(-c2cccc(I)c2)n[nH]1
Temperature: 25 °C

Procedure:
The product (1.00 g, 3.48 mmol) from Step A was added to a solution of potassium hydroxide (1.0 g) in 30 mL of absolute ethanol. The mixture was warmed to reflux and, after 5 h, cooled to room temperature. The solution was then acidified with glacial acetic acid, and concentrated under reduced pressure. The product was extracted into ethyl acetate, and the combined ethyl acetate extracts were washed sequentially with water and saturated aqueous brine, dried (magnesium sulfate) and concentrated to give the crude product as an orange semisolid. Purification by flash chromatography (silica gel, 15% ethyl acetate-hexanes) afforded the product as an off-white, sticky foam. LC/MS 316.0 (M+1).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].Cl.[CH3:12][NH:13][O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([N:13]([O:14][CH3:15])[CH3:12])=[O:2]
Reactant: O=C1OCc2ccccc21
Reactant: CNOC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of phthalide (26.8 g) in methylene chloride (600 ml) were successively added N,O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) under ice-cooling, and triethylamine (139 ml) was added dropwise over 40 min. The mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into diluted hydrochloric acid, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-methylbenzamide. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was dissolved in N,N-dimethylformamide (300 ml), and imidazole (9.53 g) and tert-butyldimethylchlorosilane (21.1 g) were added. The mixture was stirred at room temperature for 3.5 hr and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (42.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CC[C@H](CNc2ccncc2)[C@H](O)C1
Temperature: 25 °C

Procedure:
A mixture of the cis 4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (245 mg) from Step 4 above, 4-chloropyridine (105 mg) and isopropanol (0.4 mL) was heated to 120° C. in a sealed vial for 24 h, cooled to room temperature and the solvents evaporated. The resulting crude mixture was purified by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH) to give impure cis 3-hydroxy-4-(pyridin-4-ylaminomethyl)-piperidine-1-carboxylic acid benzyl ester. This was purified by preparative reverse phase HPLC (95% H2O 5% MeCN to 100% MeCN both containing 0.1% TFA). Evaporation gave an oil which was partitioned between DCM and aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and solvent evaporated to give a white solid. M.S (M+1): 342.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:17])[NH2:16])=[CH:9][CH:8]=1.[OH:23][CH:24]=[C:25]([CH2:30][C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1)[C:26](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]([CH2:30][C:25]2[C:24](=[O:23])[N:17]=[C:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=4)=[CH:12][CH:11]=3)[NH:16][CH:26]=2)=[CH:36][N:35]=1
Reactant: COC(=O)C(=CO)Cc1cnc(OC)nc1
Reactant: N=C(N)CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4cccc(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 64.3 %

Procedure:
The same procedure as E38 from a mixture of 3-(4-(3-(trifluoromethyl) phenoxy)phenyl)propanimidamide (200 mg, 0.580 mmol), methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (130 mg, 0.580 mmol) and potassium acetate (171 mg, 1.740 mmol) in toluene (10 mL) to afford the title compound (180 mg, 61.1% yield) as a yellow solid. LCMS: rt=8.88 min, [M+H]=483.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][NH:8][C:9](=[NH:11])[NH2:10])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[C:9]([NH2:11])[NH:8][N:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: N=C(N)NNC(=O)c1cccc(Cl)c1
Solvent: O
Product: Nc1nc(-c2cccc(Cl)c2)n[nH]1
Yield: 63 %

Procedure:
A solution of 2-(3-chlorobenzoyl)hydrazinecarboximidamide (7.8 g, 36.68 mmol) in water (150 ml) was stirred overnight at 90° C. The solids were collected by filtration to afford 3-(3-chlorophenyl)-1H-1,2,4-triazol-5-amine as a off-white solid (4.5 g, 63%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:13][NH:12][CH2:11][CH2:10][C:9]=2[CH2:14][OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]CN(CC)CC.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(#N)C>[CH3:16][N:12]1[CH2:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([CH2:14][OH:15])[CH2:10][CH2:11]1
Reactant: OCC1=C(c2ccccc2)CNCC1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Product: CN1CCC(CO)=C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
To a solution of (5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (230 mg, 1.04 mmol) in ACN (10 mL) was added Et3N (0.15 mL, 1.04 mmol) followed by formalin (340 mg, 4.16 mmol). After stirred at room temperature for 10 min, it was added Na(OAc)3BH (440 mg, 2.08 mmol) and was stirred for 30 min, the mixture was concentrated to remove most of the ACN, and the residue was diluted with CHCl3, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=9:1) to give (1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (140 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([O:25]C)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-methoxycarbonylmethoxyphenyl)amino]piperidine (100 mg) was dissolved in methanol (1 ml), added with 1 N aqueous sodium hydroxide (0.55 ml) and stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1 N aqueous hydrochloric acid and extracted twice with ethyl acetate (3 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 72.1 mg of the title compound. Yield: 75%.