Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][OH:21].F[B-](F)(F)F.[CH3:34][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][O:21][CH3:34]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)CO)cc1OC
Reactant: C[O+](C)C
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: COC[C@@H](C)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(OC)c(OC)c1
Yield: 70 %

Procedure:
To a solution of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide (200 mg) in 1,2-dichloroethane (10 mL) were added trimethyloxonium tetrafluoroborate (91.2 mg) and 2,6-di-tert-butyl-4-methylpyridine (158 mg), and the mixture was heated for 3 hours under reflux. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1:1). The obtained product was triturated with diisopropyl ether to give (R)-N-(3,4-dimethoxybenzyl)-2-(2-methoxy-1-methylethylamino)-5-nitrobenzamide as yellow powders (145 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:44]([C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[NH:48][CH3:49])[CH3:45]>O.ClCCl>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([N:48]([C:47]1[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=1[O:44][CH3:45])[CH3:49])=[O:9]
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Reactant: CNc1ccccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a stirring dichloromethane (40 mL) solution containing 5-bromo-4-chloro-2-hydroxybenzoic acid (2.0 g, 8.0 mmol), were added triethylamine (2.2 mL, 16.0 mmol), HATU (4.5 g, 12 mmol) and 2-methoxyl-N-methylaniline (1.19 g, 8.7 mmol). The mixture was stirred at rt for 16 hrs and water was added. The organic layer was separated, washed with NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300 mg). MS [M+H]+: 371.9; tR=2.60 min (method 1)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](OC(N1CCNCC1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:12][CH3:13])[CH2:16][CH2:15][NH:14][CH2:17][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CC1
Product: CCNCCN(CC)C(=O)OCc1ccccc1

Procedure:
Following substantially the same procedure as described in Examle 32, except that N,N'dibenzyloxycarbonylpiperazine was used as starting material, N-benzyloxycarbonylpiperazine was prepared.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1)C1C=CC=CC=1.[I:34][Si](C)(C)C>ClCCl>[IH:34].[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1ccncc21
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ccncc21
Product: I

Procedure:
Dissolve [3-(3-methyl-4-oxo-5H-2-oxa-1,5,8-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (0.45 g, 0.0010 mol) in dry dichloromethane (10 mL). add iodotrimethylsilane (0.36 mL, 0.0025 mol) and stir overnight at ambient temperature. Quench the mixture with methanol (5 mL) and concentrate in vacuo. Take up in minimal dichloromethane and add diethyl ether. Concentrate and titrate from dichloromethane/diethyl ether to form a dark solid. Decant he solvent and dry the solid in vacuo to give a near quantitative amount of the crude amine salt as a dark solid and is used directly without purification. MS(ES): (M+1)+ 313.2, 314.2 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8](O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(F)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(Br)c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
A 250 mL round bottom flask was charged with 0.4845 g (1.56 mmol, 1.0 equiv) of (R)-tert-butyl 3-((R)-(3-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate, 0.7920 g (2.39 mmol, 1.52 equiv) of carbon tetrabromide, and 15 mL of CH2Cl2. The flask was cooled with an ice bath and then 0.6258 g (2.38 mmol, 1.52 equiv) of triphenylphosphine was added in portions over 5 min. The reaction mixture was allowed to slowly warm to rt while stirring overnight. Analysis of the mixture by LC-MS showed two peaks with the same mass 236 [M-C4H8—Br]+, consistent with a ca 62:38 mixture of two isomers: tR=10.48 min and 10.93 min in 16 min chromatography, respectively. After the solvent was removed in vacuo, the residue was purified by ISCO (40 g silica gel column, 0%→30% ethyl acetate/hexanes over 40 min, flow rate 40 mL/min) to afford 0.2470 g (42%) of (3R)-tert-butyl 3-(bromo(3-fluorophenyl)methyl)piperidine-1-carboxylate. MS ESI +ve m/z 236 (M-C4H8—Br). Isomer 1 and 2, MS ESI +ve m/z 236 (M-C4H8—Br), tR=2.13, 2.17 min in 3 min chromatography.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:46][C:47](Cl)=[O:48].[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([C:47](=[O:48])[CH2:46][NH:54][CH2:53][CH2:52][N:51]([CH3:55])[CH3:50])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CN(C)CCN
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNCC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 10.5 %

Procedure:
To a stirred solution of 49 (100 mg, 0.19 mmol) and triethylamine (107 μl, 0.77 mmol) in DCM (10 ml) under nitrogen was added chloroacetyl chloride (19 μl, 0.23 mmol), and the reaction mixture was stirred at rt for 25 min. N,N-Dimethylethylene diamine (134 μl, 1.16 mmol) was added, and the reaction mixture was stirred at rt overnight, heated at 40° C. for 5 h, then at rt. The reaction mixture was concentrated, diluted with water and few drops of 1N NaOH and sonicated. The resulting gel was collected by filtration, rinsed with water and air-dried. The crude product was purified three times by Biotage [Snap 30 g cartridge KP-C18-HS (reverse phase) ×2: MeOH/water (Millipore): 20/80 to 95/05 over 40 CV; Analogix SF 25-40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 50/50 over 60 CV], to afford the desired compound 549 (13 mg, 0.02 mmol, 10% yield) as a pale yellow sticky solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.56 (bd, J=1.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.2, 1.9 Hz, 1H), 7.72 (dd, J=13.6, 2.4 Hz, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.20 (bd, J=8.9 Hz, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.61 (bd, J=1.9 Hz, 1H), 3.58 (s, 2H), 3.50-3.36 (m, 4H), 3.33 (s, 2H), 2.59-2.51 (m, 1H), 2.52 (t, J=6.3 Hz, 2H), 2.43-2.31 (m, 4H), 2.27 (t, J=6.3 Hz, 2H), 2.10 (s, 6H), 0.70-0.58 (m, 2H), 0.47-0.37 (m, 2H), one NH secondary amine is missing. MS (m/z): 647.6 (M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]Br)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(OCC)(=O)C.[Cl-].[Na+]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Yield: 92.3 %

Procedure:
Sodium azide (2.24 g, 34.2 mmol) is added to a stirred solution of 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (4.80 g, 15.6 mmol) in anhydrous DMF (DMF) (40 mL). The resultant mixture is heated in an oil bath at 55° C. under nitrogen for 3 days. At ambient temperature, ethyl acetate (160 mL) and half-saturated aqueous sodium chloride (NaCl) (200 mL) are added to the mixture. The organic layer is separated, washed with half-saturated aqueous NaCl (200 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a dark oil (3.88 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2cc(C(F)(F)F)ccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2cc(C(F)(F)F)ccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step H by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.34 (s,6H), 1.42 (s,9H), 1.98 (m,1H), 2.50 (d,14 Hz,1H), 2.63 (d,14 Hz,1H), 2.7-3.0 (m,3H), 4.50 (m,1H), 6.75 (d,7 Hz,1H), 7.10 (d,8 Hz,1H), 7.51 (br s,2H), 7.94 (br s,1H). FAB-MS: calculated for C21H28F3N3O4 443; found 444 (M+H,74%).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(O)n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(Cl)n2)CC1

Procedure:
32.85 g of ethyl trans-4-hydroxy-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are boiled under reflux for 3.5 hours with 210 ml of phosphorus oxychloride. After cooling, the mixture is concentrated in vacuo and evaporated twice further with 100 ml of toluene each time. The residue is chromatographed with methylene chloride on a column of 300 g of silica gel. There are obtained 31.3 g of crude ethyl trans-4-chloro-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate as a yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:5][CH:6]=1.Cl.O.CO>CN(C=O)C.[Pd]>[CH2:8]1[C:9](=[O:10])[C:11]2[C:16](=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[OH:19])[O:17][CH:7]1[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C1C[C@@H](c2ccccc2)Oc2cc(O)cc(O)c21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1CC(c2ccccc2)Oc2cc(O)cc(O)c21
Yield: 92 %

Procedure:
4.4 g of the benzyl protected pinocembrin in R-configuration obtained in Example 3 was dissolved in 100 ml of DMF, 20 ml of 10% aqueous HCl and 3.5 g of 10% Pd—C with a water content of 62.9% were added, and then a hydrogenation at normal pressure was performed. The reaction was monitored by TLC until completion (about 5 h). Then stopped stirring, the reaction mixture was filtered and extracted with ethyl acetate and water. The organic phase was collected, evaporated to remove solvent, and recrystallized with 95% ethanol to give a white solid of (S)-pinocembrin (3.0 g, yield 92%) with specific rotation [α]D20=−45.63° (c=0.515, methanol), and e.e %>99.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][NH:10][N:9]=2)[C:5]([OH:19])=[CH:4][C:3]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][OH:30]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:28][CH2:29][OH:30])[CH2:15][CH2:14]3)=[CH:11][NH:10][N:9]=2)[C:5]([OH:19])=[CH:4][C:3]=1[OH:20]
Reactant: OCCBr
Reactant: Oc1cc(O)c(-c2n[nH]cc2N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCN1CCN(c2c[nH]nc2-c2cc(Cl)c(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.2 %

Procedure:
A mixture of 4-chloro-6-(4-piperazin-1-yl-1H-pyrazol-3-yl)-benzene-1,3-diol (43 mg, 0.146 mmol), cesium carbonate (48 mg, 0.146 mmol), 2-bromoethanol (0.025 ml, 0.35 mmol) and dimethylformamide (1 ml) was stirred at room temperature for 3 days. The mixture was evaporated to dryness and applied to a bond elute cartridge (5 g) with dichloromethane:methanol (49:1), then eluting with dichloromethane followed by dichloromethane:ethanol:ammonia (50:8:1 then 20:8:1) gave 4-chloro-6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1H-pyrazol-3-yl}-benzene-1,3-diol as a white solid (10 mg)
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:23]=[C:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:23][C:24]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN=C=O
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CCCCCCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 24 h

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 3.2 parts of n-hexylisocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 36 hours. The solvent was evaporated in vacuo and the residue stirred with 100 parts of water for 24 hours. This phase was extracted three times with 100 parts of chloroform and the extracts dried over magnesium sulphate. Evaporation of the solvent in vacuo gave an oil which was distilled at 157°C (0.3 mm pressure). This liquid, 14-n-hexylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one, gave the following elemental analysis by weight:
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1.C1(C)C=CC=CC=1>O1CCOCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:34])=[CH:13][N:14]=3)=[C:24]([CH2:25][OH:26])[O:23][N:22]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of isopropylamine (49.6 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M, 418 μL, 0.84 mmol) and isopropylamine (49.6 mg, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=1:1 to 7:3) to afford the title compound (32 mg, 39%) as white solid. MS: m/e=386.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14](Cl)=O.S(OC)(OC)(=O)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:37]([NH:39][NH2:40])[CH3:38]>O1CCCC1>[NH2:6][C:5]1[N:39]([CH2:37][CH3:38])[N:40]=[C:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][N:8]=2)[C:4]=1[C:3]#[N:7]
Reactant: CCNN
Reactant: O=C(Cl)c1cnccn1
Reactant: N#CCC#N
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1nc(-c2cnccn2)c(C#N)c1N
Reaction time: 0.33 h
Yield: 4.7 %

Procedure:
Sodium hydride (9.72 g, 60%, 243 mmol) was added portionwise to a cooled (5° C.) solution of malononitrile (7.9 g, 120 mmol) in tetrahydrofuran (75 ml), and the mixture stirred for 20 minutes. A solution of 2-pyrazinecarbonyl chloride (J. Med. Chem. 1992, 35, 1214) (17.1 g, 120 mmol) in tetrahydrofuran (250 ml) was added dropwise so as to maintain the internal temperature below 10° C., and the mixture then stirred at room temperature for an hour. Dimethyl sulphate (18.16 g, 144 mmol) was added, the mixture heated under reflux for 3 hours, allowed to cool, triethylamine (58.5 ml, 420 mmol) and ethyl hydrazine oxalate (18 g, 120 mmol) added and the reaction mixture heated under reflux for 18 hours. The solvent was decanted from the cooled reaction mixture and the residual brown gum extracted with dichloromethane (2×150 ml). The combined organic solutions were evaporated under reduced pressure and the crude product purified by column chromatography on silica gel, using ethyl acetate:hexane (50:50) as eluant to afford the title compound, (1.2 g).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C(COC)OC.O>CCOCC>[CH3:24][C:20]1[CH:19]=[C:18]([N:17]=[CH:4][N:5]2[CH2:9][CH2:8][NH:7][C:6]2=[N:10][N+:11]([O-:13])=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Cc1cccc(N)c1
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(N=CN2CCNC2=N[N+](=O)[O-])c1
Yield: 51.8 %

Procedure:
A mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 0.92 g of m-toluidine, 5 ml of dimethoxyethane and 0.12 g of a boron trifluoride ether complex was heated under reflux for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and condensed. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.1 g of 1-(3-methylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: C1(C2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13]3)=NN=2)C=CC=CC=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[NH:29][C:30](=[O:38])[C:31]2[CH2:37][O:36][CH2:35][CH2:34][C:32]=2[N:33]=1.[C:39](#N)[CH3:40]>>[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]([N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:27][C:28]2[NH:29][C:30](=[O:38])[C:31]3[CH2:37][O:36][CH2:35][CH2:34][C:32]=3[N:33]=2)=[O:21])[CH2:16][CH2:17]1)(=[O:11])[C:40]1[CH:39]=[CH:14][CH:13]=[CH:12][CH:10]=1
Reactant: COCCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: CC#N
Reactant: O=C(O)CN1CCC(c2nnc(-c3ccccc3)o2)CC1
Product: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccccc2)CC1

Procedure:
The title compound (16.7 mg, 0.033 mmol) was prepared following the general procedure of Example 1 from [4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-piperidin-1-yl]-acetic acid (75 mg, 0.196 mmol, 1 eq) and 2-[(2-methoxy-ethylamino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (54.0 mg, 0.196 mmol, 1.0 eq). 1H NMR (400 MHz, chloroform-d) δ ppm 7.84-8.11 (m, 2H) 7.36-7.51 (m, 3H) 4.34-4.55 (m, 4H) 3.77-3.96 (m, 2H) 3.59-3.77 (m, 1H) 3.44-3.58 (m, 3H) 3.17-3.34 (m, 4H) 2.95 (dd, J=15.66, 12.13 Hz, 3H) 2.50-2.69 (m, 2H) 2.26-2.46 (m, 2H) 1.94-2.20 (m, 4H) 1.23-1.48 (m, 2H). HR-MS (m/z, MH+): 509.2519, 510.2566, 511.2614. HPLC retention time: 2.68 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:12]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:24])[O:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>C(Cl)Cl>[CH2:1]([C@H:8]([C@@H:12]([O:13][Si:14]([CH:15]([CH3:17])[CH3:16])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:20])[C@@H:11]([OH:10])[CH3:24])[CH2:9][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1Cc1ccccc1)(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)[Si](O[C@H]([C@H](CO)Cc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of (3R,4R,5S)-3-benzyl-5-methyl-4-(triisopropylsilyloxy)-dihydrofuran-2(3H)-one (9.42 g, 26.0 mmol, 1.00 equiv) in CH2Cl2 (130 mL, 0.2 M) at −78° C. (dry ice/acetone bath) was added a 1 M solution of diisobutylaluminum hydride in hexane (DIBAL-H, 65.0 mL, 65.0 mmol, 2.50 equiv). The resulting colorless solution was removed from the cold bath and stirred at 23° C. for 18 h, cooled to 0° C. (ice water bath), and quenched with sat'd aqueous Rochelle's salt solution (200 mL) and Et2O (200 mL). The resulting slurry was stirred vigorously until the mixture became clear and biphasic (1.5 h) and the resulting phases were separated. The aqueous phase was extracted with Et2O (2×200 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography (0-20% acetone in hexanes) provided (2S,3R,4S)-2-benzyl-3-(triisopropylsilyloxy)pentane-1,4-diol (6.78 g, 71.2%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.35-7.08 (m, 5H), 4.11-3.96 (m, 1H), 3.95-3.77 (m, 2H), 3.57-3.40 (m, 1H), 3.09 (d, J=2.5 Hz, 2H), 2.93-2.76 (m, 2H), 2.04 (dd, J=5.7, 2.9 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H), 1.12 (d, J =3.6 Hz, 1H), 1.05 (s, 20H); 13C NMR (101 MHz, CDCl3) δ 141.12, 129.10, 128.42, 125.98, 71.23, 59.84, 48.58, 34.81, 19.10, 18.18, 12.72; ESIMS m/z 365.3 ([M−H]−).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][OH:9])#[N:2].[CH:10](O)=[O:11]>>[C:1]([CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][OH:9])[CH:10]=[O:11])#[N:2]
Reactant: O=CO
Reactant: N#CCCNCCCO
Product: N#CCCN(C=O)CCCO

Procedure:
A solution of 127.7 g. of 3-(2-cyanoethyl)aminopropanol in 1 liter of 99% formic acid is heated at 85° for 15 hours. The reaction mixture is concentrated under reduced pressure at 80° and the residue is taken up in 60 ml. of methylene chloride-ethyl acetate (1:1). A 1500 g. silica gel G column packed in methylene chloride-ethyl acetate is prepared, and the product is purified by adsorption on silica gel G followed by elution using the 1:1 methylene chloride-ethyl acetate system. Concentration of the combined eluates yields the formate ester of 3-[N-(2-cyanoethyl)-N-formylamino]propanol.