Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH3:53].C(=[NH:67])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][N:48]1[C:49]2[C:45](=[CH:44][CH:52]=[CH:51][CH:50]=2)[C:46]([NH2:67])=[N:47]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cn1ncc2c(Br)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cn1nc(N)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of palladium(II) acetate (82 mg, 2 mol %) and Xantphos (287 mg, 3 mol %) in toluene (10 mL) was stirred for 5 min at ambient temperature. To the solution was added a solution of Example 1F (3.68 g, 17.4 mmol) and benzophenone imine (3.00 g, 17.4 mmol) in toluene (30 mL). The mixture was evacuated and purged with nitrogen two times, then stirred at ambient temperature for 15 min Sodium tert-butoxide (1.90 g, 24.4 mmol) was added and the mixture was evacuated and purged with nitrogen. The mixture was heated to between 80 and 85° C. for 2 h, cooled to ambient temperature, and diluted with water (30 mL). The layers were partitioned and the aqueous layer was extracted with additional toluene (20 mL). The combined organic layers were stirred with 6 N HCl (10 mL) for 1 h, then 40 mL of water was added to dissolve the solids. The toluene layer was discarded and aqueous layer filtered to remove insoluble material. The aqueous layer was adjusted to pH 14 with the addition of 50% NaOH and the resulting solid was filtered and dried to provide the title compound. MS (DCI/NH3) m/z 202 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C([Li])(C)(C)C.[Mg+2].[Br-].[Br-].[Cl-].[CH3:35][O:36][C:37](=[O:41])[C:38](O)=[O:39].[NH4+].[Cl-]>C1COCC1.CCCCC>[CH3:35][O:36][C:37](=[O:41])[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:15])([F:16])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25])=[O:39]
Reactant: COC(=O)C(=O)O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 17.8 %

Procedure:
To a solution of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (1.00 g) in THF (40 mL) was added tert-butyllithium (16.2 mL of a 1.6 M solution in pentane) at −78° C. After 10 min at this temperature, MgBr2 (0.15 M in THF, 10.3 mL) was added dropwise and left for another 15 min. Oxalic acid methylester chloride (284 mg) was added and the mixture was stirred at −78° C. for 1 h before it was allowed to warm to room temperature over night. Saturated aqueous NH4Cl solution was added and the mixture was extracted with MTBE. The organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (167 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Yield: 99.3 %

Procedure:
To a solution of methyl-3-hydroxybenzoate (5.0 g, 32.8 mmol) in acetone (30 mL) was added potassium carbonate (6.82 g, 49.2 mmol) and p-methoxybenzyl chloride (4.5 mL, 32.8 mmol). The contents are heated under reflux for forty eight hours, concentrated under pressure and partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield the title compound (8.87 g, 99%). 1H NMR (CDCl3): □ 7.8 (m, 2H), 7.4 (m, 3H), 7.15 (m, 1H), 6.9 (d, 2H), 5.1 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][N:25]=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][N:25]=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CC1(C)CCOc2ccc(C#Cc3ccc(CO)cn3)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCOc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure- equalizing addition funnels fitted with drying tubes. The solution is cooled to -60° C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60° C. for an additional 10 minutes. A solution of 2.82 g (10 mmol) of 2-[2-(4,4-dimethylchroman-6-yl)ethynyl]-5-hydroxymethylpyridine in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 minutes. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:15])[CH:7](CCC)[CH2:8][CH2:9][CH2:10]N)([CH3:4])[CH3:3].C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.C(=O)(O)[O-].[Na+].CCCCCC>O.ClCCl>[CH3:4][C:2]([O:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH3:10])([CH3:1])[CH3:3]
Reactant: CCCC(CCCN)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 160 mg (0.74 mmol) of rac-5-amino-2-propylpentanoic acid 1,1-dimethylethyl ester (8) in 1 mL of water and 1 mL of dichloromethane, 153 mg (0.76 mmol) of 4-nitrophenylchloroformate and 267 mg of sodium bicarbonate were added at 0° C. The mixture was stirred at room temperature overnight and then diluted with 50 mL of dichloromethane and 30 mL of water. The organic part was separated. The aqueous part was extracted with 2×50 mL of dichloromethane. The organic parts were combined and washed with 2×50 mL of 5% sodium bicarbonate followed by 50 mL of water, dried over MgSO4 and concentrated. The residue was purified by preparative thin layer chromatography using 1:1 ethyl acetate:hexane as the eluent to yield 185 mg (0.48 mmol, 66%) of rac-5-[[(4-nitrophenoxy)carbonyl]amino]-2-propyl]pentanoic acid 1,1-dimethylethyl ester (9) asan offwhite solid. NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>C1COCC1>[CH2:11]([O:13][P:14]([CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc(Cl)cc1CBr
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(Cl)ccc1F)OCC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-fluoro-benzylbromide (630 g, purity according to GC 72% a/a, 2.42 mol) was heated at 100° C. and triethylphosphite (403 g, 2.42 mol) was added slowly in 1 h 45. The mixture was stirred for 2 hours at 100° C., and slowly THF (350 ml) was added and distilled off, until no ethylbromide was detected by NMR. To isolate the crude (5-chloro-2-fluoro-benzyl)-phosphonic acid diethyl ester the reaction mixture was cooled to room temperature, yielding 681 grams (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][CH3:16])[CH:13]=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH2:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@H](O)[C@H](CC)NC(=O)OCc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 8 (680 mg, 3.1 mmol) and 1-bromopentadecane (6.55 g, 22.5 mmol), alcohol 92 was obtained as a colorless oil (800 mg, 60% yield).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([CH:20]=[CH2:21])[CH:4]=1)#[N:2]>[Pd].CO>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[N:2]
Reactant: C=Cc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
A mixture of tert-butyl N-(4-cyano-2-vinylbenzyl)-N-methylglycinate (500 mg, 1.75 mmol) and 10% palladium on carbon (50 mg) in methanol (5 mL) were stirred under an atmosphere of hydrogen for 18 hours. The suspension was filtered through a Celite pad and the filter-cake washed with DCM. The filtrate was evaporated in vacuo to afford the title compound (474 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
3-Amino-5-bromo pyridine (XXX)(leq) was dissolved in DCM and cooled to 0° C. before adding pyridine (2.2 eq) and isobutyryl chloride (XXXI) (1.1 eq). The reaction mixture was stirred at r.t. for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N—(5-bromopyridin-3-yl)isobutyramide (XXXII) as a off white solid, (71% yield). 1H NMR (CDCl3) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([C@H:8]2[CH2:11][C@@H:10]([CH2:12][O:13]CC3C=CC=CC=3)[CH2:9]2)[CH:7]=1.C(O)=O.[H][H]>[Pd].C(O)C>[F:1][C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([C@H:8]2[CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:11]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@@H](COCc3ccccc3)C2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](CO)C2)cc1F

Procedure:
A solution of 5-fluoro-1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil (250 mg, 0.79 mmol), 10% palladium on activated carbon (50 mg) and formic acid (2 mL) in ethanol (20 mL) was placed under 45 PSI of hydrogen on a Parr Apparatus for 2 h. The mixture was filtered through a pad of Celite and the charcoal was washed with ethanol (3×20 mL). Combined filtrates were concentrated under vacuum and purified by a short column of silica gel with 4% MeOH in CH2Cl2 to give 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]uracil (159 mg, 94%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:37]([NH:40][C:32]1[CH:31]=[C:30]([O:29][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([C:11]3[C:12](=[O:27])[N:13]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH3:19])=[O:10])=[C:5]([F:28])[CH:4]=2)[CH:35]=[CH:34][N:33]=1)(=[O:39])[CH3:38]
Reactant: CC(N)=O
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(NC(C)=O)c2)cc1F
Temperature: 100 °C
Yield: 51.8 %

Procedure:
N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol) was combined with acetamide (8 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol) and Xantphos (6 mg, 0.010 mmol) in dioxane (2 mL) and the mixture sparged with argon for several minutes. Pd2(dba)3 (5 mg, 0.005 mmol) was added and the mixture was sparged again with argon. The reaction vessel was sealed and heated at 100° C. overnight. The cooled reaction mixture was diluted with brine and extracted with EtOAc (2×). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (50-100% EtOAc/hexanes). The purified residue was treated with CH3CN:H2O (1:1, 2 mL), frozen and lyophilized to obtain N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 50.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 10.57 (s, 1H), 8.50 (d, J=7.9 Hz, 1H), 8.17 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.61 (br s, 1H), 7.49 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 2.03 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 555.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]([Si:41]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)Cl)([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[Si:41]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 10 ml of THF, then triethylamine (1.01 g, 10 mmol) and tert-butyldiphenyl chlorosilane (2.75 g, 10 mmol) were added with stirring. The whole system was reacted at a temperature ranging from 45° C. to 50° C. for 2 hours. After the reaction was complete, water was added to the system and the resultant mixture was extracted with diethyl ether for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid.
Reaction SMILES: [C:1]([C:3]1([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CO>[O:13]=[C:6]1[CH2:7][CH2:8][C:3]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: COC(=O)C1CC(C#N)(c2ncccn2)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC1(c2ncccn2)CCC(=O)CC1
Yield: 68 %

Procedure:
The crude methyl 5-cyano-2-oxo-5-(pyrimidin-2-yl)cyclohexanecarboxylate was completely dissolved in THF/MeOH (1/1, 8 mL) and the clear solution was treated with 1 M aqueous KOH (3.0 mL, 1.2 equiv.) and H2O (2.5 mL). After being refluxed for 24 h, The organic solvent was removed under reduced pressure. The concentrated reaction was diluted (H2O), neutralized (10% citric acid) and extracted (3×DCM). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to provide 4-oxo-1-(pyrimidin-2-yl)cyclohexanecarbonitrile (333 mg, 1.66 mmol, 68% yield) as a yellow solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:24][N:25]([CH2:27][CH2:28][CH2:29]Cl)[CH3:26]>CN(C)C=O>[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=2[F:6])[CH2:11][CH2:12]1)[CH3:26]
Reactant: CN(C)CCCCl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 10 g of sodium bicarbonate, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine, and 50 ml of dimethylformamide was treated, dropwise, with a solution of 2.00 g of dimethylaminopropyl chloride in 20 ml of dimethylformamide. After stirring at 80° C. for eight hours, the reaction mixture was filtered and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded a residue which was eluted with 20% methanol/dichloromethane on a silica gel column via flash chromatography. The desired fractions were evaporated to afford 2.74 g of 1-[3-(N,N-dimethylamino)propyl]-4-(2,3,4,5,6-pentaflurophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate 1.8 g (28%) of 1-[3-dimethylaminopropyl]-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 260° C.(dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH:17]=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([C:17]([OH:26])=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: N#Cc1ccc(C2CCc3ncc(C=O)n32)cc1F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1ccc(C2CCc3ncc(C(=O)O)n32)cc1F
Reaction time: 16 h

Procedure:
To a solution of aldehyde from Step J (990 mg, 3.88 mmol) in tert-butanol (20 mL)/2-methyl-2-butene (2 mL) was added a solution of sodium chlorite (421 mg, 4.65 mmol) and sodium dihydrogenphosphate monohydrate (642 mg, 4.65 mmol) in H2O (4 mL). The reaction mixture was stirred for 16 hours and the precipitate filtered to yield the title product as a white solid.
Reaction SMILES: C([N:8]=[C:9]([NH:42]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([NH:24][C:25]([NH:34]C(OC(C)(C)C)=O)=[N:26]C(OC(C)(C)C)=O)=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(OC(C)(C)C)=O.[ClH:50]>C(Cl)Cl.CCO>[ClH:50].[ClH:50].[NH:10]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([NH:24][C:25]([NH2:34])=[NH:26])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)[C:9]([NH2:42])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc2c(c1)Cc1cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc1-2
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)Nc1ccc2c(c1)Cc1cc(NC(=N)N)ccc1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The N′,N″-di-BOC-guanidine (4a) (0.25 g, 0.4 mmol) was dissolved in CH2Cl2 (10 mL), diluted with dry EtOH (15 mL) and the chilled solution was saturated with dry HCl. The reaction was then kept stirring at room temperature for 3 days (drying tube), when by the product started forming a precipitate over time. After evaporating the solvent to dryness, the residue was washed with ether multiple times and was dried under vacuum at 50-60° C. over night to give whitish yellow solid of the bis-guanidine dihydrochloride (0.13 g, quantitative), mp>340° C. 1H-NMR (DMSO-d6): δ 3.95 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.45 (s, 2H), 7.58 (br s, 8H), 7.95 (d, J=8.4 Hz, 2H), 10.23 (br s, 2H). 13C-NMR (DMSO-d6): δ 156.1, 156.1, 144.5, 138.6, 133.8, 123.3, 121.4, 120.9, 36.8. MS (EI): m/z 277 (M++1) (14), 252 (100). Anal. Calcd. for C15H16N6.2HCl-0.25C2H5OH (364.76): C % 51.04, H % 5.39, N % 23.04, Cl % 19.44. Found: C % 50.74, H % 5.26, N % 22.99, Cl % 19.87.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25](=[O:27])[NH2:26])=[CH:17][CH:16]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.ClCCl>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:24]([C:25](=[O:27])[NH2:26])[CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)C(N)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCN)cc1)C(N)=O
Reaction time: 18 h

Procedure:
A mixture of N-Cbz amide 110 (436 mg, 0.873 mmol) and Pearlman's catalyst (100 mg) in methanol (10 mL) and dichloromethane (10 mL) was stirred under atmospheric hydrogen for 18 h. Catalyst was removed by suction filtration over Celite and the filtrate was concentrated to give a colorless oil (318 mg, 100% crude yield). Crude product 120 was used for next step without further purification. m/z (ESI) 366 [C19H31N3O4+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]#[N:5].[CH3:14][NH:15][NH2:16]>C(O)C>[NH2:5][C:4]1[N:15]([CH3:14])[N:16]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:2]=[O:1]
Reactant: CNN
Reactant: N#CC(=NO)C(=O)c1ccccc1
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c(N=O)c1N

Procedure:
A mixture of 2-hydroxyimino-3-oxo-3-phenylpropanenitrile (2.61 g, 15 mmol) and methylhydrazine (1.1 ml, 21 mmol) was stirred at reflux in ethanol (20 ml) for 2 hours, cooled and concentrated under reduced pressure. The residue was partitioned between ether (50 ml) and dilute hydrochloric acid (50 ml, 2N solution). The aqueous phase was separated and rendered basic by the addition of saturated aqueous potassium carbonate. The red solid which precipitated was filtered off and dried, to give the title compound, 1.40 g, (46%). m.p. 230°-231° C. (literature. m.p. 230°-231° C., Gazz. Chim. Ital., (1968), 98, 569.