Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([NH:40][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)NC2CCCCC2)CC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole, described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. and a solution of cyclohexyl isocyanate (0.070 mL, 0.51 mmole) was added dropwise. The resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (25 mL) and water (25 mL). The layers were separated and the organics washed with water (25 mL), brine (30 mL) and dried over Na2SO4. Filtration and concentration gave the crude product which was purified by flash chromatography (elution with EtOAc) to yield 0.19 g (83% yield) of 1-{(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-3-cyclohexyl-1-methyl-urea. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][NH:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Si:19]([O:26][C@H:27]1[C@H:32]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:31][CH2:30][N:29]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:28]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CNCC[C@H]1N1CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CC[C@@H](N3CCOCC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)c1Cl
Temperature: 110 °C
Yield: 75.2 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (116 mg, 0.349 mmol), (+/−)-4-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)morpholine (100 mg, 0.333 mmol), Pd2dba3 (9.14 mg, 9.98 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (18.65 mg, 0.030 mmol), and cesium carbonate (217 mg, 0.666 mmol) in Dioxane (2 mL) was evacuated and filled with nitrogen three times and heated at 110° C. overnight. The reaction mixture was diluted with dichloromethane and filtered through Celite, the filtrate was concentrated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-25% ethyl acetate/hexanes). (+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg) was obtained as a white solid.
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1CCCO1.FC(F)(S(O[C:66]1[CH:75]=[CH:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([C:76]3[CH:81]=[C:80]([N:82]4[CH:87]=[CH:86][C:85](=[O:88])[NH:84][C:83]4=[O:89])[CH:79]=[C:78]([C:90]([CH3:93])([CH3:92])[CH3:91])[C:77]=3[O:94][CH3:95])[CH:72]=2)[CH:67]=1)(=O)=O)C(F)(F)OC(F)(F)C(F)(F)F.[CH3:97][S:98]([NH2:101])(=[O:100])=[O:99]>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(OCC)(=O)C>[C:90]([C:78]1[C:77]([O:94][CH3:95])=[C:76]([C:71]2[CH:72]=[C:73]3[C:68](=[CH:69][CH:70]=2)[CH:67]=[C:66]([NH:101][S:98]([CH3:97])(=[O:100])=[O:99])[CH:75]=[CH:74]3)[CH:81]=[C:80]([N:82]2[CH:87]=[CH:86][C:85](=[O:88])[NH:84][C:83]2=[O:89])[CH:79]=1)([CH3:92])([CH3:91])[CH3:93]
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0026 g, 2.80 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0033 g, 6.72 μmol) and milled potassium phosphate tribasic (0.131 g, 0.616 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.5 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (0.4 g, 0.560 mmol, Example 3-7, compound (5f)), methanesulfonamide (0.064 g, 0.672 mmol) and ethyl acetate (3 mL) were added to the 40-mL reaction vial. The temperature of the closed vial was raised to 90° C. and the contents were magnetically stirred for 16 hours. HPLC analysis of the reaction mixture showed that the product was formed in 97 area % at 210 nm.
Reaction SMILES: O1CCOCC1.[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[C:13]1([NH:19]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:7]1([NH:19][CH:13]2[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ONc1ccccc1
Reactant: C1=CCCCC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C1=CCC(Nc2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12 mL), 3 mL of cyclohexene, 1g of 4A Molecular Sieves, and 0.11 mmol of (2,6-dipicolinato)(HMPA)Mo(O) (ONPh) is heated at reflux (ca. 100° C.) under a nitrogen atmosphere while a toluene solution (50 mL) of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 12-24 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure. Chromatography of the residue over silica gel and elution with pentane afforded phenyl 3-cyclohexenyl amine (>95% one isomer by NMR, GC/MS) in 15-25% yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10]2(=[O:22])=[O:21])=[C:4]([F:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:30]1([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[O:21]=[S:10]1(=[O:22])[CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH2:14][N:9]1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH2:34][CH2:35][N:30]([C:36](=[O:38])[CH3:37])[CH2:31][CH2:32]2)=[CH:3][C:4]=1[F:23]
Reactant: O=S1(=O)C(c2ccccc2)CCCN1Cc1ccc(Br)cc1F
Reactant: CC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN3CCCC(c4ccccc4)S3(=O)=O)c(F)c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
2-[(4-Bromo-2-fluoro-phenyl)methyl]-6-phenyl-thiazinane 1,1-dioxide (208 mg, 0.52 mmol), Pd(OAc)2 (5.8 mg, 0.026 mmol), 2-dicyclohexylphosphine-2′,6′-di-iso-propoxy-1,1′-biphenyl (24.8 mg, 0.052 mmol) and cesium carbonate (254 mg, 0.78 mmol) were weighed out in a vial and the vial was purged with nitrogen. 1,4-Dioxane (2.5 mL) and 1-piperazin-1-ylethanone (100 mg, 0.78 mmol) were then added and the reaction was stirred at 80° C. for 2 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by reverse-phase HPLC to give 1-(4-(4-((1,1-dioxido-6-phenyl-1,2-thiazinan-2-yl)methyl)-3-fluorophenyl)piperazin-1-yl)ethanone (210 mg, 89% yield).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5]Cl)=[CH2:2].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].O.NN>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:1]([O:3][CH2:4][CH2:5][C:16]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:10]([NH:11][C:7](=[O:17])[C:8]=12)=[O:12])=[CH2:2]
Reactant: C=COCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NN
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C=COCCc1cccc2c1C(=O)NC2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Amine-containing enol ether copolymers (i.e. Poly(alkyl enolether-co-vinyloxy ethylamine) Polymers: 2-(vinyloxy)ethyl phthalimide (ImVE) was prepared by reacting 2-chloroethyl vinyl ether (25 g, 0.24 mol) with potassium phthalimide (25 g, 0.135 mol) in dimethyl foramide (75 mL) using tetra-n-butyl ammonium bromide as a phase transfer catalyst. This reaction mixture was stirred at 100° C. for 6 h then poured into 800 mL distilled water, and filtered and washed with a large amount of distilled water. The recovered yellowish crystals where then recrystallized twice from methanol to give white crystals, which were then dried for 48 h under reduced pressure. Polymerization was carried out in anhydrous methylene chloride at −78° C. under a blanket of dry nitrogen gas in oven-dried glassware. The reaction was initiated by adding borontrifluoride diethyl etherate to ImVE, and a mixture of enol ethers. The reaction was allowed to run for 3 h at −78° C., and then allowed to warm for ten minutes at RT, and then quenched with prechilled ammonia saturated methanol. The product was then evaporated to dryness under reduced pressure to give the product polymers. The polymer was then dissolved in a 1,4-dioxane(2)/methanol mixture and 10 equivalents (eq.) of hydrazine hydrate per mole of amine present. This solution was then refluxed for 2 h, cooled to RT, and the solvent was then removed under reduced pressure. This solution was then brought up in 0.5M HCl, and refluxed for 60-minutes. The cooled solution was then transferred to 3,000 MW dialysis tubing and dialyzed (4×5 L) for 48 h. This solution was then frozen and lyophilized. The following polymers were generated using this procedure:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([Br:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1>[Br:26][C:21]1[C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10]([C@@H:8]([NH:7][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
[(S)-1-(7-Bromo-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (220 mg, 0.66 mmol) was dissolved in hydrochloric acid in dioxane (15 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo then the residue dissolved in IPA and 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (203 mg, 0.85 mmol) and DIPEA (168 μL, 0.99 mmol) added. The reaction mixture was heated at 90° C. for 16 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% methanol in EtOAc) to yield the title compound as a white solid (267 mg, 76%). LCMS (Method C): RT=3.01 min, [M+H]+=537+538.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:7]2[CH:28]=1)(=[O:3])[NH2:2].[CH3:29][C:30]([N:32](C)C)=O.CC(N(C)C)=O.NO.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.CC(O)=O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:8]1[N:7]2[CH:28]=[C:4]([C:1]3[O:3][N:32]=[C:30]([CH3:29])[N:2]=3)[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(=O)N(C)C
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cn3c(-c4ccc(Cl)cc4Cl)c(C(=O)OC(C)(C)C)c(C)nc3n2)n1
Temperature: 90 °C
Yield: 59 %

Procedure:
To a stirred solution of tert-butyl 2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.14 mmol) in PhCH3 (3 mL) was added DMA-DMA (70 μL, 0.43 mmol). The reaction was heated to 90° C. for 2 h and was concentrated to afford the crude ester as a black oil. This crude product was dissolved in dioxane (2 mL) and AcOH (2 mL) and NH2OH.HCl (15 mg, 0.21 mmol) was added followed by NaOH (2N solution, 0.1 mL, 0.2 mmol). After heating to 90° C. for 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with H2O and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl 5-(2,4-dichlorophenyl)-7-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,2-a]pyrimidine-6-carboxylate (38 mg, 58%) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=1)[N:52]([CH2:65][C:66]([NH:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C:51]2=[O:73].[C:74]([O:78][C:79]([N:81]1[CH2:87][CH2:86][CH2:85][NH:84][CH2:83][CH2:82]1)=[O:80])([CH3:77])([CH3:76])[CH3:75].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C1(C)C=CC=CC=1>[C:74]([O:78][C:79]([N:81]1[CH2:87][CH2:86][CH2:85][N:84]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[N:54]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)[N:52]([CH2:65][C:66](=[O:67])[NH:68][C:69]([CH3:72])([CH3:71])[CH3:70])[C:51]3=[O:73])[CH2:83][CH2:82]1)=[O:80])([CH3:77])([CH3:75])[CH3:76]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(Br)cc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Temperature: 80 °C
Yield: 46.7 %

Procedure:
Racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5 mg, 0.009 mmol) and anhydrous toluene (0.5 mL) was heated in a microwave vial with stirring at 80° C. under an Argon atmosphere until a homogeneous milky solution was obtained (˜5 min). This solution was cooled to room temperature and palladium(II) acetate (2 mg, 0.006 mmol) was added. After stirring at room temperature for 2 min., 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-4H-quinazolin-3-yl]-N-tert-butylacetamide (INTERMEDIATE VI.1) (67 mg, 0.15 mmol), tert-butyl-1-homopiperazinecarboxylate (35 μL, 0.18 mmol) and freshly ground cesium carbonate (68 mg, 0.21 mmol) were added to the red solution. Anhydrous dioxane (0.2 mL) was added to rinse down solid left on the side of the vial. The vial was capped and heated in a microwave at 120° C. for 40 min. The reaction mixture was diluted with DCM (3 mL), filtered and the filtrate concentrated in vacuo. This crude product was purified by preparative TLC on silica gel with hexane:EtOAc:CH2Cl2 (1:1:1, v/v) as eluent to give 4-[3-(tert-butylcarbamoylmethyl)-2-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VIII.1) (38.9 mg, 0.07 mmol, 46%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[C:17](#N)C.IC>C[Si](C)(C)N[Si](C)(C)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:17])[C:4](=[O:9])[CH:3]=1
Reactant: CC#N
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CI
Product: Cn1c(=O)cc(N)[nH]c1=O
Reaction time: 6 h
Yield: 42.6 %

Procedure:
To a solution of the 6-aminopyrimidine-2,4(1H,3H)-dione (15 g, 118 mmol) in 1,1,1,3,3,3-hexamethyldisilazane (50 mL) was added ammonium sulfate (0.671 g, 5 mmol), then the resulting mixture was heated to reflux with stirring for 6 h. The mixture was concentrated to give a light-yellow solid. This solid was combined with acetonitrile (50 mL) and iodomethane (15 mL, 250 mmol) was added. The resulting mixture was stirred at 40° C. for 16 h. Then the mixture was concentrated, neutralized with saturated sodium bicarbonate to pH=7, filtered, and the filter cake was washed with brine and ethanol, dried under vacuum to give 6-amino-3-methylpyrimidine-2,4 (1H,3H)-dione (7.1 g, 42.6% yield) as yellow solid. LCMS MH+ 142.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:34]1([NH:40]N)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:40][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and phenylhydrazine: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4]1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][C:18](=[O:30])[CH:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:31].O.[Na+].[Cl-]>C1COCC1>[ClH:1].[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][N:9]=[C:21]2[CH2:22][CH2:23][C@@:24]3([CH3:25])[CH:19]([C:18](=[O:30])[CH2:17][C@@H:16]4[C@@H:26]3[CH2:27][CH2:28][C@@:11]3([CH3:10])[C@H:15]4[CH2:14][CH2:13][C:12]3=[O:31])[CH2:20]2)[CH2:4]1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NOC1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=NOC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3-(RS)-pyrrolidinyloxyamine dihydrochloride (III-c, Prepn. 3, 227 mg) and androstane-3,6,17-trione (495 mg) in THF: water (2/1, 27 mL) was stirred for 30 min. NaCl was added and stirred till the two phases separated. After extraction of the aqueous layer with THF, the combined organic phases were washed with brine, dried and evaporated. The crude was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-ac (464 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.59 (1H, bb), 9.41 (1H, bb), 4.74 (1H, m), 3.80-2.90 (5H, m), 2.60-1.20 (21H, m), 0.78 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichloride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(O)C>[ClH:3].[ClH:24].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCN(Cc2ccc(Cl)cc2)CC1)c1ccccc1
Yield: 129.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)piperazine dihydrochloride (5 g, 20 mmol), triethylamine (5.58 ml, 40 mmol) and 2-chloro-1-phenylethanone (4.08 g, 26 mmol) in 40 ml of anhydrous ethanol was refluxed for 8 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-3), yield 59.51%, mp 256-258° C. M+ 328.
Reaction SMILES: [NH4+].[OH:2][C:3]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([O-:13])=[O:12])[CH2:4][C:5](=[N:9]O)[C:6]([O-:8])=[O:7].[NH4+].[H][H].O[C@@](CC1C2C(=CC=CC=2)NC=1)(C(O)=O)C[C@@H](N)C(O)=O.O[C@](CC1C2C(=CC=CC=2)NC=1)(C(O)=O)C[C@@H](N)C(O)=O>N.[C].[Rh]>[OH:2][C:3]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:4][CH:5]([NH2:9])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C([O-])C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)[O-])=NO
Agent: [Rh]
Agent: N
Agent: N[C@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Product: NC(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
0.13 g (0.38 mmol) of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid ammonium salt was dissolved in 5 ml of aqueous 28% ammonia, to which 0.09 g of 5% rhodium carbon was added, for reaction at ambient temperature and a hydrogen pressure of 7.5 atmospheres. 14 hours later, the catalyst was filtered off, and the resulting solution was concentrated to dryness, to obtain a mixture of 0.075 g (0.23 mmol) of the ammonium salt of (2S, 4S)/(2R, 4R)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid (monatin) and 0.036 g (0.11 mmol) of the ammonium salt of (2S, 4R)/(2R, 4S)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid (monatin).