Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20](=[O:19])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (439 mg, 1.2 mmol), BOC2O (261 mg, 1.2 mmol), DMAP (10 mg), and THF (10 mL) was stirred at RT for 1 h then concentrated in vacuo to give the crude product. The product was purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate as a white solid (110 mg, 26%). 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 8.39 (dd, 1H, J=8.8, 1.1 Hz), 8.32 (dd, 1H, J=10.3, 2.4 Hz), 8.15 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.67 (dd, 1H, J=8.8, 8.8 Hz), 7.45 (s, 1H), 1.44 (s, 9H); MS(ESI−) m/z 349.08 (M−H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](=[O:26])[N:14]2[CH:27]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:1][C:27]1[N:14]2[C:15](=[O:26])[N:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)c(Br)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
N-bromosuccinimide (80.4 mg, 0.45 mmol) was added to a stirred solution of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.114 g, 0.41 mmol) and benzoyl peroxide (9.94 mg, 0.041 mmol) in DCE (3 mL). The mixture was stirred at RT for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-bromo-2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.102 g, 70% yield) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[C:6](=[O:22])([O:20][CH3:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:6](=[O:22])([O:20][CH3:21])[O:7][C:8]1[CH:13]=[C:12]([N+:23]([O-:25])=[O:24])[C:11]([Br:14])=[CH:10][C:9]=1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(Br)cc1C1CCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Temperature: -10 °C
Yield: 72.4 %

Procedure:
Concentrated H2SO4 (115 mL) was added to 4-bromo-2-cyclopentylphenyl methyl carbonate (26.09 g, 87.21 mmol) and the mixture stirred and cooled to −10° C. KNO3 (13.22 g, 130.80 mmol) was then added in portions with continuous stirring. The reaction was stirred at −10° C. for 1 h then quenched with ice resulting in precipitation of an off-white solid. The solid was filtered, washed with water and dried to provide the product. The water phase was extracted with dichloromethane (3×10 mL) and the combined organic extracts dried over Na2SO4. Purification by silica gel chromatography (5-20% ethyl acetate/hexane) provided additional 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (combined 21.72 g, 72% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.88 (s, 1H), 3.88 (d, J=5.7 Hz, 3H), 3.13 (dd, J=9.4, 17.2 Hz, 1H), 1.96-1.92 (m, 2H), 1.80-1.75 (m, 2H), 1.68-1.54 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](O)([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(O)c1ccc(-c2ccccc2)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 50 °C

Procedure:
The product of Example I (5 g.) was heated under reflux with methanol (50 ml.) and concentrated sulphuric acid (1 ml.) for 4 hours. The product was poured into water, extracted with ether, the ether extracts dried and evaporated to give methyl 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionate, m.p. 59°-61° C. This ester (1 g.) was dissolved in thionyl chloride (5 ml.) and heated on a water bath at 50° C. for two hours. Thionyl chloride was removed and the product was applied to preparative thin layer chromatography plates, eluted with an ether/petroleum (b.p. 62°-68° C.) mixture (5%:95%) and methyl 2-chloro-2-(2-fluoro-4-biphenylyl)propionate recovered. This was dissolved in ethyl acetate (5 ml.) and hydrogenated at room temperature using a 10% palladium/charcoal catalyst (73 mg.) for 16 hours. The solution was filtered and evaporated to give methyl 2-(2-fluoro-4-biphenylyl)propionate, whose structure was confirmed by n.m.r. This was hydrolysed by heating under reflux with aqueous ethanolic potassium hydroxide. The solution was acidified, extracted with ether and then aqueous potassium carbonate (10%) and this extract acidified and the precipitate collected to give 2-(2-fluoro-4-biphenylyl)propionic acid (m.p.t. 105°-106° C.).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-6-methoxybenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g,0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-methoxybenzothiazole.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[O:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[CH2:26]O.N1C=CC=CC=1.O>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:26][CH:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC1CCc2ccccc2O1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC1CCc2ccccc2O1)C(F)(F)F
Temperature: -5 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C. The reaction was then stirred at 0° C. for 1 h. Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDCl3): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+NH4)+
Reaction SMILES: NCC(NCC([NH:9][C@H:10]([C:16](NCC(NCC(O)=O)=O)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[OH:14])=O)=O.CC(CC(NC(C(NC(CNC(CNC(C(N)CC1C=CC(O)=CC=1)=O)=O)=O)CC1C=CC=CC=1)=O)C(O)=[O:33])C.NCC(O)=O>>[NH2:9][C@H:10]([C:16]([OH:17])=[O:33])[CH2:11][CH2:12][C:13]([OH:14])=[O:15]
Reactant: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(=O)O
Reactant: NCC(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)O
Agent: NCC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
FIG. 3 shows a product-ion spectrum of the [M+107Ag]+ ion of GGEGG (SEQ. ID. NO. 2), glycylglycylglutamylglycylglycine. Sequencing of the argentinated peptide is straightforward and similar to that discussed in Example 1 for leucine enkephalin. The difference in m/z values between the [M+107Ag]+ ion and the first [bn+OH+Ag]+ ion is 482.1−425.1=57.0, which identifies the C-terminal residue as glycine (theoretical Δm/z 57.0). The difference in m/z values between the first [bn+OH+Ag]+ and the second [bn+OH+Ag]+ is 425.1−368.0=57.1; this identifies the residue preceding the C-terminus as, again, glycine. Repeating the procedure yields the next residue, glutamic acid (experimental Δm/z=128.9 versus theoretical Δm/z=129.0). The triplet peak pattern disappears beyond glutamic acid; however, manual interpretation reveals further sequence information. The [a1−H+Ag]+ in this product-ion spectrum is weak. However, the small m/z value of the [a1−H+Ag]+ ion of the last triplet, 193.1, strongly suggests that it is the [a1−H+Ag]+ ion. This makes G-G as the only possible option for the N-terminal and second residues (theoretical m/z=193.0). Furthermore, FIG. 3 shows a small peak at m/z 136.0, which is assignable as the [a1−H+Ag]+ ion (theoretical m/z=136.0, assuming the first residue is glycine). Thus, the determined sequence is G-G-E-G-G (SEQ. ID. NO. 2).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:10][CH2:9]1.[OH-].[Na+]>O>[N:11]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:1])[CH2:12][CH2:13][O:8][CH2:9][CH2:10]1
Reactant: COS(=O)(=O)OC
Reactant: NCCCCCCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNCCCCCCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylsulphate (832 mg; 0.66 mmoles) was slowly added to 8-morpholinooctylamine (141 mg; 0.66 mmoles) under stirring, the temperature being kept below 70° C. throughout the addition. Stirring was continued overnight. Then the mixture was treated with sodium hydroxide solution (880 mg) in water (15 ml) and heated to boiling. After two hours, the mixture was cooled to room temperature. An oil was separated which was combined with the water layer benzene extracts: the mixture obtained was dried on Na2SO4 and evaporated under reduced pressure. The collected residue was purified by silica gel chromatography, eluting with CHCl3 /MeOH/NH4OH, 65:35:2, to separate the desired product of very intense colour by ninhydrin and iodine reactions.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.OC(COCC=C)CNC(C)(C)CC1C=CC(OC)=CC=1.[ClH:49].OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([Cl:1])[CH:23]=[CH:24][C:25]=1[Cl:49])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15, 0.1), 280 (11), 279 (9), 278 (64), 276 (100), 163 (9), 161 (5), 121 (29), 113 (8).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:24][C@@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[O:18])[CH:14]=[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:33])=[O:32])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44]>CO>[CH3:47][N:46]([CH3:48])[S:43]([C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][NH:34][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:20][C@@H:21]([CH3:26])[O:22][C@H:23]([CH3:25])[CH2:24]3)=[O:18])[CH:14]=[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:33])=[O:32])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4])(=[O:45])=[O:44]
Reactant: COC(=O)c1nc2n(CC(=O)N3C[C@@H](C)O[C@H](C)C3)cc(N3CCCS3(=O)=O)n2c(=O)c1O
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Solvent: CO
Product: C[C@@H]1CN(C(=O)Cn2cc(N3CCCS3(=O)=O)n3c(=O)c(O)c(C(=O)NCc4ccc(F)cc4S(=O)(=O)N(C)C)nc23)C[C@@H](C)O1
Yield: 43 %

Procedure:
1-[2-((2R,6R)-2,6-Dimethyl-morpholin-4-yl)-2-oxo-ethyl]-3-(1,1-dioxo-1lambda*6*-isothiazolidin-2-yl)-6-hydroxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (30 mg, 0.062 mmol) was dissolved in MeOH (1 mL) and 2-aminomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide (22 mg, 0.093 mmol) was added. The reaction was heated at reflux for 24 hours then filtered hot and the filtrate concentrated. The product was recrystalised from methanol and ether and isolated (17 mg, 43% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:9]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([OH:34])[C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:14]=1[N+:31]([O-:33])=[O:32]>>[CH3:11][N:12]([O:34][CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:14]=1[N+:31]([O-:33])=[O:32]
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1
Product: CN(OCC(=O)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 14, benzoylmethyl bromide is reacted with N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine to give N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]benzoylmethoxyamine (IVA; R3 is H, n is one, and R4 is phenyl).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>CN(C=O)C>[CH3:1][NH:2][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methylamine was bubbled into a solution of 6-chloronicotinonitrile (2 g, 14.4 mmol) in DMF (150 mL) at room temperature for 4 min. The reaction mixture was then stirred at 50° C. for 1 hour. The DMF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The organic layer was washed with water and dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound as a white solid (1.9 g, 99%). 1H NMR (250 MHZ, CDCl3) δ(ppm):8.3 (d, 1H); 7.55 (dd, 1H); 6.35 (d, 1H); 5.4 (brd, 1H); 2.9 (d,3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)CCO)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)CCO)CC1

Procedure:
Following general procedure II, 1-[6-chloro-4-(4-{[(2-hydroxyethyl)(methyl)amino]-methyl}cyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (30 mg, 0.076 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.11 mmol) followed by formation of the dihydrochloride salt to afford the desired product (32 mg, 73%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=11.5 Hz, 1H), 5.74-5.71 (m, 1H), 3.90 (t, J=5.1 Hz, 2H), 3.45-3.32 (m, 1H), 3.30-3.26 (m, 2H), 3.07-3.04 (m, 1H), 2.97 (s, 3H), 2.76 (s, 3H), 2.45 (s, 2H), 2.17-2.02 (m, 3H), 1.70-1.62 (m, 2H), 1.48-1.36 (m, 2H); ESI MS m/z 501 [M+H]+; HPLC 98.2% (AUC), tR=9.54 min.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:26])[N:13]([CH3:25])[CH:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:23][N:22]([CH3:24])[CH2:21]3)[CH2:16][CH2:15]2)[CH:6]=1>O1CCCC1.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:26])[N:13]([CH3:25])[CH:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:21][N:22]([CH3:24])[CH2:23]4)[CH2:18][CH2:19]3)[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ncn3)CC2)C1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 75.4 %

Procedure:
To a solution of 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]-1-methyl-1-[1-(1-methylazetidin-3-yl)piperidin-4-yl]urea (193 mg) in tetrahydrofuran (100 ml) was added 20% palladium hydroxide carbon (590 mg), followed by stirring under a hydrogen atmosphere at room temperature for 6.5 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated to provide the titled compound (136 mg, 75.4%) as pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]1([C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:42][CH:43]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(#N)C>CN(C=O)C.CCOCC>[CH3:17][N:15]([CH3:16])[C:14]1[C:9]2[CH2:8][C@@H:7]3[C:21](=[C:22]([OH:23])[C@@:24]4([OH:33])[C@@H:5]([CH2:6]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]([OH:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]4=[O:32])[C:20](=[O:34])[C:10]=2[C:11]2[O:19][C:43]([CH:42]=[C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:18][C:12]=2[CH:13]=1
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)c1cc2nc(C=C(c3ccccc3)c3ccccc3)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
9-aminominocycline sulfate salt (0.500 g, 0.748 mmol) is dissolved in anhydrous DMF and treated with β-phenylcinnamaldehyde (0.779 g, 3.74 mmol, 5 equivalents) The solution is then treated with DDQ (0.085 g, 0.374 mmol, 0.5 equivalents) and stirred at room temperature for 5 min. ES+ mass spectrometry showed a 1:1 ratio of product and starting material. A second portion of DDQ (0.068 g, 0.300 mmol, 0.4 equivalents) is added. After approximately 5 minutes, acetonitrile (7.5 mL) is added, and the entire reaction mixture is poured slowly into ether (750 mL.) The pink solid is removed by filtration and washed with fresh ether to yield 0.480 g of the crude product. This material is dissolved in water (75 mL) to give a solution at pH 2.2, which is extracted with dichloromethane (2×100 mL.) The pH of the aqueous layer is raised to 3.0 with aqueous ammonia, and the solution is again extracted with dichloromethane (2×100 mL.) The four organic extracts are dried (Na2SO4), filtered and concentrated to a volume of about 2 mL. A small portion of methanol (1 mL) is added, and the concentrated solution is treated dropwise with 1M HCl in ether. The solid precipitate is filtered, washed with fresh ether and dried under vacuum the product as its HCl salt.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cc1ccccc1N(N)Cc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:15]1(/[C:21](=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[C:15]1(/[C:21](=[CH:25]/[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)/[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)/C(=C\c1ccccc1)c1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C(=C\c1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
Sodium bis-(2-methoxyethoxy)aluminum hydride (70% in toluene) (Vitride®, 536 g, 1.86 mol) was diluted with 850 mL of toluene and the solution was cooled to -10° C. under a nitrogen atmosphere. A 170 g (0.74 mol) sample of Z-2,3-diphenyl propenoic acid was added portionwise to the Vitride solution while maintaining the temperature of the reaction mixture below 10° C. The resulting mixture was stirred at 0°-5° C. until thin layer chromatography indicated total consumption of the carboxylic acid (1.5 hours). A 1.7 L sample of n-butanol was added slowly at about 25° C. until the exotherm and foaming subsided. The speed of addition of the butanol was increased as the exotherm and-foaming stabilized. The pH of the resulting cloudy mixture was adjusted from 11 to 3.5-4.0 with 1.66 L of 3N aqueous HCl. The layers were separated. The organic layer was washed two times with water and dried (Na2SO4). The mixture was filtered and the drying agent was washed with 1:1 n-butanol:toluene (500 mL). The filtrate was evaporated in vacuo to give 170 g of an amber oil which crystallized on the addition of 50 mL of toluene and 510 mL of heptane. The solid precipitate was collected, washed with heptane, and dried to a constant weight under vacuum at 40° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(CCc1ccccc1)c1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc(CCCc2ccccc2)cc1

Procedure:
p-chlorophenyl phenylethyl ketone (25 g) was refluxed with hydrazine hydrate (13 g) and potassium hydroxide (18 g) in Digol (diethylene glycol) for one hour. The mixture was then distilled until the solution temperature in the still reached 175°. The mixture was then refluxed for 3 hours, cooled, poured into water and extracted with petroleum ether (Bpt 40°-60°). Evaporation of the extracts gave 1-(4-chlorophenyl)-3-phenylpropane Bbt. 110°/10-3 mm.