Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:9][CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:3]1.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-]>CO.O>[N:20]([CH:8]1[CH2:9][C:2]([CH3:19])([CH3:1])[CH2:3][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:5][CH:6]1[OH:7])=[N+:21]=[N-:22]
Reactant: CC1(C)CC2OC2CN(S(=O)(=O)c2ccccn2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Yield: 28.6 %

Procedure:
5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane from Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O. NaN3 (0.83 g, 13 mmol) and NH4Cl (0.7 g, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO3 and brine. Purified on column chromatography gave 0.4 g 4-azido-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (yield 29%); MS (M+H+): 326.2; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(m, 1H), 8.05-7.90(m, 2H), 7.53-7.50(m, 1H), 3.75-3.60(m, 3H), 3.49-3.30(m, 3H), 1.73-1.66(m, 1H), 1.56-1.52(d, 1H), 1.07(s, 3H), 0.99(s, 3H)
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.N>>[Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:9])[N:6]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1coc(Cl)n1
Agent: N
Product: O=C(Nc1ccc(Cl)cc1)c1coc(Cl)n1

Procedure:
Prepared from ethyl 2-chlorooxazole-4-carboxylate (83.5 mg, 0.475 mmol) and 4-chloroaniline (60.5 mg, 0.475 mmol) as described in Example 154A: 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37-7.45 (m, 2H), 7.81-7.89 (m, 2H), 8.91 (s, 1H), 10.45 (s, 1H). MS (DCI/NH3) m/z=274 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](SC)[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.[F:44][C:45]1[CH:46]=[C:47]([NH:60][C:61]([NH:63][CH2:64][CH2:65][F:66])=[O:62])[CH:48]=[CH:49][C:50]=1B1OC(C)(C)C(C)(C)O1>>[F:44][C:45]1[CH:46]=[C:47]([NH:60][C:61]([NH:63][CH2:64][CH2:65][F:66])=[O:62])[CH:48]=[CH:49][C:50]=1[C:12]1[N:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:11]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(-c2ccc(NC(=O)NCCF)cc2F)n1

Procedure:
Method as described for intermediate 5 using(S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 14). Material was purified by prep HPLC (high pH) followed by purification using a TsOH cartridge (500 mg) to afford a brown solid, (10 mg, 6%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](OC)=[CH:7][C:8](=[O:13])[C:9]([Cl:12])([Cl:11])[Cl:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[C:18]([NH:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][C:8]([OH:13])([C:9]([Cl:10])([Cl:11])[Cl:12])[N:23]([C:18]2[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[N:24]=1)(=[O:3])[CH3:2]
Reactant: NNc1ncccc1Cl
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O
Solvent: CCO
Product: CC(=O)OCC1=NN(c2ncccc2Cl)C(O)(C(Cl)(Cl)Cl)C1
Reaction time: 3 h

Procedure:
27.5 g (0.1 mol) of 5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-yl acetate and 14.4 g (0.1 mol) of 3-chloro-2-hydrazinopyridine were initially charged in 200 ml of ethanol, and the mixture was stirred at 25° c. for 3 h. The precipitate was filtered off and washed with cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:25])=[CH:26][CH:27]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CCOCC1
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cc2)cn1
Yield: 79 %

Procedure:
As described for example 3b, 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (73 mg, 79%) which was obtained as a white solid. MS: m/e=447.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27](N(C)C4C=CC=CC=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27]([NH:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=c1c2cc(CS(=O)(=O)NCc3ccccn3)ccc2ccc2ncc(Cl)cc12
Temperature: 132.5 °C

Procedure:
2-Aminomethylpyridine (55.9 ml, 546 mmol) was added to a solution of 1-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide (51.6 g, 121 mmol) in N-methyl-2-pyrrolidinone (1214 ml) at room temperature. The solution was then heated to 130-135° C. for 2 h in a pre-warmed oil bath. The solution was then cooled to room temperature and poured into aqueous sodium hydrogen carbonate (saturated, 3.0 L) and 500 mL ice-water and extracted with ethyl acetate (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (d, 1H); 8.46 (m, 1H); 8.16 (d, 1H); 7.81 (m, 3H); 7.76 (m, 1H); 7.49 (d, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.63 (s, 2H); 4.22 (d, 2H). LRMS (APCI) calculated for C21H17ClN3O3S [M+H]+, 426.1. found 426.0.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:25])[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:1][O:2][N:3]([CH3:25])[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-:34])=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)N(C)OC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (7.4 g, 21.7 mmol) by reaction with m-CPBA (9.50 g) to provide N-methoxy-N-methyl-4-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide followed by reaction with p-toluenesulfonyl chloride (7.20 g, 37.8 mmol) and ammonium hydroxide solution (200 mL) to provide 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methyl-butyramide as white crystals after recrystallization from aqueous methanol, mp 163-165° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][C:13]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=1.C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>C(Cl)Cl>[C:16]([C:14]1[N:15]=[C:11]([C:5]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])[O:12][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:40]([NH:39][CH3:38])=[O:41])[CH2:29][CH2:30]2)=[N:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: CN=C=O
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide dihydrochloride (0.060 g, 0.13 mmol) in DCM (3 mL) was added triethylamine (40 uL, 0.29 mmol) followed by methyl isocyanate (12 uL, 0.20 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC and then by SPE using a MP-TsOH resin (500 mg) cartridge to afford 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)-N-methylpiperazine-1-carboxamide (0.0057 g, 0.013 mmol, 10%) as a yellow solid. 1H NMR (DMSO) 2.58 (3H, d), 3.40 (4H, m), 3.61 (4H, m), 6.54 (1H, br. q), 6.99 (1H, d), 7.38 (2H, t), 7.65 (1H, br. s), 7.67 (1H, br. s), 7.72 (1H, m), 8.37 (1H, dd), 8.95 (1H, d). LCMS (2) Rt: 2.27 min; m/z (ES+) 443.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:33])=[CH:27][CH:26]=1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)[C@@H](c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
Using (+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 134 and -4-methoxyphenylacetic acid, the title compound was synthesized in the same manner as in Reference Example 359. Yield 74%. Melting point: 186-188° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:25]12[CH:31]([CH2:32][CH2:33][NH2:34])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:34][CH2:33][CH2:32][CH:31]2[CH:25]3[CH2:30][CH2:29][CH:28]2[CH2:27][CH2:26]3)=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C(=O)O)s1
Reactant: NCCC1C2CCC1CC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 mole of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 2-(bicyclo[2.2.1]hept-7-yl)ethylamine in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured into 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]-thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[CH3:19][CH:20]([NH2:35])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:35][CH:20]([CH3:19])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24])#[N:2]
Reactant: CC(N)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: CC(N=C(NC#N)c1ccncc1)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
Isopropyl N cyano-4-pyridinecarboximidate (0.31 g, 1.6 mmol) was dissolved in methanol (15 ml), and 1-methyl- 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.03 g, 0.08 mmol, yield 5%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]2[C:16](OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-:21].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:21])[C:10]2=[CH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CN(C)CCC1c1cccc(OC)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C(=O)N(C)CCC1c1cccc(OC)c1
Yield: 93.1 %

Procedure:
The ester ethyl 4-(3'-methoxyphenyl)-1-methylpiperidine-3-carboxylate (23 (5.0 g, 17.5 mmol), NaOH (1.49 g, 35 mmol), CH3OH (50 mL), and H2O (25 mL) were refluxed for 5 h. After the thorough removal of solvents, the residue was mixed with acetic anhydride (50 mL) and refluxed for 1 h, then cooled and evaporated and the crude reaction product partitioned between CHCl3 (50 mL) and saturated NaHCO3 (50 mL, pH 8). The aqueous layer was extracted with CHCl3 (2×50 mL) and the combined organic phases dried and evaporated. Distillation gave 3.77 g (92%) of 4-(3'-methoxyphenyl)-1-methyl-3-methylene-2-piperidone (24). Recrystallization (CH3Cl2 /hexane) gave the analytical sample: mp 67°-70° C.: NMR δ 7.29 (m, 1 H), 6.82 (m, 3H), 6.40 (t,J=2 Hz, 1H), 5.07 (t,J=2 Hz, 1H), 3.75 (s, 3H), 3.34 (m, 2H), 3.04 (s, 3H), 2.17 (m, 2H); IR (KBr) 1645, 1600 cm-1 ; mass spectrum m/e (rel intensity) 231 (100), 216 (13). Anal. Calcd for C14H17NO2 : C, 72.7; H, 7.4; N, 6.1. Found: C, 72.6; H, 7.3; N, 6.0.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:46])[CH2:25][C@H:26]([C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:54])C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:46])[C@H:25]([OH:54])[C@H:26]([C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a cooled solution (−78° C.) of sodium hexamethyldisilazide (0.38 mL, 0.38 mmol) in THF (0.5 mL) was added tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate from the previous step (0.153 g, 0.314 mmol) in THF (1 mL) dropwise and stirred for 45 min. 2-(Phenysulfonyl)-3-phenyloxaziridine (0.167 g, 0.629 mmol) dissolved in THF (0.5 mL) was added to cold solution and the mixture was stirred for 10 min. Camphorsulfonic acid, dissolved in THF (2 mL), was quickly added and the bath was removed. The reaction was warmed to room temperature, diluted with saturated aqueous NaHCO3, extracted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on a 35 g ISCO column using 0-50% EtOAc/hexanes over 40 min and the lowest spot fractions were combined and the solvent removed under reduced pressure to give an oil. This oil was purified by preparative HPLC on a Waters PrepPak using 10% to 100% CH3CN/H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The remaining aqueous solution was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give tert-butyl 3-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-hydroxy-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.068 g, 43%). TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.61 min, method B; M+H=503.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:16])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: CC(=O)CCC(C)=O
Reactant: CN1CCN(c2c(N)cncc2Br)CC1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cncc(Br)c1N1CCN(C)CC1

Procedure:
5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine (3000 mg, 11.06 mmol), hexane-2,5-dione (6.312 g, 6.487 mL, 55.30 mmol) in acetic acid (20 mL) was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and an aqueous saturated solution of NaHCO3. Combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo yielding an oil that was purified by filtration on silica to yield 1-(3-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazine as an off-white solid. MS (ES+) 351.1.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:28])[C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]([C:24]2[C:23]([Cl:28])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:18])=[O:26])[NH2:17])=[CH:12][CH:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NN(C(=O)c1c(Cl)cncc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 96 %

Procedure:
Triethylamine (1.40 mL, 1.02 g, 10.1 mmol) was added to a suspension of 4-chlorophenylhydrazine hydrochloride (1.83 g, 98%, 10.0 mmol) in THF (75 mL). The mixture was stirred under nitrogen at room temperature for 2.75 h. More triethylamine (3.0 mL, 21.6 mmol) was added followed by dropwise addition of a solution of freshly-prepared 3,5-dichloropyridine-4-carbonyl chloride (10.0 mmol) in THF (20 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were shaken together and allowed to separate. The organic phase was dried (Na2SO4) and concentrated, leaving 3.04 g of a tan solid, mp 201-203.5° C. Recrystallized from ethyl acetate/cyclohexane and then from ethanol furnished crystals which melted at 206-207.5° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32]>ClCCl>[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([NH:19][C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)=[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)=[O:32]
Reactant: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of the product from Example 1C (0.318 g, 1.081 mmol) in dichloromethane (8 mL) was added pyridine (0.256 g, 3.24 mmol). 3,3-Dimethylbutanoyl chloride (0.160 g, 1.189 mmol) was slowly added and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to yield the title compound (0.38 g, 88%). 1H NMR (400 MHz, CD3Cl) δ ppm 1.11 (s, 6H) 2.33 (s, 2H) 6.86 (dd, J=6.94, 4.12 Hz, 1H) 7.30-7.42 (m, 3H) 7.63-7.79 (m, 2H) 8.51 (dd, J=4.12, 1.73 Hz, 1H) 8.68 (dd, J=6.94, 1.63 Hz, 1H). MS ESI(+) m/z 393.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]1([CH2:15][O:14][C@@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH3:19])[CH:22]=3)=[CH:3][CH:4]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:18][CH2:17]1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCC1CC1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(-c2ccc(C[C@H](OCC3CC3)C(=O)OC)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
53 mg (0.046 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 145 mg (0.46 mmol) of methyl (S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propionate and 129 mg (0.55 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 3 ml of dimethylformamide. 0.3 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 70 mg of methyl (S)-2-cyclopropylmethoxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:22]1(NN)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: NNC1CCCCCCC1
Product: COc1ccc(C2=NN(C3CCCCCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and cyclooctylhydrazine as described for compound 35. Purified by chromatography (dichloromethane) and crystallized from petroleum ether (40-60° C.). M.p. 75-77° C.