Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([C:13]#[N:14])=[C:6]([NH:8][CH2:9][C:10]([NH2:12])=[O:11])[CH:7]=1.CC[O-].[Na+]>CC(O)C>[NH2:14][C:13]1[C:5]2[C:6](=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:15])[NH:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: N#Cc1c(F)cc(Br)cc1NCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: NC(=O)c1[nH]c2cc(Br)cc(F)c2c1N
Temperature: 25 °C
Yield: 89 %

Procedure:
17.3 g (63.6 mmol) 2-(5-bromo-2-cyano-3-fluorophenylamino)acetamide was suspended in 150 ml 2-propanol and, after the addition of 10 ml NaOEt solution (21% in EtOH), the suspension was refluxed for 14 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 15.4 g (89%) 3-amino-6-bromo-4-fluoro-1H-indole-2-carboxylic acid amide was obtained. ESI-MS [m/z]: 272, 274 [M+H]+
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:51])([F:50])[F:52])[CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (0.103 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford the title compound of Step A (0.106 g). MS 700.8 (M+1)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].[OH:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[OH:16][CH2:17][C:18]1[N:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])[NH:21][CH:22]=1
Reactant: O=c1ccccn1-c1ccc(I)c(F)c1
Reactant: OCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccccn1-c1ccc(-c2nc(CO)c[nH]2)c(F)c1

Procedure:
Alternatively as shown in Scheme 4, 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above, is treated with 4-hydroxymethylimidazole II-1 in the presence of 8-hydroxyquinoline, and K2CO3 in DMSO. The resulting mixture is degassed before being charged with CuI to give 4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1. The compound 4-1 is treated with thionyl chloride to give 4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole which is then treated with NaN3 to result in 4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2. The azide 4-2 is reduced with Ph3P to give 4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3. The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound 21.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]([O-:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:10](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(OCC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OCC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 30 %

Procedure:
Mono-ethyl ethoxymalonate (2.75 grams, 0.02 mole), prepared in Part A, 3,5-dichloroaniline (2.53 grams, 0.02 mole) and 1,3-dicyclohexylcarbodiimide (3.22 grams, 0.02 mole) were reacted in a manner similar to that described in Example LVII to give 1.92 grams (0.006 mole) of ethyl 3-[(3,5-dichlorophenyl)amino]-2-ethoxy-3-oxopropanoate having a melting point of 89.0° C.-92.5° C. An analytical sample recrystallized from ethyl acetate-hexane had a melting point of 84° C.-86° C.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(OCC)(=O)C.O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:40][CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCOc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 1 mL of an N,N-dimethylformamide solution containing 60 mg of (2-bromoethoxy)benzene were added at room temperature. After stirred at 50° C. for 30 min, it was allowed to stand overnight. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=30:1], to give 0.12 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>C1COCC1.O>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: Cc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of intermediate 19 (0.071 mol) in THF (250 ml) was cooled on an ice bath. TiCl3 15% in water (250 ml) was added dropwise. The mixture was stirred at room temperature overnight, then poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 20.5 g (82.6%) of [2-amino-5(4-methylbenzoyl)phenyl](3-chlorophenyl)-methanone (intermediate 20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[C:51]([F:53])[CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=5)=[C:22]([F:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1>COC1C=CC(CN2C=C(B3OC(C)(C)C(C)(C)O3)C=N2)=CC=1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[C:51]([F:53])[CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:30][CH2:31]5)=[C:22]([F:39])[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: [Pd+2]
Agent: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 98.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenyl)-5,6-di hydropyridine-1(2H)-carboxylate (103 mg, 0.139 mmol) was reduced with palladium hydroxide (50 mg) in ethyl acetate/ethanol 5/15 mL to afford 102 mg (99% yield) of the titled compound. MS: m/z=742.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[Br:15]N1C(=O)CCC1=O>N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N.ClCCl>[Br:15][CH2:14][C:3]1[C:4]([Cl:13])=[CH:5][C:6]2[S:10][C:9](=[O:11])[N:8]([CH3:12])[C:7]=2[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cc2sc(=O)n(C)c2c1Cl
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: Cn1c(=O)sc2cc(Cl)c(CBr)c(Cl)c21
Yield: 70 %

Procedure:
A mixture of 4,6-dichloro-3,5-dimethyl-2-benzothiazolinone (1.30 g), N-bromosuccinimide (1.03 g), 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (65 mg) and dichloromethane (26 ml) was heated under reflux for 2 hours. N-Bromosuccinimide (500 mg) was added therein and the mixture was heated under reflux for additional 4 hours. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 5-bromomethyl-4,6-dichloro-3-methyl-2-benzothiazolinone (1.20 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C.CCCC(C)C>[C:14]1([CH2:13][O:12][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCOCC1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.75 g, 30.0 mmol), tetrahydro-4H-pyran-4-ol (4.28 mL, 45.0 mmol) and triphenylphosphine (11.8 g, 45.0 mmol) were stirred under argon in THF (166 mL) and cooled to 5° C. in an ice bath. DEAD (19.6 mL, 45.0 mmol) was added dropwise to the mixture, maintaining the internal temperature below 10° C. Stirring was continued for 16 hours then the reaction mixture reduced in vacuo and the residue redissolved in ethyl acetate (60 mL) and isohexane (60 mL). The precipitate was removed, the filtrate concentrated in vacuo and purified by chromatography on silica, eluting with 0-25% ethyl acetate in isohexane (a small quantity of DCM used to assist column loading), to give the desired compound as a colourless oil (9.0 g).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([CH2:13][OH:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude material was purified through silica gel column chromatography to give the title compound as a solid, mp. 121-123° C., Anal. For C20H29N3O2 calc. C, 69.94; H, 8.51; N, 12.23; found: C, 69.73; H, 8.47; N, 11.99.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([B:10]2[O:14]C(C)(C)C(C)(C)[O:11]2)[CH:7]=[C:6]([F:19])[C:3]=1[C:4]#[N:5]>CC(C)=O.O>[C:4]([C:3]1[C:2]([F:1])=[CH:9][C:8]([B:10]([OH:14])[OH:11])=[CH:7][C:6]=1[F:19])#[N:5]
Reactant: CC1(C)OB(c2cc(F)c(C#N)c(F)c2)OC1(C)C
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1c(F)cc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (55 g) was dissolved in acetone (1 L) and water (1 L). T this stirred mixture was added NaIO4 (160 g) and NH4OAc (50 g). The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was evaporated under vacuum at 40° C. until most of acetone was removed. The residue was cooled to 0° C. and 2N NaOH (1 L) solution was added with stirring over 30 minutes. The mixture was filtered, and the filtrate was washed with CH2Cl2 (1 L). To the aqueous layer was added 5N hydrochloric acid at 0° C. until pH=2. The resulting solid was filtered and then dissolved in EtOAc (1.5 L), dried over Na2SO4, filtered and evaporated under vacuum to provide 30 g of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]3=[N:21][CH:22]=[CH:23][C:24]([Cl:25])=[C:19]3[CH:18]=2)=[CH:5]1.[Na+].[I-:38]>CC(=O)CC>[Cl:25][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[N:26]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:17]([C:6]3[C:7]4=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=[C:12]4[N:4]([CH2:3][CH2:2][I:38])[CH:5]=3)=[CH:18][C:19]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Yield: 96.4 %

Procedure:
Dissolve chlorobisazaindole 31 (110 mg, 0.202 mmol) and NaI (33.5 mg, 0.222 mmol) in 2-butanone (10 mL) and reflux for 24 h. The reaction medium is then concentrated under vacuum, the residue is dissolved in EtOAc, washed with brine, dried (Na2SO4) and concentrated, to give 32 (124 mg, 96.6%) as a yellow solid: 1H NMR (CDCl3) δ 8.25 (d, 1H, J=5.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.65 (s, 1H), 7.10 (m, 5H), 4.53 (t, 2H, J=6.4 Hz), 4.03 (s, 3H), 3.99 (s, 3H), 3.50 (t, 2H, J=6.4 Hz), 2.31 (s, 3H), TLC (EtOAc at 40%/heptane) Rf=0.20, m/z obs.=636.9 (M+1), 638.9, 639.94.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([NH:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[OH:36])[C:24]([OH:26])=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].FC(F)(F)C(O)=O.[CH2:44]([O:48][C:49]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH3:59])[CH2:52][NH:51][CH2:50]1)[CH2:45][CH2:46][CH3:47].C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[C:15]([O:19][C:20](=[O:21])[NH:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[OH:36])[C:24]([N:51]1[CH2:50][C:49]([O:48][CH2:44][CH2:45][CH2:46][CH3:47])([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH3:59])[CH2:52]1)=[O:26])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCCCOC1(c2ccccc2C)CNC1
Reactant: COc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)c(O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(OC)cc2O)NC(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 143.1 %

Procedure:
74 mg (0.4 mmol) of EDC and 52 mg (0.4 mmol) of HOBt are added to a solution of 100 mg (0.3 mmol) of 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoic acid in 5 ml of dimethylformamide. The mixture is stirred for 15 min and 107 mg (0.3 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate are added. After stirring for a further 15 minutes at ambient temperature, 0.3 ml (1.3 mmol) of diisopropylethylamine is added. The reaction medium is stirred for 2 h, and then 10 ml of a 1N aqueous solution of hydrochloric acid are added and the medium is extracted with ethyl acetate. The organic phase is washed with water and then dried over magnesium sulphate, filtered and evaporated. The residue is filtered through silica gel (eluent: 70/30 heptane/ethyl acetate). 220 mg of tert-butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a yellow oil and are used crude in the next stage.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH2:30](Cl)Cl>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([O:23][CH3:30])=[O:22])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: O=C(O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
Thionyl chloride (0.01 mol) was added to a mixture of intermediate (16) (0.0029 mol) in DCM (10 ml). The mixture was stirred overnight and then the solvent was evaporated. The residue was dissolved in DCM (10 ml). Methanol (10 ml) was added. The mixture was allowed to stand for 4 hours, then poured out into a NaHCO3 solution and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in hexane/DIPE. The precipitate was filtered off and dried, yielding 0.9 g of (±)-methyl 1-(4-nitrophenyl)-α-phenyl-4-piperidineacetate (intermediate 17, mp. 124° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([CH:12]=2)[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Clc1ccnc(Cl)n1
Product: COc1ccc(-c2ccnc(Cl)n2)cc1C=O

Procedure:
2,4 dichloropyrimidine and 3-formyl 4-methoxy phenyl boronic acid were coupled following procedure A. LC-MS showed the product was >95% pure and had the expected M+H+ of 249.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:23][CH2:22]2)=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18])=[O:8].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:72]1([C:75]2[O:76][CH:77]=[C:78]([C:80](O)=[O:81])[N:79]=2)[CH2:74][CH2:73]1>O.C(OCC)(=O)C>[Cl:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:80]([C:78]2[N:79]=[C:75]([CH:72]3[CH2:74][CH2:73]3)[O:76][CH:77]=2)=[O:81])=[C:3]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:25][CH2:26]2)[CH:4]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCOC3=O)cc2N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCOC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Yield: 25 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar, the 5-amino-2-chloro-N-[3-(2-oxo-oxazolidin-3-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 15c (73.40 mg, 0.16 mmol) was taken up in clean, dry, reagent-grade N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the reaction mixture was stirred under a nitrogen feed at room temperature until all solids were in solution. To this was then added the HATU (70.90 mg, 0.19 mmol) in one portion followed by the N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) and the reaction mixture was stirred until all solids were in solution. The 2-cyclopropyl-oxazole-4-carboxylic acid 1h (35.70 mg, 0.23 mmol) was added the reaction was allowed to stir at room temperature overnight. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous using ethyl acetate (3×20 ml). The organic phases were combined, washed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml). The organic solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The product was purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 7.5% MeOH in dichloromethane. The product required further purification and was thusly subjected to reverse-phase prep-HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. The product, 2-cyclopropyl-oxazole-4-carboxylic acid [4-chloro-5-[3-(2-oxo-oxazolidin-3-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 15d (26.60 mg, 0.04 mmol), was isolated as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17]C(=O)OCC2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[NH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CCN)CC1
Reaction time: 72 h
Yield: 124.1 %

Procedure:
A mixture of benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (3.0 g), Pd-C (0.3 g), and ethanol (100 ml) was stirred vigorously for 3 days under a hydrogen atmosphere. Pd-C was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 1-(2-aminoethyl)-4-piperidinylcarbamate (2.4 g) as a colorless oily substance.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNCC1
Solvent: CO
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCCCC1)CO2
Temperature: 120 °C
Yield: 81.5 %

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.49 g, 1.1 mmol), piperidine (1 ml, 10.1 mmol) and MeOH (2 ml) was heated under microwave radiation at 120° C. for 25 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography (MeOH/EtOAc) gave the title compound (0.31 g). The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et20 (0.25 g). MS m/z (rel. intensity, 70 eV) 345 (M+, 0.5), 124 (3), 99 (7), 98 (bp), 96 (2), 55 (4) [α]=−60° (MeOH).