Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:50])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:47](O)=[O:48])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][O:35][C@@H:36]1[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]1[OH:38])=[O:31])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][CH2:74][CH2:75][O:76][C@@H:77]1[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79])=[O:72]>CN(C=O)C>[C@@H:77]1([O:76][CH2:75][CH2:74][NH:73][C:71](=[O:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][NH:65][C:47](=[O:48])[C@@H:19]([NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:50])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][O:35][C@@H:36]2[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]2[OH:38])[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCN)[C@@H](O)[C@H](O)[C@@H]1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCNC(=O)[C@H](CCCCNC(=O)CCCCC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)NC(=O)CCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 40 mL vial was added N2-{8-(benzyloxy)-8-oxooctanoyl}-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (100 mg, 0.141 mmol) and DMF (5 mL). To the above solution at 0° C. was added EDC (40.5 mg, 0.211 mmol) and HOBt (23.7 mg, 0.155 mmol). The reaction was warmed to rt and stirred at rt for 20 min. To the above mixture was added 6-amino-N-{2-[(α-L-fucopyranosyl)oxy]ethyl}hexanamide (45.1 mg, 0.141 mmol). After stirring at rt for 18 hr, the mixture was concentrated. The residue was purified by flash chromatography eluting with 0-40% AcCN in water to give the title compound. UPLC Method B: m/e=1012.6348 [M+1]; Rt=3.28 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNC1
Product: Cc1nc(N2CCC2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and azetidine following the method used to prepare Intermediate 46. LCMS (ES+) 194 (M+H)+, RT 2.55 minutes (method 1).
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1)C.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:16][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CNC1CCN(C)CC1
Reactant: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Product: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1

Procedure:
The title compound is prepared according to the procedure described in General Method A, using 2-ethylsulfanyl-5-nitrobenzooxazole (1.17 g, 5.23 mmol) and methyl-(1-methyl-piperidin-4-yl)-amine (1.37 mL, 9.42 mmol) in anhydrous THP (10 mL) at 100° C.: (0.608 g, 40%). mass spectrum (m/e): 291.0 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH:8]=1)(=O)=O.[N:48]1[CH:53]=[C:52](B(O)O)[CH:51]=[N:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][O:43][C:40]1[C:39]([CH3:45])=[CH:38][N:37]=[C:36]([CH2:35][N:33]2[N:34]=[C:9]3[CH:8]=[C:7]([C:52]4[CH:53]=[N:48][CH:49]=[N:50][CH:51]=4)[C:16]4[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]([C:10]=43)=[N:32]2)[C:41]=1[CH3:42]
Reactant: COc1c(C)cnc(Cn2nc3cc(OS(=O)(=O)C(F)(F)F)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)cnc(Cn2nc3cc(-c4cncnc4)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[Bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl trifluoromethanesulfonate (50 mg) was dissolved in 1,4-dioxane (4 ml). Pyrimidine-5-boronic acid (13 mg), a 2 N sodium carbonate solution (2 ml) and bis(triphenylphosphine)palladium (II) dichloride (5 mg) were added and the mixture was stirred at 40° C. for two hours. Water was placed into the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound as an oil (45 mg).
Reaction SMILES: [NH2:1][C@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:25]([NH:1][C@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)[C@H](N)C(C)C)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)[C@H](NC(=O)c2ccccc2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (R)-methyl 1-(2-amino-3-methylbutanoyl)-4-(4-chlorophenyl)piperidine-4-carboxylate (396 mg, 1.123 mmol) and benzoyl chloride (0.139 ml, 1.2 mmol) in CH2Cl2 (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.401 mL, 2.3 mmol). The mixture was stirred for 1 h at rt. The reaction was quenched with NaHCO3 (aq), extracted with dichloromethane, dried over Na2SO4 and concentrated. The residue was purified via column chromatography (20% EtOAc/heptane) to give (R)-methyl 1-(2-benzamido-3-methylbutanoyl)-4-(4-chlorophenyl)piperidine-4-carboxylate (467 mg, 91% yield) as a yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([OH:27])=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
Benzyl bromide (4.34 g, 25.4 mmol) and potassium carbonate (4.80 g, 34.7 mmol) were added to 1-(tert-butoxycarbonyl)nipecotic acid (5.30 g, 23.1 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer washed sequentially with water and brine and was dried over sodium sulfate. The solvent was then evaporated to give 7.11 g (96%) of the desired compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:64])[CH3:65])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N)c2c1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (27.3 g, 109 mmol) in dry CH2Cl2 (45 mL) at 0° C., under argon, were added PYBOP (57 g, 109 mmol), 1-amino-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, as described above in Step C above (13.6 g, 44 mmol), and N,N-diisopropylethylamine (26.7 mL, 153 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 4 hours, then partitioned between 10% aqueous citric acid (400 mL) and CH2Cl2 (1 L). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—10% to 25% EtOAc to yield the titled product.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: Cc1ccccc1O
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1OC(=O)CCC1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.9 of o-methylphenol, 3.5 g of dicyclohexylcarbodiimide and 20 ml of dry pyridine was stirred overnight at room temperature. Any insoluble materials were filtered and washed with pyridine. The filtrate and washings were combined together, and the solvent was removed under reduced pressure. Ethyl acetate and ether were added to the residue to give crystals. After being air-dried, the crystals were recrystallized from water to obtain 3 g (yield: 54%) of -methylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless prisms having a melting point of 184° to 185.5° C. The IR and NMR spectra of the compound were identical with those of the compound obtained in Example 28.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36]C(B(O)O)=[CH:34][CH:33]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([C:23]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)=[C:21]([CH3:22])[C:12]=2[CH:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:7]([OH:9])=[O:8])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(Cl)cc1

Procedure:
2-(1,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (140) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 4-chlorobenzene boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.75-7.63 (m, 4H), 7.55 (dd, J=8.2, 2.4 Hz, 1H), 7.46-7.31 (m, 5H), 7.26-7.21 (m, 2H), 5.14 (s, 1H), 2.24 (s, 3H), 0.96 (s, 9H). LCMS-ESI− (m/z): [2M-2H+Na]− calcd for C58H50Cl4NaO6: 1007.2; Found: 1007.1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32]>CO.ClCCl>[OH:28][CH2:29][CH2:30][NH:31][N:32]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1
Reactant: NNCCO
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Solvent: CO
Solvent: ClCCl
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NNCCO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), 2-hydroxyethylhydrazine (29 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1.5% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg). MS (ESP): 434 (MH+) for C20H24FN5O5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][OH:14])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of ((1S)-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (25 g, 115 mmol) in dichloromethane (500 ml) cooled by an ice-water bath was successively added diisopropylethylamine (35.7 g, 276 mmol) and methanesulphonyl chloride (15.81 g, 138 mmol). The resulting solution was stirred over night during which time the mixture was allowed to gradually warm up to ambient temperature. The mixture was washed successively with water, 10% citric acid (aq), water and saturated NaHCO3 (aq), then dried with Na2SO4 and concentrated to a brown solid (32.6 g, 96%) which was used in the next reaction without further purification.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH2:16][CH:17]([NH:24][CH3:25])[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23])=O.[ClH:28]>>[ClH:28].[ClH:28].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[CH2:16][CH:17]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23])[NH:24][CH3:25]
Reactant: CNC(Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C)c1sccc1C
Agent: Cl
Product: CNC(Cc1cc(C(F)(F)F)ccc1N)c1sccc1C
Reaction time: 1 h

Procedure:
A solution of 8.29 g of 2,2-dimethyl-N-[2-[2-methylamino-2-(3-methyl-2-thienyl)ethyl]-4-trifluoromethylphenyl]propanamide and 250 ml of 6N hydrochloric acid was refluxed for 10 hr, with stirring. The cooled solution was decanted over crushed ice and water, basified with 50% sodium hydroxide solution, and extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative HPLC (Waters Associates Prep LC/System 500, silica gel, sample applied in and eluted with methanol, 200 ml/min flow rate). The appropriate fractions were combined and evaporated. The residue was dissolved in ether and allowed to stand for 1 hr. The solution was filtered and the filtrate concentrated. The residue crystallized during refrigerated storage. A solution of the residue and ~5 ml methanol was treated with excess ethereal hydrogen chloride, and the solution was gradually diluted with ether. The precipitate was collected, washed with ether, and dried in vacuo at 40° C. over sodium hydroxide pellets to give 0.29 g of product, mp 209°-212° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:28][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:28])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C[Mg]Br
Reactant: COCc1cc(C(C)=O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Solvent: C1CCOC1
Product: COCc1cc(C(C)(C)O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-(methoxymethyl)pyrimidin-4-yl)ethanone (160 mg, 0.44 mmol) in tetrahydrofuran (20 mL) was added dropwise to an ice-cold solution of methylmagnesium bromide (3.11 mL, 4.35 mmol) in tetrahydrofuran (10 mL). The mixture was stirred on ice-bath for 30 minutes and quenched with ammonium chloride (sat, aq). The mixture was extracted with dichloromethane, the organic phase was passed through a phase separator containing 1 cm layer of magnesium sulfate and the eluate was concentrated in vacuum. The residue was purified preparative HPLC to give the title compound as a solid, 124 mg (74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[CH3:27][C:22]1([CH3:28])[C:23](=[O:24])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[O:18]1
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one (1.68 g) in 100 ml dry THF, was added portion-wise at 0° C. 60% oil dispersion of sodium hydride (270 mg). The reaction solution was stirred at the same temperature for 1 hour. Then 1.2 ml of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while warming gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 1.21 g of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.48 (s, 3H), 7.26-7.39 (m, 7H), 7.67 (m, 1H), 7.81 (m, 1H). IR (cm−1): 1696, 1421, 1388, 1238.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:8][CH2:1][CH:2]1[CH2:7][CH2:6][N:11]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: NC(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NCC1CCN(C(=O)NCc2ccccc2)CC1

Procedure:
) 4 g of benzylurea 14a were dissolved in a mixture of ethyl acetate/CH3OH 3:1 with heating and, after addition of 0.2 g of 10% Pd on activated carbon, hydrogenated under standard conditions at 35 to 40° C. After the reaction was complete, the mixture was filtered through Celite and evaporated. 2.8 g; ESI-MS [M+H+]=248.15
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[CH:35]1[CH2:38][CH2:37][CH2:36]1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Nc1ncnc(Cl)c1C1CCC1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CCC4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-cyclobutyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=501, obsd=501).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:17]1)(C)(C)C>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[C:24]([F:4])[CH:23]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h

Procedure:
TFA (1 mL) is added to a solution of {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (200 mg, 0.52 mmol) in DCE (4 mL). This solution is stirred for 1.5 h, and the mixture is concentrated under vacuum to afford TFA salt of 1-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one. TEA (105 mg, 1.04 mmol) is added to a solution of the above salt in MeOH (4.0 mL) followed by difluorothioacetic acid-O-(3,3-diphenyl-propyl)ester (84 mg, 0.25 mmol). The mixture is stirred for 4 h at 50° C., and the solvent is removed under vacuum. The crude product is purified by silica gel column chromatography (eluent: 1.5% MeOH in EtOAc). MS (m/z): 382 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ7.93 (d, J=7.7 Hz, 1H), 7.73 (d, J=9.3 Hz, 2H), 7.49 (d, J=9.3 Hz, 2H), 6.69 (t, J=55.2 Hz, 1H), 5.21–5.17 (m, 2H), 4.38 (t, J=9.1 Hz, 1H), 4.18–4.12 (m, 4H), 4.05 (dd, J=6.3 and 9.1 Hz, 1H), 3.48 (d, J=7.1 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH3:11]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)c1cccc(Br)n1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(Br)n1
Temperature: 70 °C
Yield: 45 %

Procedure:
6-Bromopicolinic acid (1000 mg, 4.95 mmol) was suspended in thionyl chloride (15 mL) and heated at 70° C. for 5 h. The reaction was cooled to room temperature and the volatiles were condensed under reduced pressure. A solution of ammonia (2M in dioxane (15 mL) was added to the residue and then the solvents were removed under reduced pressure. The crude residue was purified by MPLC with a gradient of 0 to 20% MeOH/dichloromethane to give 6-Bromo-pyridine-2-carboxylic acid amide as a white powder (555 mg, 45%). MS ES (MH+=201.0/203.0).