Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]3[N:14]([CH3:13])[N:15]=[N:16][C:17]=3[CH:22]=2)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(c2)nnn3C)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(c2)nnn3C)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 30).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].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.O.C(O)C>[C:14]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc(-c2ccccc2)ccn1
Temperature: 150 °C
Yield: 87.7 %

Procedure:
A mixture of 4-bromo-N-propylpyridine-2-carboxamide (450 mg), phenylboronic acid (330 mg), potassium carbonate (380 mg), tetrakis(triphenylphosphine)palladium (210 mg), dimethylformamide (6.5 mL) and ethanol (3.5 mL) was stirred under irradiation with microwave while heating at 150° C. for 10 min. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed with water and brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=67:33-50:50) to afford 4-phenyl-N-propylpyridine-2-carboxamide (390 mg).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]>CO.[Pd]>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D8, 1.2 g, 3.02 mmol) in methanol (25 ml) was added Pd/C 10% wt (210 mg) and the mixture was stirred under hydrogen (1 atm) for 6 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (870 mg, 94%); Rt (HPLC): 3.61 min; Rf (cyclohexane:ethyl acetate=1:1): 0.18; MS: (ES/+) m/z: 329 [M+Na+]. C16H22N2O4 requires 306; 1H NMR (300 MHz, d6-DMSO) δ ppm: 9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H); 4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m, 1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([OH:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:22](I)[CH3:23].CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][C:11]([O:19][CH2:22][CH3:23])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1(OCC)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)-4-hydroxypiperidine-4-carboxylate (0.50 g, 1.51 mmol) in DMF (5 mL) was added NaH (0.066 g, 1.67 mmol, 60% dispersion in mineral oil) portion wiseand the mixture stirred at 0° C. for 10 minutes followed by drop wise addition of ethyl iodide (0.58 mL, 7.57 mmol). The reaction was stirred at 0° C. for 2 h. After completion of reaction (by TLC), the reaction was quenched with saturated NH4Cl solution (100 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with water and brine and dried over Na2SO4. The crude residue was purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow liquid (0.24 g, 44% yield). 1H NMR (DMSO-d6): δ 8.27 (s, 2H), 4.31 (m, 2H), 4.22 (q, J=6.40 Hz, 2H), 3.44 (m, 4H), 1.96 (m, 4H), and 1.28 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[O:13][CH2:14][CH3:15])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:11][CH2:10][CH2:9][CH:8]([P:12]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[O:13][CH2:14][CH3:15])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CCN)c1ccc(Cl)cc1

Procedure:
A solution of 20 g of ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate in 85 ml of ethanol is added to 131 g of an 8% solution of ammonia in ethanol. To this are added 8.5 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-1-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate, b.p. 190° C./0.02 mbar, 31P=+41.5 and +41.3 ppm (CDCl3).
Reaction SMILES: O.[C:2]1(C(C)C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13](=[O:15])[CH3:14]>CC(C)=O>[C:2]1([OH:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: CC(C)c1ccccc1
Agent: CC(=O)CO
Solvent: CC(C)=O
Solvent: O
Product: Oc1ccccc1

Procedure:
In U.S. Pat. No. 4,251,325 (assigned to BP Chemicals), the work-up of a fraction which has been substantially freed of low boilers, water, and acetone has been optimized by operating the cumene column in such a way that a mixture comprising cumene, AMS and hydroxy acetone is taken off at the top, with this mixture being separated virtually completely from the crude phenol remaining in the bottoms and thus not having to be removed in a costly fashion during the work-up of the phenol. This process gives phenol containing less than 30 ppm of hydroxy acetone. A disadvantage of this process is the fact that the input mixture has to be substantially freed of water, which is why an acetone fraction comprising low boilers and also the major part of the water present in the cleavage product mixture has to be separated from the cleavage product mixture in the preceding separation step. The work-up of such an acetone fraction by methods of the prior art is relatively uneconomical, since a high expenditure for apparatus is required.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:35])([CH3:34])N1C(=O)CCC1=O.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:36][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:35])([CH3:34])[CH3:25])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)N1C(=O)CCC1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 42 %

Procedure:
The clear solution that was obtained after refluxing a mixture of 357 mg (1.02 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide, 50 ml of chloroform and 2 ml (about 10 mmoles) of N-trimethylsilylsuccinimide for one and a half hours was cooled in an ice-bath. Bromination was carried out in half an hour using 0.24 mg (1.35 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 42% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:25]([O:28][CH:29]=[CH2:30])(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[C:25]([O:28][CH:29]1[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])(=[O:27])[CH3:26]
Reactant: C=COC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (11.3 mg, 34 micromol), vinyl acetate (0.1 ml), and solid sodium bicarbonate in dry dichloromethane was kept 2 days at ambient temperature, filtered through florisil, and evaporated under vacuum. The residue was chromatographed on one 15 cm ×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.20 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 5.5 mg (41%) p-nitrobenzyl 2-(2-acetoxyaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1 ; NMR (CDCl3): δ 1.90 dd (J1 =6 Hz, J2 =7 Hz, 1H), 2.10 t (J=7 Hz, 1H), 2.13 s (3H), 2.76 bd (J=5 Hz, 2H), 2.85 dd (J 1 =2.5 Hz, J2 =15 Hz, 1H), 3.25 dd (J1 =5 Hz, J2 =15 Hz, 1H), 4.12 m (1H), 4.87 dd (J1 =6 Hz, J2 =7 Hz, 1H), 5.27 s (2H), 7.49 d (J=9 Hz, 2H), 8.25 d (J=9 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=2[CH:11]=[CH:10]1>>[CH:1]1([CH2:7][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=3[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2CC1CCCCC1
Yield: 84.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.93 g of cyclohexylmethyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 2.82 g of 1-cyclohexylmethylindole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 85%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=[O:20]>>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:19]([C:15]2[S:16][CH:17]=[CH:18][C:14]=2[CH3:13])=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: Cc1ccsc1C(=O)Cl
Agent: Cl
Product: COC(=O)C1(NC(=O)c2sccc2C)CCCCC1
Yield: 46.7 %

Procedure:
581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 482 mg (3 mmol) of 3-methyl-2-thiophenecarbonyl chloride was used instead of phenylacetyl chloride in the process according to Reference Example 1 to obtain 394 mg (47%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([OH:15])=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)=[O:15])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COc1ccc2c(c1)CC(C(=O)O)CC2
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (250 mg, 1.21 mmol), and 4-chloro-3-(trifluoromethyl)aniline (260 mg, 1.33 mmol) in DMF (12.0 mL) was added DIPEA (1.06 mL, 6.07 mmol) and then HATU (508 mg, 1.34 mmol). The solution was allowed to stir at rt for 18 h. 1N HCl was added and the mixture was extracted with EtOAc. The organic solution was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography to give N-[4-chloro-3-(trifluoromethyl)phenyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide as a white solid (233 mg, 50%). LCMS: (FA) ES+ 384.1, ES− 382.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:13]1([NH:19][C:20]([NH:1][C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1NC(=O)Nc1ccccc1

Procedure:
To a solution of 5-amino-4-ethoxycarbonyl-1-methylpyrazole (0.845 g) in benzene (50 ml), were added phenyl isocyanate (0.543 ml) and triethylamine (0.70 ml), and the mixture was refluxed in a sealed tube for 3 h. The reaction mixture was evaporated under reduced pressure followed by repeated addition of ether, and the title compound was obtained as crystals (0.36 g, yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[S:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:38]([O:40][P:41]([CH2:46][NH2:47])(=[O:45])[O:42][CH2:43][CH3:44])[CH3:39].C(Cl)CCl.P(=O)([O-])OCN>C(Cl)Cl>[CH2:38]([O:40][P:41]([CH2:46][NH:47][C:27](=[O:29])[CH2:26][CH2:25][S:24][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=1)[N:15]=[CH:14][CH:13]=[CH:12]3)(=[O:45])[O:42][CH2:43][CH3:44])[CH3:39]
Reactant: CCOP(=O)(CN)OCC
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O
Agent: NCO[PH](=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOP(=O)(CNC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1)OCC

Procedure:
To a solution of 24 (15 mg, 0.035 mmol) in 0.35 mL of CH2Cl2 (0.35 mL) was added diethyl(aminomethyl)phosphonate oxalate (27 mg, 0.105 mmol), EDC (20 mg, 0.105 mmol) and TEA (15 μL, 0.105 mmol). The solution was stirred at room temperature for 1 day when the same amount of the aminomethyl phosphonate, EDC and TEA were added. The reaction was stirred for another day when complete conversion of starting materials to the desired product was observed by LCMS. The product 26 was purified by reverse phase HPLC using 5-95% A. Buffer A contained CH3CN-1% HOAc and buffer B was H2O-1% HOAc. 1H NMR (300 MHz, CDCl3) δ 1.33-1.40 (m, 6H), 2.37-2.45 (m, 4H), 3.60-3.72 (m, 2H), 4.05 (s, 3H), 4.06-4.18 (m, 4H), 4.44 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=14 Hz), 5.49 (s, 1H), 6.17 (br s, 1H), 6.98-7.08 (m, 2H), 7.33-7.43 (m, 2H), 7.55-7.63 (m, 1H), 8.50-8.57 (br d, 1H), 8.97 (br s, 1H); 31P (121.4 MHz, CDCl3) δ 22.7; 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 590.4 [M−H]−, 614.2 [M+Na].
Reaction SMILES: ClCCl.[C:4]([NH:12][C:13]([NH:15][C@@:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][CH2:18][C@H:17]1[CH2:24]O)=[S:14])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C@:16]12[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][CH2:18][C@H:17]1[CH2:24][S:14][C:13]([NH:12][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:15]2
Reactant: CO[C@H]1CC[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dichloromethane (20 mL) and pyridine (264 μL, specific gravity: 0.978 g/cm3) were added to (±)-1-benzoyl-3-[(1S*,2R*,5S*)-1-(2-fluorophenyl)-2-hydroxymethyl-5-methoxycyclohexyl]thiourea obtained in Preparation Example 57-(6) (453 mg) according to the method of Preparation Example 18-(5). The mixture was cooled to −78° C. under a nitrogen atmosphere and stirred for 15 minutes. Trifluoromethanesulfonic anhydride (358 μL, specific gravity: 1.72 g/cm3) was slowly added to the reaction solution. After completion of the addition, the mixture was stirred for 15 minutes and then further stirred for one hour while warming to 0° C. After adding ethyl acetate, a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine and dried over anhydrous magnesium sulfate. The solid was removed by filtration. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (268 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=3[Cl:30])=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:42][NH:43][CH3:44]>>[Cl:29][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:30])[C:23]=1[C:21]([NH:20][CH2:19][CH2:18][CH:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)[C:7]2[CH:8]=[CH:9][C:4]([C:3](=[O:2])[N:43]([CH3:44])[CH3:42])=[CH:5][CH:6]=2)[CH2:12][CH2:13]1)[CH3:31])=[O:22]
Reactant: CNC
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(Cl)cncc3Cl)CC2)cc1
Product: CC(CCNC(=O)c1c(Cl)cncc1Cl)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N(C)C)cc2)CC1
Yield: 49.4 %

Procedure:
Using general procedure K with COMPOUND 107 (36 mg, 0.06 mmol) followed by general procedure E with the resulting acid and dimethylamine (2.0M in THF, 31 μL, 0.062 mmol) afforded COMPOUND 128 as a white solid (18 mg, 50% over 2 steps). 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.29 (d, 3H, J=5.7 Hz), 1.54-1.58 (m, 1H), 1.71-1.80 (m, 3H), 2.17-2.25 (m, 1H), 2.56-2.64 (m, 1H), 2.81-2.95 (m, 3H), 3.03 (s, 6H), 3.33-3.40 (m, 1H), 3.70-3.87 (m, 2H), 3.92 (s, 2H), 6.51 (d, 2H, J=8.7 Hz), 7.26-7.28 (m, 2H), 7.46-7.55 (m, 4H), 8.47 (s, 2H), 8.76 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 29.79, 30.85, 40.47, 43.94, 48.36, 52.30, 56.17, 60.52, 112.38, 112.61, 113.15, 119.26, 125.14, 129.54, 129.75, 129.84, 130.05, 131.11, 131.17, 141.47, 147.98, 149.42, 172.01. ES-MS m/z 607 (M+H). Anal. Calcd. for C32H36N6Cl2O2.0.6CH2Cl2: C, 59.46; H, 5.69; N, 12.76. Found. C, 59.52; H, 5.64; N, 12.41.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH3:20][O:21][C:22]([CH3:24])=[CH2:23]>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:20][O:21][C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])([CH3:24])[CH3:23]
Reactant: C=C(C)OC
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(C)(C)OC

Procedure:
2-methoxy-2-(octadecyloxy)propane was prepared by reacting stearic alcohol (0.025 mole) with 2-methoxypropene (4 equivalents) for 2 hours at 20° C. in the presence of one drop of phosphoryl chloride (POCl3) then adding 5 drops of triethylamine and distilling the excess enol ether.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=[O:18])([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:2][CH:3]=[C:4]([O:18][C:15]2[CH:4]=[CH:3][CH:2]=[CH:11][CH:6]=2)[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
Methyl 5-chloro-2-nitrobenzoate (1) is reacted with an appropriately-substituted phenol (2) and base such as potassium carbonate in a solvent such as NMP to form the corresponding phenoxy-2-nitro-benzoic acid methyl ester (3). Compound (3) is hydrolyzed upon treatment with basic solution such as NaOH in water/MeOH to provide benzoic acid (4). Benzoic acid (4) is treated with thionyl chloride in solvent such as DMF to provide an intermediate acid chloride, which upon treatment with NH4OH in solvent such as THF provides benzamide (5). The nitro-benzamide (5) can be hydrogenated in solvent such as EtOH to provide amino-benzamide (6).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([NH:16][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:25]=2)[CH:21]=[N:22]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2c1
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 159.8 mg (1.2 mmol) of 6-aminoindazole in 10 mL of 2-ethoxyethanol was added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr. After cooling, most of solvent was evaporated off and the residue was diluted with ether. The precipitate was collected by filtration and was taken into water. The aqueous suspension was neutralized to PH 7-8 by addition of sat. sodium carbonate aqueous solution and stirred for 15 min. The separated solid was filtered off and washed with water and ether. After drying in vacuo, 297.5 mg (94.3%) of the product was obtained as a deep yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 315.8. HRCIMS m/z: cacld 315.112 for C18H13N5O (M+), obsd 315.1124