Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:20])OC1C=CC=CC=1.[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CS(C)=O.O>[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:38])([F:39])[F:37])[N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Nc1ccc2ccccc2n1)Oc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)nc1SC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)nc1SC1CCCCC1)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
Phenyl quinolin-2-ylcarbamate (A) (60 mg, 0.23 mmol) and (2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methanamine (69 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.06 mL, 0.45 mmol) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(quinolin-2-yl)urea (example compound II) (55 mg, 53%).
Reaction SMILES: C(NCCO)C1C=CC=CC=1.Cl.ClCCNCC1C=CC=CC=1.S(Cl)(Cl)=O.Cl.C(NCCNC1C=CC=CC=1C)C1C=CC=CC=1.NC1C(C)=CC=CC=1.BrC(CBr)C(N)=O.[CH2:62]([N:69]1[CH2:74][CH2:73][N:72]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[CH3:81])[CH2:71][CH:70]1[C:82](=[O:84])[NH2:83])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.[H][H]>C(Cl)Cl.CO.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:62]([N:69]1[CH2:74][CH2:73][N:72]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[CH3:81])[CH2:71][CH:70]1[C:82](=[O:84])[NH2:83])[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1.[C:82]([CH:70]1[CH2:71][N:72]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[CH3:81])[CH2:73][CH2:74][NH:69]1)(=[O:84])[NH2:83]
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Agent: Cc1ccccc1NCCNCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1N
Product: Cc1ccccc1N1CCNC(C(N)=O)C1

Procedure:
2-Benzylaminoethanol (20 g, 0.13 mol) was converted to N-(2-chloroethyl)-N-benzylamine hydrochloride with thionyl chloride (31 g, 0.26 mol) according to the procedure described in J. Chem. Soc. 1955, p. 896. N-(2-chloroethyl)-N-benzylamine hydrochloride (4.0 g, 19 mmol) was converted to N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride by the procedure of Syn. Comm., 1988, vol. 18, p. 45-50, using o-toluidine (6.1 g, 57 mmol) in place of aniline. 1-Benzyl-2-carbamoyl-4-(2-methylphenyl)-piperazine was prepared from 2,3-dibromopropionamide (7.9 g, 34 mmol) by the procedure of J. Med. Chem., 1992, vol. 35, p. 743-750 using N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride (4.95 g, 18 mmol) in place of N-benzyl-N'-phenyl-1,2-diaminoethane hydrochloride (TLC: Rf=0.51 (5% methanol in methylene chloride; FABMS: M+H @ m/e=310). 1-Benzyl-2-carbamoyl-4-(2-methyl-phenyl)piperazine (2.64 g, 8.53 mmol) and palladium hydroxide/carbon (430 mg) were combined in a mixture of methanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere of hydrogen at 55 psi for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was reconcentrated in vacuo from ether three times to provide 2-carbamoyl-4-(2-methylphenyl)piperazine as a solid.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C2C(=CC=CC=2)CCC1.[Pd]>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1=C(Oc2ccccc2)CCc2c(/C=C/c3ccccc3)n[nH]c21
Agent: [Pd]
Solvent: c1ccc2c(c1)CCCC2
Product: C(=C/c1n[nH]c2cc(Oc3ccccc3)ccc12)\c1ccccc1
Temperature: 155 °C
Yield: 55 %

Procedure:
A suspension of 3-(E-styryl)-6-phenoxy-4,5-dihydro-1H-indazole (200 mg, 0.64 mmol) and 5% Pd/C, (200 mg) in 10 mL of tetralin was heated at 155° C. for 18 h. The catalyst was removed by filtering the hot solution and washed with THF, EtOAc and MeOH. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to provide 3-(E-styryl)-6-phenoxy-1H-indazole as an off-white solid (110 mg, 55%). 1H NMR (DMSO-d6) δ 6.96 (s, 2H), 7.10 (d, 2H, J=7.7 Hz), 7.20 (t, 1H, J=7.1 Hz), 7.30 (t, 1H, J=7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, J=7.5 Hz), 8.20 (d, 1H, J=9.2 Hz), 12.90 (s, 1H). Anal. Calc. for C21H16N2O.0.1H2O: C, 80.28; H, 5.20; N, 8.92. Found: C, 80.20; H, 5.21; N, 8.93.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C@H:3]1[C:9]([OH:11])=O.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=1.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.N>C(Cl)Cl.CO>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:9]([C@@H:3]2[CH2:4][C:5]([CH3:7])([CH3:8])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:17][CH:18]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CC(C)(C)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(C)(C)C[C@H]1C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of Intermediate 87a (1.70 g, 5.00 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (600 mg, 5.00 mmol) and DIPEA (1.29 g, 10.0 mmol) in DCM was added HATU (2.28 g, 6.00 mmol) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow oil (950 mg, 71%). 1H NMR (400 MHz, CDCl3): 1.13 (3H, s), 1.15 (3H, s), 1.74 (1H, dd, J 12.5, 6.2), 2.12 (1H, dd, J 11.6, 10.0), 2.29 (1H, d, J 8.9), 2.46 (3H, s), 2.88 (1H, d, J 8.9), 3.15 (1H, dd, J 9.7, 6.5), 6.56-6.65 (2H, m), 7.28 (1H dt, J 8.6, 2.9), 8.03 (1H, d, J 2.5), 9.09 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH:13]C(=O)C(F)(F)F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH2:8][CH3:9])[NH2:13]
Reactant: CCc1cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1cc([N+](=O)[O-])c(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 1.4 g (4.7 mmol) of 33 and 10 mL of 7% K2CO3 in methanol/H2O (3:2) was stirred at room temperature for 2 h. It was diluted with 15 mL of water, filtered, washed with water, and dried to leave 691 mg (73%) of a yellow solid; mp 100-101° C.; (Lit. 104-106° C. Lambooy & Lambooy, supra). 1H NMR (CDCl3), 1.228 (t, 3, J=7.5), 2.665 (q, 2, J=7.5), 5.957 (sb, 2), 6.859 (s, 1), 7.995 (s, 1).
Reaction SMILES: N([O-])=O.[Na+].Cl.[NH2:6]C1C=CC=CC=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21].[OH-].[Na+].O.NN>O.[Ni]>[Cl:20][C:19]1[C:14]([Cl:13])=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=1[NH2:6]
Reactant: Nc1ccccc1
Reactant: Oc1cccc(Cl)c1Cl
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Product: Nc1ccc(O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
At 0-5° C., a solution of 7.3 g (0.105 mol) of NaNO2 in 22 ml of H2O is added dropwise to 50 ml of aqueous HCl (15%) and 9.3 g (0.1 mol) of aniline in a 250 ml two-neck flask fitted with internal thermometer and magnetic stirrer. After 30 min, this diazonium salt solution is added slowly at 5-10° C. to a solution of 16.4 g (0.1 mol) of 2,3-dichlorophenol and 12.4 g (0.31 mol) of NaOH in 100 ml of H2O. The suspension is allowed to warm to room temperature and stirred for a further 1 h, and 0.5 g of Raney nickel are then added. 6 g (0.06 mol) of hydrazine hydrate are then added at 40-50° C. over a period of 2 h. After the addition, stirring is continued for 1 h and the solution is filtered over a bed of silica gel. With cooling, the solution is then adjusted to pH=5.7 with 20% strength HCl. The precipitated solid is washed with 50 ml of water and 50 ml of toluene and dried. 16.8 g (94.3% of theory) of pure 2,3-dichloro-4-hydroxyaniline are obtained.
Reaction SMILES: C([NH:4][C:5]1([CH2:13][NH:14]C(=O)C)[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2)(=O)C.[ClH:18]>O>[ClH:18].[ClH:18].[NH2:4][C:5]1([CH2:13][NH2:14])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2
Reactant: CC(=O)NCC1(NC(C)=O)CC2CCC1CC2
Agent: Cl
Solvent: O
Product: NCC1(N)CC2CCC1CC2

Procedure:
The procedure is as Example 1, but starting from 2-acetylamino 2-acetylaminomethyl-bicyclo[2.2.2]octane (4.6 g) in a 6N solution (100 cc) of hydrochloric acid in water for 48 hours under reflux; taking up the residue from the evaporation in ethanol (25 cc) and diethyl ether (75 cc), 2-amino-2-aminomethyl-bicyclo[2.2.2]octane dihydrochloride (3 g) is obtained in the form of white crystals which melt at 302°-303° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (251 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (74.8 mg, 33%) as a pale-brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:12]1([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCN2CCOCC2)cc1

Procedure:
The mixture containing 4-[2-(4-nitrophenyl)ethyl]morpholine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(2-morpholin-4-ylethyl)phenylamine. MS: MH+=206.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[N:22][N:23]=3)[CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.[ClH:32].C(OCC)(=O)C>>[ClH:32].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[N:22][N:23]=3)[CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1nnc2ccc(-c3cccc(NC(=O)OC(C)(C)C)c3)cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nnc2ccc(-c3cccc(N)c3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 6-(3-(tert-butoxycarbonylamino)phenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (78 mg, 0.19 mmol) in HCl/ethyl acetate (2M, 20 mL) was stirred at room temperature for about 3 h. The mixture was concentrated under reduced pressure to give the crude compound. It was recrystallized in MeOH/ethyl acetate to give the title compound (9.8 mg, 15% yield) as yellow solids. 1H NMR (DMSO-d6): 8.36 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.78-7.60 (m, 5H), 7.49 (d, J=6.9 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.23 (t, J=6.6 Hz, 1H), 3.92 (s, 3H). MS: m/z 317.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[C:11][Si:10]([CH3:14])([CH3:13])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-2-methyl-pyridine and 2.3 mL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N-:28]=[C:29]=[O:30].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])[NH2:28])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [N-]=C=O
Reactant: Cc1c(C(=O)c2ccc(N)cc2)c2ccccc2n1CCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C(=O)c2ccc(NC(N)=O)cc2)c2ccccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 12.0 g. (0.03 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]- 1H-indole (Example 4B) in 15 ml of glacial acetic acid and 30 ml. of water was added a solution of 4.5 g. (0.06 mole) of sodium isocyanate in 30 ml of water. The mixture was stirred at room temperature for two hours, then diluted with water and made alkaline with 10% sodium hydroxide The solid which separated was collected and recrystallized from DMF to give 5.9 g (48%) of 2-methyl3-(4-carbamylaminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m p. 192°-202° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C@@H:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O.CN1CCOCC1.[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C@@H:3]([N:2]([CH3:1])[CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:23][CH:22]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A solution of (S)-2-dimethylamino-4-methyl-pentanoic acid (433 mg, 2.72 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (809 mg, 2.72 mmol) in dry DMF (12 mL) was treated with Triton® B (1.80 mL, 3.96 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.). The clear solution was cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.03 g, 2.72 mmol) was then added. After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 15 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether, white precipitate forms and was removed by filtration. The filtrate was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (5% MeOH in 1:1 EtOAc/hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 361 mg (30%) of the pure titled compound as a white foam; mp 60-72° C. APCI-MS m/z 403.3 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18](=[O:34])[CH2:19][CH:20]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2)[C:21](O)=[O:22])([CH3:16])([CH3:15])[CH3:14].C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:21](=[O:22])[CH:20]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]=[CH:29]3)[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:34])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C)OC(=O)CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and 4-tert-butoxy-2-(5-isoquinolinyl)-4-oxobutanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 447 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 1.23 (s, 9H), 1.25 (s, 9H), 2.71 (dd, 1H), 3.02 (dd, 1H), 4.22 (m, 2H), 4.71 (m, 1H), 6.57 (s, 1H), 7.08 (d, J 8.5, 2H), 7.24 (d, J 8.5, 2H), 7.67 (m, 1H), 7.78 (m, 1H), 8.03 (d, J 7.8, 1H), 8.13 (d, J 7.1, 1H), 8.55 (d, J 6.8, 1H), 8.63 (m, 1H), 9.31 (s, 1H); Anal. Calcd for C28H34N2O3+1CH3CN+0.8H2O: C, 71.77; H, 7.75; N, 8.37. Found: C, 71.64; H, 7.38; N, 8.16.
Reaction SMILES: [OH:1][C:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/[OH:25])/[NH2:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([O:12]CC)=[O:11])[CH2:5]1.[C:26]1([C:32]2[C:36]([C:37]([F:40])([F:39])[F:38])=[C:35]([C:41](F)=O)[O:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[OH:1][C:2]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:41]([C:35]3[O:34][N:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:36]=3[C:37]([F:40])([F:38])[F:39])[O:25][N:24]=2)=[CH:20][CH:21]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5]1
Reactant: CCOC(=O)[C@H]1CCCN(CC(C)(O)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CN1CCC[C@H](C(=O)O)C1)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
To a mixture of (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)propyl)piperidine-3-carboxylate (72 mg, 0.206 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (53.4 mg, 0.206 mmol) in acetonitrile (5 mL) was added DIEA (0.072 mL, 0.412 mmol). After 2 hr, TBAF in THF (0.206 mL, 0.206 mmol) was added and the reaction was stirred overnight at RT. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass and concentrated in vacuo. The residue was treated with 6N HCl with MeCN as a co-solvent and heated at 50° C. for 4 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 12 mg of (35)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.10-8.19 (2H, m), 7.68-7.80 (2H, m), 7.59 (2H, d, J=6.59 Hz), 7.44-7.56 (3H, m), 3.59-3.81 (2H, m), 3.31-3.53 (2H, m), 3.01-3.19 (1H, m), 2.73-3.00 (2H, m), 1.73-2.12 (2H, m), 1.60 (3H, d, J=15.82 Hz), 0.68-1.45 (3H, m). HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]([CH3:29])=[CH:22][C:23]=1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=O>>[CH3:29][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH2:13]>C1COCC1>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:13][CH3:12])=[O:6]
Reactant: CN
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3-Methyl-2-aminobenzoic acid (3.43 g, 22.7 mmol) and N,N′-carbonyldiimidazole (4.05 g, 24.9 mmol) were stirred in THF at 40° C. for 3 hours. After cooled to room temperature, methylamine (2.0 M in THF, 22.7 ml) was added thereto, and further stirred for 1 hour at room temperature. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (3.43 g, yield 92%) as a milky white solid.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=CC=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1>>[C@@H:10]12[CH2:9][C@@H:5]1[CH2:6][N:8]([CH2:6][CH2:5][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=1)[CH2:2]2
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: NC(=O)c1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCCCN2C[C@H]3C[C@H]3C2)cc1

Procedure:
The experimental procedure is the same as Steps 1 and 2 of Example 3, but replacing the 4-hydroxybenzamide in Step 1 by N-(4-hydroxyphenyl)acetamide.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:17][C:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.[OH-].[Na+]>C(Cl)Cl.O>[OH:9][CH2:8][C@H:7]([NH:10][C:21]([C:18]1([Br:17])[CH2:20][CH2:19]1)=[O:22])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)C1(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H](CO)c1ccccc1)C1(Br)CC1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
739 mg of D-(−)-α-phenylglycinol is dissolved in 27 ml of methylene chloride, and 678 mg of sodium carbonate is added to 11 ml of water and 1.09 g of acid chloride 107 at room temperature. It is stirred overnight and then mixed with methanolic sodium hydroxide solution, the organic phase is separated, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.09 g of (1R)-1-bromocyclopropanecarboxylic acid-2-hydroxy-1-phenylethylamide 110 is isolated as a colorless oil.