Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][O:24]C3C=CC(OC)=CC=3)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)OC(C)(C)C)CCO2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepane-4-carboxylate (4.75 g) in acetonitrile (70 mL) and water (14 mL) was added ceric ammonium nitrate (16.18 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.36 g).
Reaction SMILES: CO.[OH-].[Na+].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1>CN(C)C=O>[CH3:26][C:27]1[N:28]=[C:29]([CH2:33][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[C:12]([C:11]4[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=4)[O:16][N:15]=3)=[CH:19][CH:20]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Cc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added 2-chloromethyl-6-methyl-pyridine (31.8 mg, 0.22 mmol) described in Manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 20 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36 mg, 51.7%).
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[N:4][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][N:7]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:14][C:13]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)[S:20][C:19]=1[C:18]([O:17][CH2:15][CH3:16])=[O:21]
Reactant: N#Cc1nc(-c2ccco2)cnc1Br
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 3-bromo-6-(furan-2-yl)pyrazine-2-carbonitrile 57 (1.21 g, 4.84 mmol), ethyl-2-mercaptoacetate (0.587 mL, 0.640 g, 5.32 mmol) and sodium carbonate (0.564 g, 5.32 mmol) in ethanol (20 mL) was stirred 1 h at rt, 1 h at 40° C. and 1 h at 50° C. Cooled down to −10° C., the resulting precipitate was collected, washed with cold ethanol (5 mL) and dried to give ethyl 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylate 58 (1.4 g, 100%). NMR (400 MHz, DMSO-d6) 1.32 (t, J=7.0, 3H), 4.33 (q, J=14.0 and 7.0 Hz, 2H), 6.78 (dd, J=3.5 and 2.0, 1H), 7.05 (br s, 2H), 7.47 (dd, J=3.5 and 0.8 Hz, 1H), 8.00 (dd, J=2.0 and 0.8 Hz, 1H), 9.16 (s, 1H). (m/z)=290 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:7].[H-].[Na+]>CN(C)C=O.O>[CH2:24]([N:21]1[C:18]2=[N:19][CH:20]=[C:15]([C:13]3[O:12][N:11]=[C:10]([CH2:9][N:8]4[CH2:2][CH2:3][CH2:4][CH2:5][C:6]4=[O:7])[N:14]=3)[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]2[CH:23]=[N:22]1)[CH3:25]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCCl)no3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN4CCCCC4=O)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 120 (46 mg, 0.1 mmol) in dry dimethylformamide (2 ml) was added to sodium hydride (60% dispersion in mineral oil, 4.4 mg, 0.11 mmol), and the resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with water (2 ml) and extracted with chloroform (3×5 ml). The combined organic extracts were dried over anhydrous sodium sulphate and evaporated to give the crude product. Purification of the crude product on a SPE cartridge (silica, 2 g) using a gradient of ethyl acetate in petroleum ether afforded Example 174. LCMS showed MH+=426, TRET=2.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:12]=2[N:11]=1.CN(C(O[N:31]1[N:39]=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:38]1([O:21][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:19]=2)=[O:22])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:39]1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)On3nnc4ccccc43)ccc21
Reaction time: 72 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.0 g, 3.0 mmol), TBTU (955 mg, 3.0 mmol) and TEA (835 μL, 5.9 mmol) in 15 mL DMF was stirred for 72 h. The mixture was poured onto water, the solid filtered off, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([Cl:17])=[N:12][CH:13]=[N:14][C:15]=1Cl)=[O:9].[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:18]1([C:15]2[C:10]([C:8]([C:3]3[CH:4]=[N:5][N:6]([CH3:7])[C:2]=3[Br:1])=[O:9])=[C:11]([Cl:17])[N:12]=[CH:13][N:14]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2Cl)c1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(5-Bromo-1-methyl-1H-pyrazol-4-yl)(4,6-dichloropyrimidin-5-yl)methanone (C26) (1.14 g, 3.39 mmol) was combined with azetidine (98%, 0.212 mL, 3.08 mmol) and N,N-diisopropylethylamine (0.645 mL, 3.70 mmol) in acetonitrile (30 mL) at 0° C. The mixture was then allowed to warm to room temperature and stir for 18 hours. After removal of volatiles in vacuo, the residue was purificed via silica gel chromatography (Eluent: 100:1 ethyl acetate/methanol) to afford the product. Yield: 1.07 g, 3.00 mmol, 97%. LCMS m/z 356.2, 358.2, 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.25-2.36 (m, 2H), 3.94 (s, 3H), 3.96-4.09 (br m, 4H), 7.85 (br s, 1H), 8.37 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)C.[CH2:36](Br)[C:37]1C=CC=[CH:39][CH:38]=1>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Agent: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Product: CC(C)(C)NC(=O)C(C)(C)N(OCc1ccccc1)C(C)(C)C
Yield: 92 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and benzylbromide in 92% yield as colorless oil. Elemental analysis calculated for C19H32N2O2: C 71.21%; H 10.06%; N 8.74%. Found: C 71.22%; H 10.07%; N 8.94%.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].C=CC1OC1>CCCCCC>[CH2:6]([OH:10])[CH:7]=[CH:8][CH2:9][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CCCCO
Agent: C=CC1CO1
Solvent: CCCCCC
Product: CCCCCC=CCO
Temperature: 0 °C
Yield: 49.1 %

Procedure:
A hexane solution of n-butyllithium (2.1 mmol) was cooled at 0° C. under the argon atmosphere. A hexane solution of n-butanol (75.9 mg; 1.0 mmol) was added dropwise thereto and stirred. To the resulting solution, there was further added dropwise a hexane solution of 3,4-epoxy-butene-1 (70.0 mg; 1 mmol), and after the addition was completed, the resulting mixture was cooled at 0° C. for 1 hour and at room temperature for 30 minutes, followed by the usual work up. Removal of the solvent and distillation of the residue gave 63 mg of 2-octen-1-ol (yield, 49%). After acetylation of the thus obtained product, gas chromatographic analysis (PEG 20M, 4 m) was effected at a temperature of 130° C. The retention times of Z-isomer and E-isomer were respectively 13.7 minutes and 14.7 minutes, and the Z/E ratio was 89.1/10.9.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]3[CH:30]=[CH:31][C:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27][CH:28]=3)=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc(N)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1

Procedure:
Acylation of 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [I-].[K+].[CH3:3][C:4]([CH3:6])=[O:5].ClCC(=O)C.[CH3:12][O:13][P:14]([O:17]C)[O:15][CH3:16]>C(#N)C>[O:5]=[C:4]([CH3:6])[CH2:3][P:14](=[O:17])([O:15][CH3:16])[O:13][CH3:12]
Reactant: COP(OC)OC
Reactant: CC(C)=O
Agent: CC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COP(=O)(CC(C)=O)OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
A 2-liter eggplant type flask was charged with 179.2 g (1.081 mol) of potassium iodide, 300 ml of acetone and 250 ml of acetonitrile, to which 100 g (1.081 mol) of chloroacetone were added, thereby forming a white suspension. Further, 134 g (1,081 tool) of trimethylphosphite were added to stir the resulting mixture for 6 hours at 20° C. and for 4 hours at 50° C. After the thus-obtained solution was filtered through Celite, the solvent was distilled off to obtain a product in the form of a brown oil. This oily product was subjected to fractional distillation under reduced pressure (at 81-85° C. and 0.02 mmHg) to obtain 127.5 g (yield: 71%) of dimethyl 2-oxopropylphosphonate. The result of analysis of this compound by 1H-NMP is described below.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O[Li].O>CO.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COC(=O)C1(c2ccc3onc(C)c3c2)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1noc2ccc(C3(C(=O)O)CC3)cc12
Yield: 32.2 %

Procedure:
To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (0.80 g, 19 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature overnight before the MeOH was removed by evaporation under vacuum. Water and Et2O were added and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 1H NMR (400 MHz, DMSO) δ 12.40 (br s, 1H), 7.76 (s, 1H), 7.60-7.57 (m, 2H), 2.63 (s, 3H), 1.52-1.48 (m, 2H), 1.23-1.19 (m, 2H). MS (ESI) m/z (M+H+) 218.1.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:38]=[CH:37][C:21]([C:22]([O:24][CH:25]2[CH2:30][O:29]C(C3C=CC=CC=3)[O:27][CH2:26]2)=[O:23])=[CH:20][CH:19]=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][CH3:16].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:25]([CH2:26][OH:27])[CH2:30][OH:29])=[O:23])=[CH:37][CH:38]=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][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC2COC(c3ccccc3)OC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(CO)CO)cc1

Procedure:
A mixture of 2-phenyl-1,3-dioxan-5-yl 4-(n-hexadecylamino)benzoate, palladium black, and acetic acid is shaken under one atmosphere of hydrogen until hydrogen uptake ceases. The catalyst is separated by filtration and the solvent is evaporated. Crystallization from acetonitrile affords 1,3-dihydroxy-2-propyl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCO
Product: Cc1ccc(S(=O)(=O)NCCO)cc1

Procedure:
The preparation is carried out as in Example 1(a) but this time 381.3 g of p-toluenesulphonyl chloride (2 mol) and 128.3 g of ethanolamine (2.1 mol) are used for the reaction.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[CH:16]=[N:15]2
Reactant: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(N)cnc2c1
Yield: 86.1 %

Procedure:
N-(2,4-Dimethoxybenzyl)-6-methylquinoxalin-2-amine (0.84 g, 2.72 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous Na2CO3 (200 mL) was added to the red residue, which then precipitated a tan solid. The mixture was extracted extensively with DCM. The organic layer was dried over sodium sulfate, concentrated, and dried under vacuum to afford 6-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (640 mg, 2.343 mmol, 86% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:31])[N:17]([CH2:19][C:20]4[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=4)[N:18]=[C:3]3[C:2]=2[C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 161.8 %

Procedure:
To a suspension of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (53 mg, 0.103 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.414 mmol), and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) in toluene (2 mL) was added (Ph3P)4Pd (36 mg, 0.03 mmol), and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (30-70%) in hexanes to obtain 85 mg of the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 32 mg (62%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.00 min, [M+H]+=510.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7].[F:11][C:12]1[C:17](O)=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22].C(Cl)CCl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:17]2[C:16]([F:19])=[C:15]([F:20])[C:14]([F:21])=[C:13]([F:22])[C:12]=2[F:11])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18, 2.16 g, 10.59 mmol) was dissolved an THF (10 ml). Pentafluorophenol and EDC (2.03 g, 10.59 mmol) were added and the mixture was stirred at room temperature for 6 h. The solvent was removed under vacuum and EtOAc (50 ml) was added. The organic phase was washed with water, 10% Na2CO3 (2×25 ml), water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give the title compound as an off white solid (2.23 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:36]1([CH:32]2[CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution (5 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g) and morpholine (0.14 mL) in acetic acid was added sodium cyanoborohydride (0.34 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]([F:75])([F:74])[CH2:72][NH2:73]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:35])([C:36](=[O:37])[NH:73][CH2:72][C:71]([F:75])([F:74])[F:70])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 2,2,2-trifluoroethylamine hydrochloride (25 mg, 0.185 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19 mg).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O=[CH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CO.C(OCC)(=O)C>[CH2:10]([N:9]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(I)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine (4.0 g, 9.3 mmol) and sodium cyanoborohydride (1.45 g, 23 mmol) in methanol (80 ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G.; Balme, G.; Barieux, J. J. and Gore, J.Tetrahedron, 1988, 44, 5821) (2.4 g, 18 mmol) in methanol (20 ml) over a period of 10 min. The resulting mixture was stirred at 22° C. for 24 h, and then diluted with ethyl acetate (600 ml), washed with brine (3×250 ml). The aqueous phase was extracted with ethyl acetate (150 ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 8:1 to 6:1) to afford the title compound (4.5 g, 89%) as a colorless oil.