Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([S:12]C(=O)N(C)C)[CH:6]=[CH:5][C:4]=2[CH2:3]1.[OH-].[K+].Br[C:21]([CH3:30])([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[BH4-].[Na+]>CO>[C:25]([O:24][C:22](=[O:23])[C:21]([S:12][C:7]1[CH:6]=[CH:5][C:4]2[CH2:3][CH:2]([NH2:1])[CH2:11][CH2:10][C:9]=2[CH:8]=1)([CH3:30])[CH3:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CCC(N)C2
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CCC(N)C2
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To dimethylthiocarbamic acid S-[6-amino-5,6,7,8-tetrahydronaphthalen-2-yl) ester (6.1 g; 24.4 mmol), dissolved in MeOH (25 mL) is added a solution of KOH (4.1 g; 73.2 mmol) in MeOH (25 mL) at RT. The solution is stirred at reflux for 5 h and cooled to RT. tert-Butyl 2-bromoisobutyrate (16.3 g; 73.2 mmol) is added to the solution and stirred for 16 h at RT. NaBH4 (9.2 g; 2.44 mol) is added and the reaction is stirred for an additional 48 h at RT. The reaction is quenched with H2O, the solvent evaporated under reduced pressure, and the crude residue partitioned between H2O and CH2Cl2. The aqueous phase is extracted with CH2Cl2 and the combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford 4.7 g (60%) of 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a brown oil. LC/MS: C181H27NO2S: m/z 266 (M+1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13](N(CC)CC)C.CO>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a mixture of indole-5-carboxylic acid (3.0 g) and triethylamine (1.9 g) in dry THF (100 mL) was added 1,1-carbonyldiimidazole (3.08 g). The mixture was stirred for 30 minutes at room temperature, at which time methanol (25 mL) was added. The mixture was stirred at room temperature for 1 h, partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (200 mL) using CH2Cl2 as eluent to give 0.794 g of the title compound: 1H NMR (CDCl3) δ 3.93, 6.66, 7.28, 7.41, 7.91, 8.34, 8.42.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][C:9]3=[N:10][N:11]=2)[CH2:2]1.Cl[C:16]1[N:21]=[C:20]([NH2:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[N:10]1[N:11]=[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:16]3[N:21]=[C:20]([NH2:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=3)[CH2:2]2)[N:8]2[CH2:14][CH2:13][CH2:12][C:9]=12
Reactant: C1CNCC(c2nnc3n2CCC3)C1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCCC(c3nnc4n3CCC4)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (900 mg, 4.68 mmol) in acetonitrile (50 mL) was added 6-chloro-3-nitropyridin-2-amine (730 mg, 4.2 mmol) and triethylamine (1.42 g, 14.04 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at reflux, then allowed to cool down to room temperature and stirred for 16 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate, concentrated under reduced pressure and purified via column chromatography to afford the title compound (1.0 g, 64.9%). MS (ES+) (M+H) 330.33; LCMS retention time: 2.85 min (Method S).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24].[Cl-].[CH3:26][O:27][C:28]([CH2:30][NH3+:31])=[O:29].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O>[CH3:26][O:27][C:28](=[O:29])[CH2:30][NH:31][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24]
Reactant: COC(=O)C[NH3+]
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCBr)c4ccccc43)c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)CNCCn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
1-(2-Bromo-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (30 mg, 0.075 mmol) is dissolved in CH3CN (0.5 mL)) and Methoxycarbonylmethyl-ammonium chloride (11 mg, 0.09 mmol) and Et3N (0.025 mL, 0.18 mmol) are added. The mixture is first stirred at room temperature for 16 hr. And then 11 mg of Na2CO3 is added and the mixture is stirred at room temperature for another 48 hr. Since the reaction is not completed, another 11 mg of Methoxycarbonylmethyl-ammonium chloride, 0.025 mL of Et3N and 11 mg of Na2CO3 are added. The mixture is then heated at 80° C. for 20 hrs. Then 10 mL of water is added and the mixture is extracted with EtOAc (3×15 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 30 mg (98%) of {2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethylamino}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:10]#[C:11][CH3:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH:9]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:17][CH:18]=1)[C:10]#[C:11][CH3:12])[C:3]([O:2][CH3:1])=[O:20]
Reactant: CC#CC(c1ccc(N)cc1)C(C(=O)OC)C(=O)OC
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CC(c1ccc(NCc2cccc(-c3ccccc3)c2)cc1)C(C(=O)OC)C(=O)OC
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A mixture of compound 35.2 (1.0 mmol), 3-(bromomethyl)biphenyl (1.3 mmol) and K2CO3 (2.0 mmol) in DMF (10 ml) was stirred at 90° C. for 19 h. After diluting with ethyl acetate, the mixture was washed with aqueous Na2CO3 and then with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate=2/1) to give compound 35.3.
Reaction SMILES: C1(C)C=C[C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=CC=1.Br>C(O)(=O)C>[CH3:4][S:7]([N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCNCCNCC1
Yield: 62.5 %

Procedure:
A mixture of 1,4,-bis-(p-toluenesulfonyl)-7-methanesulfonyl-1,4,7-triazacyclononane (38.8 g, 0.08 mol) 800 mL of glacial acetic acid and 150 mL of 48% hydrobromic acid was refluxed for 72 hours. The reaction solution was cooled to 25 C. and most of the solvents were removed under reduced pressure. Then 50 mL of 48% hydrobromic acid were added and the solvents were again evaporated. This procedure was repeated two more times to remove acetic acid. A mixture of 100 mL of absolute ethanol and 200 mL of diethyl ether was added and the solids were filtered. The solids were combined with sodium hydroxide pellets (18.0 g, 0.45 mol) in 250 mL of toluene and the mixture was refluxed for 15 hours. The remaining solid was filtered and washed with 75 mL of hot toluene. The filtrate was concentrated to a volume of 60 mL and allowed to cool slowly to 25 C. The colorless crystals were filtered and dried to give 1-methanesulfonyl-1,4,7-triazacyclononane (11.1 g, 0.05 mol, 71%).
Reaction SMILES: C(Cl)(Cl)[Cl:2].O[CH:6]([N:14]1[CH:17]([S:18][CH2:19][C:20]#[C:21][CH3:22])[CH:16]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]1=[O:43])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.S(Cl)(Cl)=O>O1CCCC1.O1CCOCC1>[Cl:2][CH:6]([N:14]1[CH:17]([S:18][CH2:19][C:20]#[C:21][CH3:22])[CH:16]([NH:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15]1=[O:43])[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: ClC(Cl)Cl
Reactant: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(C)(C)C

Procedure:
vmax (CHCl3) 3400, 1765, 1730 cm-1. iv. 1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (0.44g) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (10ml) and the solution, under nitrogen, was cooled to -10°. Pyridine (0.2g) in dry dioxan (2.5ml) was added, followed by the dropwise addition of thionyl chloride (0.19ml) in dioxan (2.5ml) over 2-3 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added to the residue and decanted off from any solid. The organic solution was evaporated to dryness and re-evaporation from dry ether gave 1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous solid (0.45g).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:19]([CH3:30])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:31].O.O[Li].O>C1COCC1>[CH3:34][C:2]([CH3:1])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:19]([CH3:30])[CH:18]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:31]
Reactant: CCOC(=O)COc1ccc(C(CC)(CC)c2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Compound 5 (50.0 mg, 0.1066 mmol) was dissolved in THF (1.0 mL) and H2O (0.5 mL) and LiOH.H2O (9.0 mg, 0.2133 mmol, 2.0 equiv.) was added. After stirring for 2 h, the reaction was quenched by the addition of sat. aq. NH4Cl solution and diluted with H2O. The resulting mixture was extracted with EtOAc (×3), and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by preparative tlc (1:5:94 AcOH/MeOH/CH2Cl2) to afford the title acid 6 (31.4 mg, 67%)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1ccc(Cl)nn1
Product: COc1cc(-c2ccc(C)nn2)ccn1
Yield: 45.5 %

Procedure:
3-Chloro-6-methylpyridazine (343 mg, 2.67 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (470 mg, 2.0 mmol) were reacted according to Example 31 (step a) to provide the title compound (183 mg, 45%) as a cream solid: 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J=5.3 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.59 (dd, J=5.3, 1.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl-].[Cl-].[CH3:6][C:7]([CH3:30])([CH3:29])[CH2:8][C:9]1[N:10]=[C:11]([CH:14](F)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][NH+:23]=3)=[CH:18][CH:17]=2)[NH2+:12][CH:13]=1>O1CCCC1>[CH3:6][C:7]([CH3:30])([CH3:29])[CH2:8][C:9]1[N:10]=[C:11]([CH:14]([NH:3][CH2:1][CH3:2])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[NH:12][CH:13]=1
Reactant: CC(C)(C)CC1=C[NH2+]C(C(F)Cc2ccc(-c3cccc[nH+]3)cc2)=N1
Reactant: CCN
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCNC(Cc1ccc(-c2ccccn2)cc1)c1nc(CC(C)(C)C)c[nH]1
Temperature: 25 °C

Procedure:
Ethylamine (2 M in tetrahydrofuran) (excess) was added to an ambient temperature solution of 2-(4-{2-[4-(2,2-dimethylpropyl)-1H-imidazol-1-ium-2-yl]-2-fluoroethyl}phenyl)pyridinium dichloride (for synthesis see Example 2) (10 mg, 0.03 mmol) in tetrahydrofuran (3 mL). After stirring at ambient temperature until no further reaction (LCMS), the reaction mixture was concentrated. Preparative plate chromatography eluting with 40% methanol/ethyl acetate afforded the title compound. (M+H) found: 363.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CCCCCC>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Br
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of 23.0 g (120 mmole) of 4-bromochlorobenzene in 150 ml of dry tetrahydrofura: was cooled to -78° C. under nitrogen and 78 ml (120 mmole) of 1.55M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 14.0 ml (120 mmole) of 2-bromo-benzaldehyde was added and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 75 ml portions of 1.0M sodium bisulfite, followed by 50 ml of 1.0M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 35.3 g (99%) of crude 2-bromo-α -(4-chlorophenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[C:7]1=[O:25].[CH3:30]O.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:30][O:18][C:17](=[O:19])[CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:25])[N:6]([CH2:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: CO
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
(R)-3-(1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(thiophen-2-yl)propanoic acid (0.631 g, 0.00151 mol;) was dissolved in Methanol (10 mL, 0.2 mol;) and cooled to 0 C. Thionyl chloride (600 uL, 0.008 mol;) was then added and the reaction was allowed to warm up o/n. LC-MS showed the formation of product at 1.63 432.97. The reaction was diluted with methylene chloride then washed 1× with sodium bicarbonate and 1× with brine before drying and concentration. The reaction was then concentrated and dissolved in methylene chloride for purification by combiflash using a 0-100 hexanes/ethyl acetate gradient. ES (+) MS m/e=432.97
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:14][CH2:13][C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1oc(CO)c(Br)c2ccccc12
Reactant: OB(O)c1ccccc1
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: [Cs+]
Product: O=c1oc(CO)c(-c2ccccc2)c2ccccc12
Yield: 26.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, starting from 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.8 g, 3.14 mmol), phenylboronic acid (0.467 g, 3.83 mmol), Pd(PPh3)4 (0.181 g, 0.379 mmol) and Cs2CO3 (3.29 g, 10.11 mmol) to afford the title compound (210 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C@H:8]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@H:8]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[C:9]([OH:11])=[O:10])=[CH:28][CH:29]=1
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)O)cc1

Procedure:
A solution of 1.62 g (4.08 mmoles) of benzyl 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionate (prepared as described in Preparation 14) in 50 ml of ethanol was stirred at room temperature for 4 hours in the presence of 160 mg of 10% w/w palladium-on-charcoal and under an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCc1ccccc1C(F)(F)F
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccccc3C(F)(F)F)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.4. HPLC (Condition A), Rt: 4.78 min (HPLC purity: 95.4%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:39]([CH2:41][C:42](O)=[O:43])#[N:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:39]([CH2:41][C:42]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:43])#[N:40]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (75 mg, 0.14 mmol) was dissolved in 4 mL DMF. To it were added 2-cyanoacetic acid (36 mg, 0.42 mmol), DIEA (250 μL, 1.40 mmol) and then PyBOP (150 mg, 0.28 mmol). The mixture was stirred at RT for 45 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (500), as HCl salt (76 mg). LC-MS (ESI): m/z (M+1) 575.3. UV: λ=262, 329, 337 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=1)[CH:6]=[N:5]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: NCc1cccc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: Clc1cccc(CNc2cnc3cc(Br)ccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-Bromo-2-chloro-quinoxaline (0.3 g, 1 eq., 1.23 mmol) in DMSO (9 mL), was added 3-chloro benzyl amine (0.87 g, 5 eq., 6.2 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (60 mL) was added and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The organic layer was concentrated under vacuum to obtain the crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.Br[C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1[CH3:39]>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]([CH2:39][C:32]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][CH:31]=2)[CH:7]=[N:8][CH:9]=1
Reactant: Cc1ccc(C#N)cc1Br
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (8.00 g, 20.9 mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4. 10g, 20.92 mmol) and heated at 55° C. for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at 55° C. for 18 hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30 min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75 ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCO3 (300 ml) and CH2Cl2 (300 ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid: