Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10]1)=[O:8]
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(C(=O)C2CNc3ccccc3C2=O)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2CN(Cc3ccccn3)c3ccccc3C2=O)cc1C

Procedure:
Compound 4n was prepared following the procedure outlined in Step 3 of Example 1 using 32 mg (0.8 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3 mL of anhydrous dimethylformamide, and 101.2 mg (0.40 mmol) of 2-bromomethylpyridine hydrobromide. The crude product 4n was purified by flash chromatography to yield 32 mg pale yellow solid (29%): LC-MSD, m/z for C24H20N2O2, [M+H]+=369.4, [M+2H]+=370.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.084 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.32 (d, 6H), 5.50 (s, 2H), 7.1 (d, 1H), 7.2 (d, 1H), 7.25-7.3 (m, 1H), 7.3-7.5 (m, 2H), 7.54-7.62 (m, 2H), 7.62-7.7 (m, 2H), 8.34 (s, 1H), 8.4-8.5 (m, 1H), 8.62 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:11][C:4]1[CH:5]=[C:6]([C:8]([NH:28][C@@H:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:27])=[O:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: COC(=O)c1c(Cl)cc(C(=O)[O-])cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 96 %

Procedure:
A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4; 3.00 g, 12.0 mmol), (R)-(+)-1-(1-naphthyl)ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol), HOBT (2.04 g, 15.1 mmol), and diisopropylethylamine (6.20 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was back-extracted with ethyl, acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (4.52 g, 96%) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=[N:3]1>C1COCC1.[Cl-].[NH4+].[Zn]>[CH3:1][N:2]1[C:6]([C:7]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCc1ccccn1
Reaction time: 0.25 h
Yield: 144.6 %

Procedure:
To a solution of 2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy-methyl]-pyridine (158 mg, 0.37 mmol) in THF (3 mL) and saturated ammonium chloride (1 mL) was added zinc dust (192 mg, 2.96 mmol) at 0° C. The mixture was stirred at the same temperature for 15 minutes and then filtered through celite. The solution was concentrated in vacuo to give the title compound as a solid (150 mg, 100%). Exact mass calculated for C16H16N4O 280.1, found 281.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:18])[NH:13][C:14](=O)[CH2:15]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([NH:13][C:12]([O:11][CH3:10])=[O:18])[N:1]=2)[CH:4]=1
Reactant: COC(=O)NC(=O)CCl
Reactant: CSc1ccc(N)nc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(SC)ccc2n1
Temperature: 100 °C

Procedure:
A suspension of 2-amino-5-(methylthio)pyridine (0.667 mol) and methyl(chloroacetyl)carbamate (0.667 mol) in 325 ml of HMPT is heated at 100° C. for 5 hours. After dilution with 2000 ml of H2O, the product is collected by filtration, successively washed with H2O, MeOH and CH2Cl2, and dried.
Reaction SMILES: O=[C:2]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1>[N:18]1([CH2:2][CH2:3][O:4][CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCN2CCCC2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)piperidine-1-carboxylate (105)(3.5 g, 11.20 mmol) was dissolved in dry THF (50 mL), to this was added borane-methyl sulfide complex (8.40 mL, 16.81 mmol) and the reaction was stirred at 40° C. for 3 hours then at ambient temperature overnight. The gummy mixture was evaporated and was quenched with 2.0 N sodium carbonate (50 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a colourless liquid, which was taken through directly to the next stage; 1H NMR (400.132 MHz, CDCl3) δ 1.38-1.58 (m, 9H), 1.73-1.86 (m, 4H), 1.86-1.97 (m, 2H), 2.09-2.21 (m, 2H), 2.79-2.91 (m, 2H), 2.96 (t, 2H), 3.06-3.17 (m, 2H), 3.18-3.27 (m, 2H), 3.49 (septet, 2H), 3.65-3.76 (m, 2H), 3.92 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O>[N:1]([C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
73 mmol of 5-aminoisophtalic acid were placed in a beaker together with 100 mL of water. 18 mL of HCl (37%) were added dropwise. The mixture was cooled in an ice bath at 0-5° C. 75.3 mmol of NaNO2 were dissolved in 25 mL of distilled water and added dropwise to the mixture, stirring it for 30 minutes. Then, 73 mmol of NaN3 were dissolved in 25 mL of distilled water and added dropwise to the mixture. A solid was formed and gas evolution was observed, making it difficult to keep the stirring. The mixture was stirred until the evolution of gas was no longer detected. The product was then filtered off, washed with distilled water, and dried at room temperature. Yield: 85%. M.p.: 250° C.
Reaction SMILES: C(N)C=CC#CCC.[S:9]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22]Br)=[CH:10]1.[ClH:27].[CH2:28]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:29].Cl>>[ClH:27].[CH2:28]([N:30]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([CH2:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[CH:20]=1)[CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:29]
Reactant: BrCc1cccc(COC/C=C/c2ccsc2)c1
Reactant: CCNC/C=C/C#CC(C)(C)C
Agent: CCC#CC=CCN
Agent: Cl
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(COC/C=C/c2ccsc2)c1

Procedure:
Compounds of Examples 2 to 7 were obtained by s performing the same reaction as in Example 1 except that the corresponding bromomethyl or chloromethyl derivatives and/or 2-hepten-4-ynylamine derivatives were used instead of the starting compounds, (E)-3-[3--(3-thienyl)-2-propenyloxymethyl]benzyl bromide and/or (E)- N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which were used in the above-mentioned reaction. ( When the reaction product was a free base, the hydrochloride producing step in the after-treatment was not included.)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[F:33][C:9]1[CH:8]=[C:7]([C:40]2[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=2)[CH:12]=[CH:11][C:10]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Solvent: COCCOC
Product: COc1cn(-c2ccc(-c3cnn(C)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (104 mg, 0.50 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (162 mg, 81% yield) as a white solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.96 (3H, s), 6.38 (1H, t, J=8.3 Hz), 7.06 (1H, ddd, J=0.8, 1.9, 8.3 Hz), 7.23 (1H, dd, J=1.9, 12.8 Hz), 7.30 (1H, d, J=1.9 Hz), 7.36-7.47 (5H, m), 7.64 (1H, s), 7.74 (1H, d, J=0.8 Hz), 7.79 (1H, d, J=1.9 Hz), 7.81 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 443 [M+H]+. Anal. Calcd for C24H19FN6O2: C, 65.15; H, 4.33; N, 18.99. Found: C, 65.15; H, 4.30; N, 19.02.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][N:24]1[C@H:28]([CH3:29])[C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C:25]1=[O:36].Cl.[CH3:38]O>>[CH3:38][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])[CH:4]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To {4-hydroxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (1.5 g, 3.74 mmol) in MeOH was added hydrochloric acid (4N in 1,4-dioxane), and the reaction was stirred at 80° C. for 2 hours. The mixture was concentrated to dryness, and the residue was worked-up with EtOAc and saturated aqueous NaHCO3 to give the title compound.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([OH:5])=[O:4].[N+](=[CH2:28])=[N-].C(O)(=O)C>CO.CCOCC>[OH:1][CH:2]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH3:28])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
To a solution of 452 mg of 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetic acid in 5 ml of methanol is added a solution of diazomethane in ether. After the excess amount of diazomethane is decomposed with acetic acid, the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in ether. The resulting solution is washed with 10% aqueous sodium sulfate and water, dried over sodium sulfate and evaporated under reduced pressure to yield 468 mg of methyl 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetate as a mixture of erythro and threo.
Reaction SMILES: O[CH:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(S(F)(F)[F:34])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:34][CH:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(O)c2ccccc2)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(F)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(α-hydroxybenzyl)phenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.106 g, 2.77 mmol) in DCM was added DAST (0.040 mL, 3.05 mmol). The reaction was stirred overnight and poured into saturated NaHCO3 solution and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel with 2:1 DCM/EtOAc to give the title compound as a clear oil. 1H NMR: 8.47 (dd,J=4.9, 1.5 Hz, 1H), 8.33 (d,J=2.0 Hz, 1H), 7.63 (dt,J=7.8, 2.0 Hz, 1H), 7.38-7.28 (m,4H), 7.24-7.16 (m,6H), 4.89 (AofAB,d,J=14.8 Hz, 1H), 4.83 (BofABd,J=14.8 Hz, 1H), 3.07 (q,J=7.3 Hz, 2H), 1.40 (t,J=7.3 Hz, 3H). MS calcd. 384.1; MS (M+1) 385.1.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14](I)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C-:25]#[N:26].[Na+]>O1CCCC1.C(OCC)(=O)C.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.[Cu]I>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]([C:25]#[N:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: Ic1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2

Procedure:
A mixture of 3-cyclobutyl-7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E226) (250 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.029 mmol), copper (I) iodide (11 mg, 0.058 mmol) and sodium cyanide (56 mg, 1.15 mmol) in tetrahydrofuran (5 ml) was heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate, filtered through celite, washed with water then brine and dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by reverse phase HPLC to afford the title compound; MS (ES+) m/e 333 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29]>>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: Cc1cccc(Br)c1C(=O)O
Product: Cc1cccc(Br)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-bromo-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-bromo-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 240-242° C. FAB-HRMS m/e calcd for C24H24BrN3O5 (M+H) 514.0978, found 514.0965.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[NH:8][CH2:7][CH2:6][C:5]2=1.CCN(CC)CC.[NH:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32]>C1COCC1>[C:44]([O:43][C:41]([NH:29][CH2:30][C:31]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)=[O:32])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CNC(=O)OC(C)(C)C)C3c1cccc(O)c1
Reaction time: 2 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and Boc-Gly-OSu (1.2 equiv). After 2 h, the solvent was removed to give a residue, which was purified via prep-HPLC to give 3-{2-[N-(tert-butoxycarbonyl)-glycyl]-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)}phenol 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][NH:22]C(=O)OCC4C=CC=CC=4)[CH2:16]3)[C:7]=2[N:33]=1>CO.[Pd].O=[Mn]=O>[NH2:22][CH2:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:33][C:7]2=3)[CH2:16]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: O=[Mn]=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CN)C3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of phenylmethyl [((3S)-1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-3-piperidinyl)methyl]carbamate (0.37 g, 0.83 mmol) in MeOH (20 mL) was added 10% Pd/C (0.10 g). The solution was hydrogenated on a Parr apparatus at 50 PSI for 3 h. The Pd/C catalyst was filtered off, MnO2 (0.22 g, 2.48 mmol) was added, and the solution stirred at ambient temperature for 16 h. The MnO2 was filtered off and the crude material (yellowish oil) was used without further purification (0.26 g, 97% over 2 steps).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.[C:19]1([C:25]#[C:26][CH:27]=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[C:19]1([C:25]#[C:26][CH:27]([OH:28])[C:2]#[C:1][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=[CH:5][CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CC#Cc1ccccc1
Reactant: C#Cc1ccnn1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1)C#Cc1ccnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 5-ethynyl-1-phenyl-1H-pyrazole (0.500 g) in THF (20.0 mL) was added dropwise 2.5M butyllithium in THF solution (1.55 mL) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of 3-phenylprop-2-ynal (0.464 g) in THF (5.00 mL) at −78° C., the mixture was stirred for 45 min, and saturated aqueous ammonium chloride solution (10.0 mL) was added. The mixture was extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.73 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH:20]1[CH:25]=[C:24]([CH2:26][O:27][C:28](Cl)=[O:29])[C:23]([Cl:31])=[CH:22][CH:21]=1>>[Cl:31][C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][C:24]=1[CH2:26][O:27][C:28](=[O:29])[NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][C:9]2[CH:17]=[CH:18][CH:19]=[C:7]([C:2](=[O:6])[CH3:1])[CH:8]=2)[N:15]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CC1(c2cccc(Cn3ncc(N)n3)c2)OCCO1
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)c1

Procedure:
Following general procedure D (step 2) followed by B, starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-2H-[1,2,3]triazol-4-ylamine and 2-chlorobenzylchloroformate.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[NH2:14][C@@H:15]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:29]1([CH2:28][C@H:15]([NH:14][C:5]([C:4]2[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=2)[C:1]([O:12][CH3:13])=[O:11])=[O:7])[CH2:16][N:17]([CH3:27])[C:18]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of mono-methyl isophthalate (0.3230 g, 1.79 mmol, 1.0 equiv), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylmethylcarbamate (0.5573 g, 1.77 mmol, 0.99 equiv), EDC (0.6200 g, 1.8 equiv), HOBT (0.4035 g, 1.66 equiv), and DIEA (3.6 mL, 11 equiv) in CH2Cl2 (20 mL) was stirred at rt for 18 h. The reaction mixture was quenched with 10% aq Na2CO3, extracted with CH2Cl2 and dried over Na2SO4. After the solvent was removed, the crude (S)-methyl 3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoate (1.397 g) was used in the next step without further purification. LC-MS (3 min) to=2.29 min, m/z 499 (M+Na+), 449, 359.