Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH:8]1[C:23]([O:25][CH3:26])=[O:24])(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.CCO.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:29][C:30]1[CH:31]=[C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][C:8]=2[C:23]([O:25][CH3:26])=[O:24])[CH:33]=[CH:34][C:35]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
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: CCOCC
Solvent: CCO
Product: COC(=O)C1=C(c2ccc(C(F)(F)F)c(Cl)c2)CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 3-methyl 1-(phenylmethyl) 4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3 g) (P38) and [3-chloro-4-(trifluoromethyl)phenyl]boronic acid (1.826 g) in dry toluene (37 mL) under N2 atmosphere at 0° C., Pd(PPh3)4 (292 mg) dissolved in absolute EtOH (26 ml), was added followed by Na2CO3 2M (21 mL). The reaction mixture was heated to 80° C. for 2 h. Et2O was then added to the solution and the organic phase was separated. The aqueous layer was extracted with Et2O and the combined organic phases were washed with saturated NaCl aqueous solution, dried and concentrated under vacuum. The crude was purified by flash-chromatography (eluting with cyclohexane/ethyl acetate from 9:1 to 8:2) to give the title compound (3.03 g).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:10][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][C@H:4]1[O:5][CH2:6][CH2:7]2.CC(C)=[O:21].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O>[C:14]([O:13][C:12]([NH:11][C@@H:9]1[CH2:8][C@H:4]2[O:5][CH2:6][CH2:7][C@@:3]2([C:2]([OH:21])=[O:1])[CH2:10]1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product of Step H (426 g, 1.57 mol) and acetone (8.1 L) was added Jones reagent (710 mL) over 1 h 20 min. The resulting suspension was stirred at rt for 1 h, after which isopropyl alcohol (40 mL) was added, and the reaction stirred for 25 min at rt. Water was added, and the water/acetone was decanted off and evaporated. The insoluble material was dissolved separately in water and extracted with CH2Cl2. The green water/acetone concentrate was extracted with CH2Cl2 and the combined organic extracts were washed with brine, diluted with water and EtOAc and the organic layer was dried with Na2SO4. The organic layer was filtered, concentrated and the product was crystallized from MeCN, and the product of Step I was isolated by filtration as a white solid. 1H NMR (400 MHz, DMSO-d6) d=12.39-12.59 (m, 1H), 6.85-7.02 (m, 1H), 4.28 (d, J=5.4 Hz, 1H), 3.89-3.97 (m, 1H), 3.79-3.85 (m, 1H), 3.43-3.51 (m, 1H), 3.30-3.36 (m, 1H), 2.35-2.42 (m, 1H), 1.90 (d, J=11.0 Hz, 3H), 1.59-1.70 (m, 1H), 1.42-1.50 (m, 1H), 1.37 (s, 9H). Elemental anal calc for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.34; H, 8.18; N, 5.08 mp: 147.4-149.1° C.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][N:30]=3)[C:27]=2[OH:28])=[C:19]([CH3:38])[CH:18]=1)#[N:16].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(#N)C>[OH:28][C:27]1[N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:35])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][C:19]=1[CH3:38]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)CC3)cn2)c1O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Combined EDC (599 mg, 3.12 mmol), HOBT (211 mg, 1.561 mmol) and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.561 mmol) in DMF (10 ml) and added 1-methylpiperazine (519 μl, 4.68 mmol) and DIPEA (818 μl, 4.68 mmol) and the solution was stirred at 20° C. overnight. The reaction mixture was then purified by preparative HPLC (15-40% ACN in water under basic conditions) to give the free base, which was suspended in acetonitrile (28 mL) and treated with 1N aqueous hydrochloric acid (2.341 mL, 2.341 mmol). The resulting cloudy mixture was heated until cleared and allowed to cool to ambient temperature. The mixture was filtered and the filtrate was cooled to 0° C. and filtered again. The filtrate was diluted with ethyl ether (10 mL) to give a solid and the mixture was heated until all solids dissolved, and then cooled to ambient temperature to give a solid. The mixture was cooled to 0° C. and filtered, and the solid was dried in vacuum at 80° C. for 1 hour to give the title compound as a hydrochloride salt (94 mg, 13.7%) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3 H) 2.79 (s, 3 H) 3.16 (br. s., 4 H) 3.64-4.57 (m, 4 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.12 (d, J=7.33 Hz, 1 H) 8.21 (br. s., 1 H) 8.51 (br. s., 1 H) 8.57-8.61 (m, 1 H); ESI-MS m/z (M+H)+ calc'd for C22H22N6O2, 403.18; found 403.2.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC(Cl)C.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Cl-].[Cl-].[Al+3].Cl>O>[C:24]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=1[CH2:13]2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2

Procedure:
A mixture of 130 g. of methyl 7-methylxanthene-2-carboxylate in 200 ml. of dichloroethane is cooled to -5° C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. The resultant solution is stirred at room temperature for 1.75 hours. After this time, the solution is poured into a mixture of 300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloric acid. The mixture is then extracted with three 500 ml. portions of methylene chloride. The combined extracts are washed with 10% aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 5-acetyl-7-methylxanthene-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:8][C:9]2[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=2[N:11]=1.O(Cl)Cl.O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[CH:26]([C:6]1[N:2]([CH3:1])[C:3]([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:5]=1)=[O:27]
Reactant: Cn1cccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CN(C)C=O
Agent: ClOCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(C=O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 2-(1-methylpyrrol-2-yl)-5,6-dichlorobenzimidazole (65 mg, 0.24 mmol) in dimethylformamide (2 mL) was added phoshorus oxychloride (0.067 mL, 0.72 mmol), and the mixture was stirred at room temperature for 24 h. Water and aqueous sodium hydroxide (1.0 mol/L) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-(2-formyl-1-methylpyrrol-5-yl)-5,6-dichlorobenzimidazole (50 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.O[N:41]1[C:45]2C=[CH:47][CH:48]=[CH:49][C:44]=2N=N1.C(N(CC)C(C)C)(C)C.N1CCCCC1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:41]3[CH2:47][CH2:48][CH2:49][CH2:44][CH2:45]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:27][CH:28]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCCCC2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and piperidine (50 μL, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% hexanes to 50% ethyl acetate:hexanes. Yield: 86 mg (White solid)
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Yield: 28.4 %

Procedure:
tert-Butyl 3-hydroxypiperidine-1-carboxylate (4.38 g) (21.76 mmol), phthalimide (4.82 g, 32.76 mmol), and triphenylphosphine (8.62 g, 32.86 mmol) were added to tetrahydrofuran (60 ml), 40% diethyl azodicarboxylate-toluene solution (15 ml) was slowly added at room temperature with stirring, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with diethyl ether, and the precipitated colorless solid was filtered off. The mother liquor was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.04 g, yield 28%) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH3:11])=[CH:6][CH:5]=1.[Li]>C1COCC1>[CH:3]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH3:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C1CC1)c1ccc(C=O)cc1
Temperature: 50 °C

Procedure:
To 1.95 g (7.89 mmol) 4-[1-(S)-(cyclopropanecarbonyl-amino)-ethyl]-benzoic acid methyl ester in 20 mL THF are added slowly 685 mg (31.6 mmol) lithium borhydride and stirred at 50° C. over night. The reaction is quenched by the addition of a sat. aq. NaHCO3-solution and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 29.5 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (100 mg, 0.27 mmol), commercially available 2-aminopyridine (30 mg, 0.31 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (40 mg, 0.29 mmol), and N-hydroxybenzotriazole (HOBt) (56 mg, 0.29 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-pyridin-2-ylpropionamide (36 mg, 30%), as a white solid. 1H NMR (DMSO-d6) δ: 10.86 (br. s., 1H), 8.34 (d, J=3.4 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.05-7.16 (m, 2H), 5.10 (d, J=6.8 Hz, 1H), 4.43 (d, J=19.1 Hz, 1H), 4.06 (d, J=19.1 Hz, 1H), 3.83 (br. s., 2H), 1.51-1.87 (m, 7H), 0.75-1.30 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH:10]=[N:11][NH:12][C:13]([O:15][CH3:16])=[O:14]>[Pt].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH2:10][NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCC(C=NNC(=O)OC)c1ccc(Cl)cc1Cl
Agent: [Pt]
Solvent: CC(=O)O
Product: CCCC(CNNC(=O)OC)c1ccc(Cl)cc1Cl

Procedure:
1.2 g of a platinum/charcoal catalyst (5% by weight of Pt) are added to a solution of 12.0 g (0.04 mol) of 1-[2-(2,4-dichlorophenyl)-pentylidene]-2-methoxycarbonylhydrazine in 80 ml of acetic acid, and the mixture is hydrogenated at 40° C. under a hydrogen pressure of 50 bar for 2 hours. Filtration of the reaction mixture and column-chromatography of the residue after evaporation yield 9.4 g (78% of theory) of the above product:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N

Procedure:
Prepared from (2′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B10) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a yellow solid (1.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][CH2:12][N:13]([CH2:15][C:16]([OH:18])=O)[CH3:14].[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[Cl:1][C:2]1[C:3]2[CH2:11][CH2:12][N:13]([CH3:14])[CH2:15][C:16](=[O:18])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCc1c(Cl)cccc1[N+](=O)[O-])CC(=O)O
Reactant: [H][H]
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2c(Cl)cccc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(2-chloro-6-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (12 g, approximately 0.049 molE, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 1.2 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (1.5 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (20.0 g, 0.097 mole) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 4.0 g of the title compound as a white solid. 1H NMR (CDCl3): 7.50 δ (broad, 1H); 7.30 δ (d, 1H); 7.20 δ (s, 1H); 7.00 δ (d, 1H); 3.18 δ (s, 2H); 2.80 δ (broad s, 4H); 2.40 δ (s, 3H). MS(ES) m/z 225 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:45]=[N:44][C:43](=[O:46])[N:42]3[CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])=[CH:37][CH:36]=2)OC1(C)C>>[N:23]1([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:35]3[CH:36]=[CH:37][C:38]([N:41]4[CH:45]=[N:44][C:43](=[O:46])[N:42]4[CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])=[CH:39][CH:40]=3)=[CH:3][N:4]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(-n3cnc(=O)n3COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 25.1 %

Procedure:
Compound 3a (400 mg, 0.910 mmol) was subjected to Suzuki coupling conditions with 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydro-1H-1,2,4-triazol-3-one (1.14 g, 2.73 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 11e as a brown solid (148 mg, 25% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H40N8O3Si: 649.3 (M+H). Found 649.3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:40]=[C:28]([CH2:29][O:30][CH2:31]3)[CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:40]=[C:28]([CH2:29][O:30][CH2:31]3)[CH:27]=[CH:26][CH:25]=2)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cccc(c1)COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCc1cccc(c1)COC3
Yield: 50 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.113,17.02,7]triaconta-2,4,6(30),8,13(29),14,16-heptaen-3-yl}acetate (20 mg, 0.034 mmol) and NaOH (0.169 mL, 0.169 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then filtered and purified by preparative HPLC to isolate (2S)-2-(tert-butoxy)-2-{4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.113,17.02,7]triaconta-2,4,6(30),8,13(29),14,16-heptaen-3-yl}acetic acid (10 mg, 0.017 mmol, 51.4% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.27 (m, 1H), 7.22 (s, 1H), 7.16 (d, J=7.3 Hz, 2H), 6.50 (s, 1H), 5.62 (s, 1H), 4.62-4.40 (m, 4H), 4.17 (t, J=12.5 Hz, 1H), 3.65-3.56 (m, 1H), 3.38-3.23 (m, 2H), 2.77 (d, J=11.4 Hz, 1H), 2.74-2.66 (m, 1H), 2.59-2.53 (m, 1H), 2.50 (br. s., 4H), 1.91 (d, J=12.5 Hz, 1H), 1.84-1.75 (m, 1H), 1.75-1.62 (m, 3H), 1.58-1.44 (m, 3H), 1.43-1.33 (m, 2H), 1.17 (s, 3H), 1.14 (s, 9H). LCMS (M+1)=565.3.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:3]=1.C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[CH:37]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:6]([CH2:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])[N:5]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1Br)N1CCN(c2ccccn2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1C#Cc1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
20 mg triphenylphosphinpalladium(II)chloride and 5 mg cupper(I)iodide were added to 100 mg 2-(5-bromo-3-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone, 250 μl triethylamine and 45 mg ethynyl-benzene acid in 5 mL tetrahydrofuran. The reaction was stirred 2 h at 70° C. The reaction was filltered and evaporated. The residue was purified by HPLC to give 5 mg desired product. Rt: 1.24 min (method B), (M+H)+: 467
Reaction SMILES: [N:1]1([CH2:10][O:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][C:13]=2[CH:14]=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[N:1]1([CH2:10][O:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][C:13]=2/[CH:14]=[CH:28]/[C:27]([C:30]2[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[O:29])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COc1cc(OCn2nnc3ccccc32)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCn2nnc3ccccc32)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 56 %

Procedure:
The title compound was prepared by condensing 2-(benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-115A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Light yellow solid, 56% yield, mp 255° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.09 (d, 3H, J=9.4 Hz), 8.01 (d, 1H, J=7.8 Hz), 7.93 (d, 2H, J=7.8 Hz), 7.75 (d, 2H, J=9.4 Hz), 7.56–7.69 (m, 4H), 7.42–7.47 (m, 1H), 7.38 (s, 1H), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 7.05 (s, 2H), 4.05 (s, 3H). MS (ESI) m/z=547 ([M+H]+, 100%). Anal. Calcd. C27H22N4O5S2: C, 59.33; H, 4.06; N, 10.25; S, 11.73. Found: C, 59.45; H, 4.27; N, 9.92; S, 11.27.