Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-:35])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reaction time: 2.5 h

Procedure:
A mixture of 4.2 g (11 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester and 3.15 g (14.5 mmol) of m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at 0° for 2.5 hr. The mixture was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 224°-226°. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 226°-227°.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=[C:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:10])=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Product: O=C1Nc2ncccc2C1=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 80.7 %

Procedure:
The title compound (59 mg, 81%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 5:2 mixture of Z/E isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H, NH), 11.30 (s, 1H, NH), 8.95 (s, 1H), 8.91 (d, 1H), 8.47 (d, J=4.4 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.19 (d, J=7.2 Hz, 1H), 8.13-8.07 (m, 4H), 7.72 (d, J=16.8 Hz, 1H), 7.59 (d, J=17.2 Hz, 1H), 7.42 (dd, J=8.0 Hz, 4.4 Hz, 1H), 7.50 (dd, J=7.2 Hz, 5.6 Hz, 1H); MS ESI 444.3 [M+H]+, calcd for [C22H15N5O+H]+ 366.1.
Reaction SMILES: C([Si:4]1([C:11]2[CH:16]=[CH:15]C=CC=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)CC.Br[C:18]1[CH:23]=[C:22](F)[C:21]([C:25]([Cl:28])=[CH:26][Cl:27])=[C:20](F)[CH:19]=1>>[CH2:11]([Si@H:4]1[CH2:5][CH2:6][C@H:7]([C:18]2[CH:23]=[CH:22][C:21]([C:18]3[CH:23]=[CH:22][C:21]([C:25]([Cl:28])=[CH:26][Cl:27])=[CH:20][CH:19]=3)=[CH:20][CH:19]=2)[CH2:8][CH2:9]1)[CH2:16][CH3:15]
Reactant: Fc1cc(Br)cc(F)c1C(Cl)=CCl
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(C(Cl)=CCl)cc3)cc2)CC1

Procedure:
The general procedure of Example 35 was repeated using 4-propyl-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone, and 4-bromo-2,6-difluoro-1-(1,2-dichlorovinyl)benzene instead of 4-bromo-2,6-difluoro-1-(2,2-difluorovinyloxy)benzene, thereby obtaining the intended compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][CH3:22].CCOCC>C1C=CC=CC=1>[CH3:22][O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: COCC1CCCN1N
Reactant: O=C1CCN(c2ccccc2)C1=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCC1CCCN1N=C1CCN(c2ccccc2)C1=O

Procedure:
A solution of the product of Example 61 and chiral 1-amino-2-methoxymethylpyrrolidine (SAMP or RAMP; 1 equiv) in benzene is refluxed under Dean-Stark conditions for 20 h. After cooling, Et2O is added and the mixture is washed with water. The organic layer is dried (MgO4) and evaporated to give a residue which is chromatographed on silica gel to give the title compound.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC([O-])=O.[Na+].C[O:36][CH:37]1[CH:41]([CH:42]=O)[CH2:40][CH:39](OC)O1>C(Cl)Cl.O>[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([N:29]5[CH:39]=[CH:40][C:41]([CH:37]=[O:36])=[CH:42]5)[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5ccc(C=O)c5)C4)n23)cc1
Temperature: 40 °C
Yield: 33.3 %

Procedure:
To a suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.175 g, 0.373 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.100 g, 1.22 mmol) in DCM (3 mL) and water (2 mL) was added 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (0.600 g, 3.37 mmol). The reaction was heated to about 40° C. for about 24 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown residue. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 20-100% EtOAc in DCM to give 1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.059 g, 33%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=2.10 min; MS m/z: 475 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(O)n2nc(CBr)nc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)n2nc(CN=[N+]=[N-])nc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.8 %

Procedure:
2-Bromomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidin-7-ol (3.6 g) are dissolved in 50 ml of dimethylformamide, treated with 0.99 g of sodium azide and stirred at room temperature for 2.5 hours. The dimethylformamide is evaporated in a high vacuum at 40° C. and the residue is treated with 35 ml of water. The thus-obtained suspension is stirred in an ice bath for 45 minutes. A white precipitate is filtered off under suction, washed with a small amount of water and dried in a high vacuum. There are obtained 2.0 g of 2-azidomethyl-5-methyl[1.2.4]-triazolo[1,5-a]pyrimidin-7-ol as white crystals of melting point 193°-194° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[CH:15][CH:14]=1>CCOCC>[CH3:7][O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([Cl:2])=[CH:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccc(CCC(C)C(=O)OC)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC=C(Cl)c1ccc(CCC(C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
193 g of phosphorus pentachloride are added to a solution of 76.8 g of 2-methyl-4-(4-propionylphenyl)butyric acid methyl ester in one liter of anhydrous ether, and the mixture is stirred at room temperature for 16 hours and is subsequently heated at reflux for one hour. The mixture is slowly poured on ice, is stirred for one hour and extracted with ether. The 4-[4-(1-chloro-1-propenyl)phenyl]-2-methylbutyric acid methyl ester obtained after evaporating the ether extract, is distilled in a vacuum (bulb type). B.P. 160°-170° at 0.06 mm of Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15](I)[CH:16]=[C:11]2[N:10]=[CH:9]1)[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:16]=[C:11]2[N:10]=[CH:9]1)[CH3:2]
Reactant: CCOc1cc(Cn2cnc3cc(I)cnc32)ccc1OCc1ccc(OC)nc1
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOc1cc(Cn2cnc3cc(N4CCN(C)CC4)cnc32)ccc1OCc1ccc(OC)nc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
To a stirred suspension of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridine (0.37 g, 0.71 mmol) in dimethylsulfoxide was added 1-methylpiperazine (0.086 g, 0.85 mmol), copper(I) iodide (0.033 g, 0.18 mmol), L-proline (0.041 g, 0.35 mmol), and potassium carbonate (0.24 g, 1.77 mmol). The mixture was degassed under vacuum/backfilled with N2 (×3) and then heated to 120° C. After 16 h, the dark brown mixture was allowed to cool to room temperature and was diluted with 5N ammonium hydroxide solution (50 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.36 g of a brown oil. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 5-10% 2M ammonia in methanol/dichloromethane elute) afforded 0.14 g (41%) of the product as an orange solid:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[C:53]([NH:57][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), tert-butylamine (0.195 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–100% ethyl acetate/hexanes gave the title compound (0.334 g, 78% yield). ES-MS (m/z) 445 [M+1(−Tr)]+
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].O>ClCCl>[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH:31][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cccc(CCc2c(CCN)ccc(OC)c2OC)c1
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccccc3)ccc(OC)c2OC)c1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (1.2 g) and N,N'-carbonyldiimidazole (0.77 g) in dry dichloromethane (50 ml) was stirred at 20° for 2 hours and a solution of 3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (1.5 g) in dry dichloromethane (10 ml) was added. The mixture was stirred at 20° for 16 hours. Water (50 ml) was added and the organic phase was separated and washed with 2N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting solid was crystallised from isopropanol to yield 2.1 g of the sub-title compound as colourless prisms, mp 150°-151°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:7]([OH:9])=[O:8])[CH3:2]>[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCOc1cc(C(=O)O)ccc1N
Yield: 92.1 %

Procedure:
3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium on charcoal under an atmosphere of hydrogen (1 bar) for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to leave the product as a beige solid (0.245 g; MS: ES− (M-H) 180).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2=CCC(C(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCC(C(C)(C)C)CC2)cc1

Procedure:
A room temperature mixture of Example 5B (230 mg, 0.84 mmol) and 10% Pd/C (100 mg) in ethyl acetate (5 mL) was stirred under a hydrogen atmosphere for 3 hours, filtered through a pad of silica gel (10 g) with diethyl ether (10 mL), and concentrated to provide the desired product as a ˜2:1 mixture of diastereomers. MS (DCI) m/e 275 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:42])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.[N+:55]([C:58]1[CH:63]=[C:62]([N+:64]([O-:66])=[O:65])[CH:61]=[CH:60][C:59]=1[NH:67][CH2:68][C:69](O)=[O:70])([O-:57])=[O:56]>ClCCl>[N+:55]([C:58]1[CH:63]=[C:62]([N+:64]([O-:66])=[O:65])[CH:61]=[CH:60][C:59]=1[NH:67][CH2:68][C:69]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:42])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:70])([O-:57])=[O:56]
Reactant: NCCOCCOCCNC(=O)CCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCOCCOCCNC(=O)CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 78.6 %

Procedure:
To a stirred solution of 3 (0.25 g, 0.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1 g, 0.5 mmol) in dichloromethane (50 mL) was added N-(2,4-dinitrophenyl)glycine (0.11 g, 0.51 mmol), and the solution was left to react at room temperature overnight. The solution was washed with 0.01 M HCl (1×100 mL), 0.2 M NaOH (1×100 mL), and brine solution (1×100 mL). The solution was dried (MgSO4) and evaporated to dryness. The crude compound was chromatographed (SiO2/EtOAc→MeOH) to yield 0.26 g (0.33 mmol, 79%) of 6 as a yellow oil. 1H NMR (CDCl3, 500 MHz): δ1.12-1.42 (br m, 14H), 1.57-1.62 (br m, 2H), 1.63-1.72 (br t, 2H), 2.12-2.21 (br m, 2H), 3.41-3.61 (br m, 12H), 4.17-4.21 (d, 2H), 5.87-5.92 (br s, 1H), 6.89-6.94 (d, 1H), 7.14-7.24 (m, 6H), 7.31-7.39 (m, 9H), 8.26-8.32 (d, 1H), 9.14-9.21 (br d, 1H). C44H55N5O8S (813.38): m/z 812.7 [M−H+]−.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.[F-].[K+]>[Pd].C1COCC1>[CH3:9][N:10]1[CH:14]=[C:13]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:12]=[N:11]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1C=C(Br)CCC1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=CC(=O)CCC2)cn1
Temperature: 60 °C
Yield: 29.4 %

Procedure:
To a 50 mL round bottom flask containing a stir bar was added 0.152 g of 3-bromocyclohex-2-enone (0.868 mmol), 0.216 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.04 mmol), 5 mL of THF, 4.0 mL of an aqueous solution of 2.0 M KF solution, and 0.139 g of 5% Pd on activated charcoal (Degussa type E105 CA/W, 7.5 mol %). The reaction was stirred, placed under nitrogen, and heated to 60° C. in an oil bath overnight. The reaction was not complete by TLC so the temperature was raised to 80° C. and heated an additional 18 hours. The reaction was worked up by filtering the crude mixture through a celite plug and extraction with methylene chloride (2 times with 5 mL). The organic phases were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was passed through a Fisher Prep Sep SCX column eluting with 8 mL of CH2Cl2 followed by 5 mL of methanol/ammonia (7N). The fractions were not pure so purification was accomplished using flash chromatography on the Biotage system utilizing gradient elution (0% to 80% ethyl acetate/hexanes). The product fractions were combined and concentrated to give a white powder (45 mg, 29%). 1H NMR (CDCl3, 300 MHz): δ 2.09 (quintet, J=6.3 Hz, 2H), 2.41-2.46 (m, 2H), 2.63 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 6.26 (t, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.69 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.5, 27.9, 37.4, 39.4, 121.5, 128.6, 137.6, 151.9, 199.3. LCMS (ESI): mass calcd for (C10H12N2O) m/z 176.09; measured [M+H]+: m/z 177.08.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[C:2](=[O:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (2-oxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2-dihydropyridin-4-yl)methylcarbamate 56-6 (95 mg, 0.26 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes. The solvent and TFA was removed by rotary evaporation to give crude 4-(aminomethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2(1H)-one 56-7. MS m/z 270.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC.ClCCl.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>[CH2:2]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(CBr)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: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1cccc(Cc2ccccc2)c1
Yield: 84.2 %

Procedure:
A mixture of methyl 3-(bromomethyl)benzoate (1.50 g; 6.35 mmol), phenylboronic acid (0.790 g; 6.35 mmol), sodium carbonate (1.35 g; 12.70 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.074 g; 0.063 mmol) in water (4 mL) and dimethoxyethane (12 mL) was irradiated in a microwave oven at 130° C. for 10 minutes. The mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 15 to 100% dichloromethane in heptane) to afford 1.21 g (84%) of methyl 3-benzylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Paraanisidine (136.34 g, 1.108 mol) was dissolved in dichloromethane (500 ml), triethylamine (234 ml, 1.66 mol) and acetic anhydride (114.8 ml, 1.22 mol) were added thereto, and the resulting mixture was stirred for 1 hour. After completion of reaction, the reaction solution was concentrated. Water (800 ml) was added to the residue and the resulting mixture was stirred and filtered to give 168.0 g (1.16 mol, Yield 92%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)Cc1ccccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccccc1OCc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.72 g, 19.9 mmol) and diisopropyl azodicarboxylate (DIAD, 3.67 g, 18.2 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 2-(2-hydroxyphenyl)acetate (3 g, 16.6 mmol) and triphenylphosphine (4.76 g, 18.2 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 6 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.