Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CN1CCOCC1>[Cu].[Cu]Cl.CN(C)C(=O)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Temperature: 115 °C
Reaction time: 10 h

Procedure:
To N,N-dimethylacetamide 150 mL solution of 2-chloro-4-nitrobenzoic acid 30 g, were added 4-fluoroaniline 29 mL, copper powder 2.8 g, copper (I) chloride 5.3 g and N-methylmorpholine 33 mL at room temperature, and it was stirred at 110 to 120° C. for 10 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and 1.0 mol/L hydrochloric acid 700 mL and ethyl acetate 700 mL were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-nitrobenzoic acid 9.7 g of red solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36].O>ClCCl>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)OC(=O)Cl
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and TEA (92 mg) were dissolved in dichloromethane, followed by ice-cooling. Isopropyl chlorocarbonate (83 mg) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain isopropyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (155 mg).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O1CCOCC1.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>[NH3:4].[CH3:23][N:21]1[N:20]=[N:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)=[N:22]1
Reactant: Cn1nnc(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)n1
Product: N
Yield: 72.6 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-amine (49.4 mg, 0.133 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (51.6 mg, 0.266 mmol), Pd(PPh3)4 (39.3 mg, 0.034 mmol), 1.5 M Na2CO3 (0.710 mL, 1.07 mmol) in (2:1) DMF-dioxane (1.5 mL). Purification by Isolute FlashSilicaII cartridge chromatography eluting with 97:3 DCM:NH3 (7M in MeOH) affords the title compound as a white solid (17.3 mg, 36%). LCMS: Rt 2.60 min (96%), m/z 359 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 4.45 (3H, s), 7.72 (1H, s), 7.81 (1H, s), 8.05 (2H, d), 8.10 (1H, s), 8.21 (1H, s), 8.33 (2H, d), 8.48 (1H, s), 9.91 (1H, s), 13.42 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O.O>[C:17]([C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1)#[N:18]
Reactant: CCC(Oc1cncc(Br)c1)C(=O)OC
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(Oc1cncc(C#N)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl 2-(5-bromo-3-pyridyloxy)butyrate (1.37 g) and copper (1) cyanide (0.67 g) in dry N-methylpyrollidin-2-one (5 ml) was stirred at 150° C. under an atmosphere of nitrogen for 3.25 hours then cooled to ambient temperature and stored for 18 hours. The mixture was diluted with water and extracted with ethyl acetate (four times). The extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give a liquid which was fractionated by chromatography (silica; ethyl acetate) to give the required product, 0.29 g, as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][NH:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:24].[CH2:25](N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:13][NH:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:24].[C:32]([N:14]1[C:15]([CH3:16])=[C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[N:4]([CH3:23])[C:5]=3[CH:10]=2)[C:12]([C:17]2[CH:18]=[C:19]([CH3:25])[CH:20]=[CH:21][CH:22]=2)=[N:13]1)(=[O:34])[CH3:33]
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: Cc1[nH]nc(-c2ccccc2)c1-c1ccc2c(c1)n(C)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)n1nc(-c2cccc(C)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C)c1C
Reaction time: 0.33 h

Procedure:
1,3-Dimethyl-5-(5-methyl-3-phenyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one is prepared according to the procedures outlined in Example 337. 1,3-Dimethyl-5-(5-methyl-3-phenyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (70.9 mg) is diluted with dichloromethane and is treated with triethylamine (0.1 mL) and acetyl chloride (0.05 mL). The mixture is allowed to stir for 20 minutes then is diluted with saturated sodium bicarbonate and extracted into dichloromethane. The organic layer is dried over sodium sulfate and concentrated to give 8 mg 5-(1-Acetyl-5-methyl-3-m-tolyl-1H-pyrazol-4-yl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]1([C:19]([OH:21])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[CH2:22]([C@@H:29]1[CH2:34][C@@H:33]([N:35]([CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:46]=[CH:45][CH:44]=2)[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH2:32][CH2:31][NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:22]([C@@H:29]1[CH2:34][C@@H:33]([N:35]([CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:46]=[CH:45][CH:44]=2)[C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])[CH2:32][CH2:31][N:30]1[C:19]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:21])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc2ccccc12)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
92 μl (0.655 mmol) of 1-chloro-N,N,2-trimethyl-1-propen-1-amine are added to a solution of 96 mg (0.561 mmol) of 1-naphthoic acid in 2 ml of dry, methylene chloride at 0°, and the mixture is stirred at 0° for 1 hour and at room temperature for 1 hour. Subsequently a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine in 3 ml of methylene chloride is added dropwise over the course of 10 minutes to this yellow solution at room temperature. After stirring at room temperature for 3 hours, water is added, the organic phase is separated off and washed twice more with water. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (800:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.49, FD-MS: M+ =581.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[C:2]1[CH:8]=O.COP([CH:16]([NH:20]C(=O)C)[C:17](=[O:19])[CH3:18])(=O)OC.C1CCN2C(=NCCC2)CC1>ClCCl>[S:1]1[C:2]2=[CH:8][N:20]=[C:16]([C:17](=[O:19])[CH3:18])[CH:6]=[C:3]2[CH:4]=[CH:5]1
Reactant: COP(=O)(OC)C(NC(C)=O)C(C)=O
Reactant: O=Cc1ccsc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)c1cc2ccsc2cn1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 2,3-thiophenedicarboxaldehyde (600 mg, 4.28 mmol) in dichloromethane (50 ml) was cooled to 0° C. under an atmosphere of nitrogen. (1-Acetylamino-2-oxo-propyl)-phosphonic acid dimethyl ester (1.05 g, 4.70 mmol) was added [literature procedure: Kitamura, et al. Tet. Lett., 36(32), 1995, pp. 5769-5772], followed by DBU (0.471 ml, 4.70 mmol), and the mixture allowed to warm to ambient temperature overnight, then concentrated in vacuo, and the residue was then purified by flash chromatography (0-50% ethyl acetate in hexanes) to provide 1-thieno[2,3-c]pyridin-5-yl-ethanone as a white solid (326 mg, 43%). 1HNMR (250 MHz, CDCl3): δ 9.20 (s, 1H), 8.50 (d, 1H, J=1.02), 7.80 (d, 1H, J=5.36), 7.51 (d, 1H, J=5.36), 2.81 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[C:34]1([C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:43]2[CH2:44][CH2:45][C:40]([OH:46])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:41][CH2:42]2)=[O:18])[N:8]([C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=2)[CH2:12]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)(c3ccccc3)CC2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=499.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:21][CH2:20][C:13]3(C(=O)CCC3=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:23]1CCCC1>>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:21][CH2:20][C:13](=[O:23])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)C12CCC(COCc1ccccc1)CC2
Agent: Cl
Product: O=C1CCC(COCc2ccccc2)CC1
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of the compound of Example 106 (18.43 g, 70.2 mmol) in tetrahydrofuran (400 ml) was added 50 ml of a 2% aqueous HCl solution and stirred for 24 hours. The mixture was concentrated in vacuo and the residual solution layered with ether. The ether layer was dried (MgSO4), concentrated in vacuo, then chromatographed to give 11.16 g (73% yield) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C:16]([OH:21])([CH:19]=C)[CH:17]=C)[O:14][CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=[O+][O-].[BH4-].[Na+].[OH2:34].C[OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C:16]([OH:21])([CH2:17][OH:36])[CH2:19][OH:34])[O:14][CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC(O)(C=C)[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CO
Reactant: O
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(O)(CO)CO)[C@H](c2ccc(Cl)c(Cl)c2)C1

Procedure:
Into a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(3-hydroxypent-1,4-dien-3-yl)-1,4-oxazepane-4-carboxylate (2.31 g) in methanol (50 ml) was introduced an ozone gas (from ozone developing apparatus) at −78° C. with stirring. When the solution turned pale-blue, introduction was stopped, and a nitrogen gas was introduced instead until the pale-blue color disappeared. Sodium tetrahydroborate (612 mg) was added at −78° C., and the mixture was warmed with stirring to room temperature, and stirred for 10 min. Water was added to quench the reaction, methanol was evaporated under reduced pressure, and the residue was extracted three times with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (10%-100%)) to give the title compound (800 mg) as a colorless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9][CH2:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:21])[CH2:18][CH2:19][OH:20])[CH:14]=[CH:13][N:12]=1>C(O)(=O)C>[Cl:1][C:16]1[C:11]([CH2:10][OH:9])=[N:12][CH:13]=[CH:14][C:15]=1[N:17]([CH3:21])[CH2:18][CH2:19][OH:20]
Reactant: CN(CCO)c1ccnc(CO)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CN(CCO)c1ccnc(CO)c1Cl

Procedure:
N-Chlorosuccinimide (25 g, 187 mmol) is added in 5 portions to a solution of 2-[(2-hydroxymethyl-pyridin-4-yl)-methyl-amino]-ethanol (30 g of the crude product isolated in step a), 140 mmol) in acetic acid (170 ml) over a period of 3 h. Stirring is continued for I h and the solvent is evaporated in vacuo. The residue is treated with 6N sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane 2:1) to give the title compound as a brown solid. M.p. 49-53° C.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([NH:28][CH2:20][CH:2]([OH:1])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)O[Si](C)(CCCOCC1CO1)O[Si](C)(C)C
Solvent: CC(C)O
Product: C[Si](C)(C)O[Si](C)(CCCOCC(O)CNCc1ccccc1)O[Si](C)(C)C
Temperature: 80 °C

Procedure:
A 500-ml, three-necked, round-bottomed flask equipped with a stirrer, addition funnel, and condenser was charged with 100 g (0.30 mole) of the epoxy trisiloxane (Compound I) of Example 1 dissolved in 200 ml of isopropanol. The addition funnel was charged with a solution of 42.8 g (0.4 mole) of benzylamine (Aldrich) in 100 ml of isopropanol the solution was added drop-wise to the flask contents at room temperature. The resulting reaction solution was heated at 80° C. for eight hours, after which time the solvent was removed under reduced pressure using a rotary evaporator. The residue, an oil, was passed through a short silica column using 10% ethyl acetate in hexane as eluent. The yield of Compound V, a colorless oil, was 127.8 g (979). The following elemental analysis was obtained:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:45])[C:32]4[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=4[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:31]([OH:45])[C:32]3[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=3[S:39]([N:42]([CH3:43])[CH3:44])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4cc(Br)ccc4S(=O)(=O)N(C)C)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(C(O)c3cc(Br)ccc3S(=O)(=O)N(C)C)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 72 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of 2-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (30.0 mg, 0.036 mmol) in DCM (0.5 mL) was treated with TFA (0.5 mL) followed by triethylsilane (0.3 mL). The mixture was stirred at 72° C. for 16 h. An additional 1 mL of TFA was added, the mixture was placed in a sealed tube, and heated at 100° C. for 4 h to give a much darker orange solution. The mixture was concentrated, neutralized with 2 N NH3/MeOH, concentrated and purified by prep HPLC to give 2-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (20 mg, 0.033 mmol, 93% yield) as a yellow solid. m/z (ESI, +ve ion) 601/603 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[NH2:3][C:4]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Sodium hydride (60% in oil, 1.26 g) was added to a 0° C. solution of 2-aminopyridine (2.00 g) in THF (10 ml) and the resultant mixture stirred at 0° C. for 1 h. A solution of 2-fluoronitrobenzene (2.21 ml) in THF (8 ml) was added dropwise and the resultant mixture allowed to attain rt overnight. Saturated aqueous sodium carbonate (10 ml) was added and the separated aqueous phase extracted into dichloromethane (3×10 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. Flash column chromatography (cyclohexane: ethyl acetate; 3:1 as eluant) gave the title compound (2.23 g) as an orange/red solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl.N1C=CC=CC=1>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cnc2c(c1)c(-c1cncc(N[C@H](C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
To a solution of N2-[5-(5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (1.5 mL) and pyridine (0.2 mL) was added acetic anhydride (9.23 μL, 0.098 mmol) and the mixture was stirred for 2 h. The reaction was concentrated and the residue 5-2a was carried on without further purification.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21](C)=[CH:20]C=2O)=[CH:15][CH:14]=1)(=O)C1C=CC=CC=1.[C:29]([O:32][C@@H:33]1[O:50][C@H:49]([CH2:51][O:52]C(=O)C)[C@@H:44]([O:45]C(=O)C)[C@H:39]([O:40]C(=O)C)[C@H:34]1[O:35]C(=O)C)(=O)[CH3:30].C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:32]([C:29]1[CH:30]=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:24])[C:18]=1[CH2:17][C:16]1[CH:27]=[CH:28][C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[CH:14][CH:15]=1)[C@@H:33]1[O:50][C@H:49]([CH2:51][OH:52])[C@@H:44]([OH:45])[C@H:39]([OH:40])[C@H:34]1[OH:35]
Reactant: Cc1cc(C)c(Cc2ccc(CCCOC(=O)c3ccccc3)cc2)c(O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Cc2ccc(CCCO)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.7 %

Procedure:
To a solution of 2-[4-(3-benzoyloxypropyl)benzyl]-3,5-dimethylphenol (0.72 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (2.3 g) in toluene (7 mL) and dichloromethane (3 mL) was added boron trifluoride diethyl ether complex (0.73 mL), and the mixture was stirred at room temperature for 10 hours. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and tetrahydrofuran (4 mL), sodium methoxide (28% methanol solution, 0.19 mL) was added to the solution, and the mixture was stirred at 30° C. for 7.5 hours. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10 mL), sodium methoxide (28% methanol solution, 0.075 mL) was added to the solution, and the mixture was stirred at 30° C. for 14 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to give 2-[4-(3-hydroxypropyl)-benzyl]-3,5-dimethylphenyl β-D-glucopyranoside (0.58 g).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:18]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:18])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)N(C)c1ccccc1S2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
To a solution of 2-acetylphenothiazine (Aldrich) (2.41 g, 10 mmol) in dimethylformamide (25 mL) was added potassium t-butoxide (1.5 g, 13.4 mmol) and the mixture was stirred for 15 minutes. Methyl iodide (1.9 g, 13.4 mmol) was then added, dropwise, to the resulting solution and the mixture stirred for 30 minutes. Ice-water was added to the reaction mixture followed by ethyl acetate. The organic layer was decanted, washed with brine, dried over Na2SO4 and evaporated to dryness. The oily residue was chromatographed on flash silica gel eluting with 10% ethyl acetate/hexane to afford the pure title product (1.0 g, 39%).