Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:11]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccccc1CC
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triphenylphosphine (15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (100 mL) was added dropwise DIAD (12.1 g, 60 mmol). After stirring for 18 hours, mixture was evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give 1-ethoxy-2-ethyl benzene (7.2 g) as a clear liquid. GC-MS shows one peak, RT=5.6 minutes. MS 150 (M+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH3:11])[N:5]=1.Cl.C([O-])(O)=O.[Na+]>>[CH3:11][NH:10][C:6]1[N:5]=[C:4]([CH:3]=[O:2])[CH:9]=[CH:8][N:7]=1
Reactant: CNc1nccc(C(OC)OC)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1nccc(C=O)n1
Temperature: 48 °C
Reaction time: 17 h

Procedure:
(4-Dimethoxymethyl-pyrimidin-2-yl)-methylamine (Step A, 3.60 g, 19.6 mmol) and 3 N HCl (14.4 mL, 43.2 mmol) were combined and stirred at 48° C. for 17 h. After cooling to RT, 4.3 g of NaHCO3 was added in portions. The mixture was extracted with EtOAc, the combined organic portions were dried over MgSO4, filtered, and condensed to give the titled compound as a yellow solid. MS (ES+): 138.3 (M+H)+. Calc'd for C6H7N3O-137.14.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[CH:6]1)[CH3:2].[CH3:24][Mg]Cl>CCOCC>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:24])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: CCOCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The compound was also obtained, for example, by Grignard synthesis from 7-ethoxymethyl-3-methyl-1-(5-oxohexyl)xanthine with methylmagnesium chloride in anhydrous ether analogously to Example 9.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]2)[CH:20]=1>CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)=[O:18]
Reactant: N[C@H]1CCN(Cc2cccnc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Product: O=C(N[C@H]1CCN(Cc2cccnc2)C1)[C@@H]1CCCCN1c1nc2ccccc2s1

Procedure:
The title compound was prepared by a similar method to Example 1, excepting that a catalytic amount of 4-dimethylaminopyridine was also used, from (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 43] and (3S)-1-(3-pyridinylmethyl)pyrrolidine-3-amine [see Preparation 41] to afford (2S)-1-(1,3-benzothiazol-2-yl)-N-[(3S)-1-(3-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@@:7]1(C)[C@H:13]2[C@H:11]([O:12]2)[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[N:19]([C@H:11]1[CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C@@H:13]1[OH:12])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H]2O[C@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl-dimethyl-[[(1R,5R,6R)-5-methyl-7-oxabicyclo[4.1.0]heptan-5-yl]oxy]silane, 50c, (0.05 g, 2.15 mmol) in methanol (5 mL) and H2O (0.6 mL) was added NH4Cl (0.23 g, 0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide (0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmed to 60° C., stirred for 12 h, at which point TLC-analysis revealed traces of the starting material. The reaction mixture was cooled to ambient temperature, quenched with H2O (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3×15 mL), washed with brine (10 mL), dried over MgSO4, filter and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10% ethyl ether in hexanes gradient) to afford 254 mg of (1R,2S,6R)-2-azido-6-[tert-butyl(dimethyl)silyl]oxy-cyclohexanol, 50d, as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([O-:3])=[O:2].C(O)(=O)C(O)=[O:17].O1CCOCC1>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:17])[CH2:10][OH:9])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Reactant: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCC(O)CO
Yield: 13 %

Procedure:
To a stirred solution of 38 parts of 2-(2-nitrophenoxymethyl)-oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane are added 100 parts of water. The whole is stirred and refluxed for 2 days. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and recrystallized from 2,2'-oxybispropane, yielding 29.5 parts (13%) of 3-(2-nitrophenoxy)-1,2-propanediol; mp. 96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[N:11]=[N:12][C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2nc(-c3ccc(Cl)nn3)[nH]c2c1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: Clc1ccc2nc(-c3ccc(N4CCNCC4)nn3)[nH]c2c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-chloro-2-(6-chloropyridazin-3-yl)-1H-benzoimidazole (0.212 g, 0.800 mmol) and piperazine (0.260 g, 3.000 mmol) in 1-methyl-2-pyrrolidone (15 mL) was heated at 140° C. and stirred for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water (100 mL) and stirred for 15 minutes. A white precipitate was formed which was collected by filtration and dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]=[CH:15][CH3:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=COc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 mmol of 2-chloro-5-hydroxy nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at 0° C. After 30 min, allyl bromide was added and the mixture was stirred at rt for 16 h. Solvent was removed and the residue was washed with water and extracted with EtOAc to give 2-chloro-5-propenyloxy nitrobenzene.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(Br)c1
Reactant: c1cn[nH]c1
Product: COc1cccc(-n2cccn2)c1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-bromo-3-methoxybenzene (126 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=40/60) to provide 150 mg (86% isolated yield) of the desired product as an uncolored oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1>>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)=[CH:23][CH:24]=1)[CH3:30]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1
Yield: 33.4 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 1-bromo-4-ethoxybenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 265 mg (yield 33%). Melting point was 117 to 119° C. (ethanol-water).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.CO[C:19]1[CH:27]=[C:26](OC)[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:8]1([C:21]([C:20]2[C:19]3[C:27]4=[C:15]5[C:14](=[CH:13][CH:12]=3)[CH:1]=[CH:2][CH:3]=[C:4]5[CH:5]=[CH:6][C:26]4=[CH:25][CH:24]=2)=[O:22])[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2ccc3cccc4ccc1c2c34)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrene (10.1 g; 0.05 mol) and 2,4-dimethoxybenzoyl chloride (10 g; 0.05 mol) were dissolved in 400 ml of anhydrous methylene chloride. Anhydrous aluminium chloride (6.6 g; 0.05 mol) was added to the reaction mixture in small portions over 1 h at 0° C. with intense stirring. The reaction mixture was stirred for another 2 h at 0° C., 2 h at rt and then poured onto a mixture of ice and HCl (500 ml) and transferred into a separating funnel. The organic layer was washed with water (1×500 ml), saturated NaHCO3 (2×500 ml) and saturated NaCl (1×500 ml). The organic fraction was evaporated and recrystallised from toluene to give pyrenylketone as white solid (15.7 g; 86%). Found: C, 82.09; H, 4.81. C25H18O3 (MW 366.41) requires C, 81.95; H, 4.95%. 1H-NMR (CDCl3, d): 8.65-6.45 (m, 12 H, arom.), 3.91 (s, 3H, OCH3), 3.55 (s, 3H, OCH3). Mass-spectrum, MALDI-TOF: 388.89 (MI+Na; 15), 366.89 (100), 203.82 (40). Calculated exact mass for C25H18O3: 366.12559; found 366.12617 [1.6 ppm error].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][CH:8]=1)=[O:6].I[CH:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][N:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc[nH]c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)C)c1
Reaction time: 1.5 h

Procedure:
NaH (58.1 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid methyl ester [2703-17-5] (38.8 mmol) in DMF (80 mL) at 0° C. and the mixture was stirred for 1.5 h. 2-Iodo-propane (78 mmol) was added and the mixture was stirred at rt for 4 h. The reaction mixture was quenched with 1N aqueous KHSO4 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as an orange-brown oil. tR: 3.80 min (HPLC 1); ESI-MS: tR=0.92 min, [M+H]+ 168 (LC-MS 1); TLC: Rf=0.22 (1:6 EtOAc/heptanes).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12]O)[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][Cl:16])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: CCn1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 mg (0.11 mmol) 1-ethyl-2-hydroxymethylbenzimidazole was dissolved in 2 ml dichloromethane. Thionyl chloride (24 μl, 0.33 mmol) was diluted 20 times with dichloromethane and the solution was added to the reaction mixture. Reaction mixture was stirred at room temperature for two hours, evaporated to dryness and washed with water to yield 1-ethyl-2-chloromethylbenzimidazole as pale yellow crystals, 36 mg (95%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:39][CH:38]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(Br)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.2 g), 4-bromophenol (0.93 g) and triphenylphosphine (1.4 g) were dissolved in tetrahydrofuran (1.5 mL), a solution of diisopropyl azodicarboxylate (2.8 mL, 1.9 M toluene solution) in tetrahydrofuran (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 40%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(trans-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225□l, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (97.5:2.5:0.25, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-Fluoro-N-(trans-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (60 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][CH:13]=[CH2:14])[CH:6]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2]
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)ccc1O
Yield: 115.4 %

Procedure:
A mixture of ethyl-3-allyl-4-hydroxybenzoate (4.12 g), palladium on carbon (10% w/w) and ethanol (100 ml) was stirred under an atmosphere of hydrogen until 500 ml of hydrogen had been consumed. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using 4:1 (v/v) n-pentane/ethyl acetate as eluent to give ethyl-3-propyl-4-hydroxybenzoate (4.8 g) as a solid, m.p. 78°-79° C.; microanalysis, found: C, 69.2; H, 8.1%; C12H16O3 requires: C, 69.2; H, 7.74%; NMR (CDCl3): 0.97(3H,t), 1.38(3H,t), 1.67(2H,m), 2.60(2H,t), 4.35(2H,q), 5.71(1H,s), 6.79(1H,d) and 7.75-7.87(2H,m); m/z 209(M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([OH:29])=O)[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([NH:31][CH3:30])=[O:29])[CH:3]=1
Reactant: Cc1nc(N)cc(OCC(=O)O)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-(6-amino-3-((1-benzyl-1H-pyrazole-4-carboxamido)methyl)-2-methylpyridin-4-yloxy)acetic acid (35 mg, 0.051 mmol) was dissolved in DMF (1 ml), CDl (16.65 mg, 0.103 mmol) was added. After stirring for 15 min at rt Methylamin 2M in THF (0.257 ml, 0.513 mmol) was added and the reaction mixture was stirred 6 h at rt. Purification by prep HPLC (Nucleosil C18, 250×40 mm 5 to 100% ACN and 0.1% TFA, flow 40 mml/min.) offered the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.71 (d, 3H), 4.37 (d, 2H), 4.67 (s, 2H), 5.34 (s, 2H), 6.20 (s, 1H), 7.24 (m, 5H), 7.79 (s, 2H), 7.89 (s, 1H), 8.25 (d, 2H), 8.28 (s, 1H), 8.35 (t, 1H). HPLC/MS (Method B) Rtb=0.46 min, MS [M+H]+=409.4.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH3:18])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:21]>O>[C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH:18]=[O:21])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Se]=O
Reactant: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Solvent: O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reaction time: 33.5 h
Yield: 65 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and an argon filled balloon, 7-butyramido-2-methylquinoline- 5,8-dione (30) (prepared as described in Example 30) (0.516 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml. of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and found to be complete after 33.5 hours. The selenium metal was allowed to settle, and the supernatant solution was piperted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml. ). All filtrates were combined and stored at 4° C. overnight. This solution was diluted with 50 ml of dichloromethane and washed with a 3% sodium bicarbonate solution (2×50 ml.). The organic layer was dried with magnesium sulfate and rotoevaporated to give a pale yellow product. The solid was dried under vacuum overnight and weighed 0.356 g. (yield of 65%). The product was recrystallized from ethyl acetate: mp. 208°-210° C.; 1H NMR (CDCl3) δ1.02 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 1.70-1.89 (2 H, m, 7NHCOCH2CH2CH3), 2.52 (2 H, t, J=7.4 Hz, 7NHCOCH2CH2CH3), 8.06 (1H, s, C-6H), 8.31 (1H, d, J=8.0 Hz, C-3H), 8.39 (1H, br. s, C-7NH), 8.61 (1H, d, J-8.0 Hz, C-4H), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3299, 3081, 2966, 2935, 2876, 1723, 1694, 1638, 1606, 1505 cm-1 ; EIMS, m/e (relative intensity) 272 (54), 202 (36), 175 (9); HRMS, m/e for C14H12N2O4 calculated 272.079707, found 272.078696; analysis for C14H12N2O4 calculated C, 61.76; H, 4.44; N, 10.29; found C, 61.31; H, 4.36; N, 9.94.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[C@@H:6]([OH:36])[CH2:5]1.C(N(CC)CC)C.C(Cl)Cl.[Br:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1>>[OH:36][C@@H:6]1[C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])[N:19]4[N:18]=3)=[C:12]([O:34][CH3:35])[CH:11]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:52](=[O:53])[C:51]2[CH:55]=[CH:56][C:48]([Br:47])=[CH:49][CH:50]=2)[CH2:5]1
Reactant: COc1cc([C@H]2CCN(CCO)C[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([C@H]2CCN(CCOC(=O)c3ccc(Br)cc3)C[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of (3R,4R)-1-(2-hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol (Example 16b; 40.00 mg, 0.082 mmol) and triethylamine (12 uL, 0.09 mmol) in methylene chloride (0.400 mL, 6.24 mmol) was added 4-bromo-benzoyl chloride, (19 mg, 0.086 mmol) at 0° C. The reaction was stirred overnight allowing the cooling bath/reaction to slowly warm to room temperature. The volatile were evaporated and the crude residue was further dried on high vacuum, The product was isolated by preparative reverse phase hplc (Gilson) and the free base was released by using a strong cation exchange resin column (Strata, from Phenomenex) to give 33 mg (60% yield) of 4-bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester. 1H NMR (CDCl3): 8.70 (br s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.47 (br s, 1H), 7.46-7.40 (m, 1H), 7.12 (app t, J=7.5 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.85 (d, J=4.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.76 (br s, 1H), 4.50 (app t, J=5.8 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (m, 1H), 3.31 (m, 1H), 3.04 (br d, J=11.3 Hz, 1H), 2.90 (app t, J=5.8 Hz, 2H), 2.35 (m, 1H), 2.26 (m, 1H), 2.15 (app t, J=10.2 Hz, 1H), 1.86 (m, 2H), 1.67 (br s, 1H).