Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([Cl:11])[C:3]=1[F:12].[Li]C(CC)C.B(OC(C)C)(OC(C)C)[O:19]C(C)C.OO.N([O-])=O.[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[Cl:11][C:4]1[C:3]([F:12])=[C:2]([OH:19])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(Br)c(F)c1Cl
Agent: O=N[O-]
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(O)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
30.02 g of the compound (C2) was dissolved in 300 mL of THF. sec-BuLi (1.01 M solution, 124 mL) was added dropwise to the resulting solution in a temperature range of −70 to −75° C., and after completing the dropwise addition, the mixture was stirred for 1 hour in that temperature range. 40 mL of a THF solution having 18.71 g triisopropyl borate dissolved therein was added dropwise to the resulting solution in a temperature range of −70 to −75° C., and after completing the dropwise addition, the mixture was stirred for 1 hour in that temperature range. Thereafter, the temperature of the solution was gradually increased to room temperature, followed by stirring over night. After adding 11.92 g of acetic acid to the reaction mixture, followed by stirring for 30 minutes, 29.95 g of hydrogen peroxide was added dropwise thereto slowly at room temperature, and after completing the dropwise addition, the mixture was stirred for 4.5 hours at room temperature. A sodium nitrite aqueous solution and ethyl acetate were added to the reaction mixture, followed by mixing, and the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was a yellowish solid. 30.97 g of the residue was purified by a preparative column chromatography using a mixed solvent of heptane and ethyl acetate (heptane/ethyl acetate=5/1 by volume) as a developing solvent and silica gel as a mediator to obtain 13.29 g of 3-chloro-4-ethoxy-2-fluorophenol (b64). The resulting compound (b64) was a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[O:23]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:23])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2cc(C=Cc3cc(Cl)cc(Cl)c3)cnc2n1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2cc(C=Cc3cc(Cl)cc(Cl)c3)cnc2n1
Temperature: 24 °C

Procedure:
A suspension of 0.4 g (1.2 mM) of 2,4-diamino-6-[2-(3,5-dichlorophenyl)ethenyl]pyrido[2,3-d]pyrimidine (prepared as described in Example 3), in 80 ml of 1N sodium hydroxide was heated at reflux for 24 hours. Since not all the starting material had dissolved, 10 ml of 5N sodium hydroxide and 25 ml of dioxane were added, and the mixture was heated at reflux for an additional 24 hours. The reaction mixture was cooled to 24° C., filtered, and the filtrate was diluted with 30 ml of glacial acetic acid. The precipitate which formed was collected by filtration, washed with 50 ml of water, and then with 50 ml of diethyl ether, and dried at 100° C. under vacuum to provide 160 mg of 2-amino-4-hydroxy-6-[2-(3,5-dichlorophenyl)ethenyl]pyrido-[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][OH:17])[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].O[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Oc1cccnc1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCO)C2=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-4-(2-hydroxyethyl)-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, from Example 86, Part B, (24 mg, 0.064 mmol) in 1 mL of toluene was added 3-hydroxypyridine (9 mg, 0.096 mmol), triphenylphosphine (20 mg, 0.077 mmol) and diethylazodicarboxylate (0.035 mL, 0.077 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:2 to 1:2 hexane/ethyl acetate) to afford 20 mg of the title compound which was contaminated with a small amount of triphenylphosphine oxide. LRMS (ESI): 452.3 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)cc1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-methoxybenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 550 ([MH]+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[BrH+][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[K+].CN(C)C=O>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: N#Cc1ccc(C[BrH+])cc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Mix 5-formylindole (0.50 g, 3.4 mmol), 4-bromniomethyl-benzonitrile (0.74 g, 3.8 mmol), powdered potassium hydroxide (0.23 g, 4.1 mmol) and dimethylformamide (7 mL) in a flask. Stir at rt overnight. Pour into water (20 mL) and extract with EtOAc/Hexanes (2:1, 3×50 mL). Evaporate solvents to give a yellow oil. Purification on silica using a 10% EtOAc/Hexanes to 30% EtOAc/Hexanes gradient eluent yields the product (0.75 g, 83%). Mass spectrum (ion spray): m/z=259.2 (M−1); 1H NMR (CDCl3) 10.04 (s, 1H), 8.20 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.77 (d, J=3.1 Hz, 1H), 5.44 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][CH2:31][C:30]6[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=6[NH:28][C:27]5=[O:39])[CH2:22][CH2:21]4)[CH:15]=3)=[O:13])[CH2:9][C:10]=2[CH:11]=1.[H][H]>[Pd].CO>[N:4]1[C:5]2[CH2:6][CH2:7][N:8]([C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][CH2:31][C:30]6[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=6[NH:28][C:27]5=[O:39])[CH2:22][CH2:21]4)[CH:15]=3)=[O:13])[CH2:9][C:10]=2[CH:11]=[CH:2][CH:3]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncc(Br)cc5C4)ncn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncccc5C4)ncn3)CC1)C(=O)N2

Procedure:
Under a hydrogen atmosphere 77 mg (0.12 mmol) 3-{1-[6-(3-bromo-7,8-dihydro-5H-1,6-naphthyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 40 mg palladium on charcoal (10%) were hydrogenated in 10 mL methanol at 50° C. under 50 psi hydrogen pressure. Then the catalyst was removed by suction filtering and the filtrate was evaporated down i. vac. The residue was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:18][Mg]Br.[NH4+].[Cl-]>CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][C:14]([OH:17])([CH3:18])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(c2cccc3c2OCCO3)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(c2cccc3c2OCCO3)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.5 g (15 mmol) of 1-(2,3-dihydro[1,4]benzodioxin-5-ylpiperid-4-one are dissolved in 30 ml of ether. The solution is cooled to 0° C. and, while that temperature is maintained, 10 ml of a 3M methylmagnesium bromide solution in ether are added. The whole is stirred for 1 hour at that temperature and then for 1/2 hour at room temperature, hydrolysed by pouring into 100 ml of a saturated aqueous NH4Cl solution, and extracted with 100 ml of ether. The extract is dried and evaporated to yield a residue of 3.3 g, which is purified by flash chromatography on silica (eluant CH2Cl2 /CH3COOC2H5 : 90/10). In that manner, 1.3 g of the expected product are isolated.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][C:37]1[CH:38]=[C:39]([CH:68]=[CH:69][CH:70]=1)[C:40]([NH:42][NH:43][C:44](=[O:67])[C@H:45]([NH:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]#[N:64])=[C:59](Cl)[C:58]=1C)[C@@H:46]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH3:47])=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[CH2:71]([Cl:73])Cl>>[Si:49]([O:48][C@@H:46]([CH3:47])[C@@H:45]([NH:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]#[N:64])=[C:71]([Cl:73])[C:62]=1[CH3:61])[C:44]1[O:67][C:40]([C:39]2[CH:68]=[CH:69][CH:70]=[C:37]([O:36][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH:38]=2)=[N:42][N:43]=1)([C:52]([CH3:55])([CH3:53])[CH3:54])([CH3:50])[CH3:51]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (100 mg, 0.3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (3 mL) followed by addition of solid iodine (76 mg, 0.30 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (0.17 mL, 1.2 mmol). This mixture was allowed to stir at room temperature for an additional ten min. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (95 mg, 0.15 mmol) was taken up in methylene chloride (5 mL) and slowly added to the heavily stirred reaction mixture. After a period of 20 min, the solid polymer was filtered out and washed with additional methylene chloride (20 mL). The organic filtrate was then washed with 10% sodium thiosulfate/water (2×10 mL), brine (1×20 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown oil/solid, which was purified via silica gel chromatography eluted with 20% EtOAc/hexanes to provide the title compound as a white solid (63 mg, 68%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.52 (m, 1H), 7.38 (m, 1H), 7.33 (m, 2H), 6.99 (m, 1H), 6.46 (d, J=8.6 Hz, 1H), 5.37 (d, J=8.8 Hz, 1H), 4.80 (dd, J=1.8, 8.8 Hz, 1H), 4.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), 0.06 (s, 3H), −0.20 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH2:12][OH:13])=[CH:8][CH:9]=[C:10]([I:11])[N:5]2[N:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10]([I:11])[N:5]2[N:4]=1
Reactant: OCc1ccc(I)n2nc(C(F)(F)F)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(I)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.6 %

Procedure:
The compound of Example 112 (3.26 g) was dissolved in dichloromethane (50.0 mL). To this solution, activated manganese dioxide (8.29 g) was added and the mixture was stirred at room temperature for 14 hours. Subsequently, the reaction mixture was filtered through Celite and the filtrate was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=4:1) afforded the title compound as a yellow powder (2.97 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([NH2:7])=[N:5][OH:6].[C:9]1([S:15][CH2:16][C:17](Cl)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:17]([CH2:16][S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)=[O:8]
Reactant: O=C(Cl)CSc1ccccc1
Reactant: COC(=O)C(N)=NO
Solvent: C1CCOC1
Product: COC(=O)c1noc(CSc2ccccc2)n1
Yield: 54.1 %

Procedure:
300 mg (2.54 mmol) of amino-hydroxyimino-acetic acid methyl ester and 428 mg (2.29 mmol, 0.9 eq) of phenylsulfanyl-acetyl chloride were stirred in 10 mL of THF at RT for 1 hour. The solvent was evaporated, the residue dissolved in dioxane, and the reaction mixture was heated at reflux over night in the presence of molecular sieves. Filtration, concentration under vacuum and column chromatography over silica gel with EtOAc/heptane 1:1 yielded 310 mg (49%) of 5-phenylsulfanylmethyl-[1,2,4]oxadiazole-3-carboxylic acid methyl ester as light yellow oil, MS: 268 (MNH4+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:42]1[C:39]2[CH:40]=[CH:41][C:36]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:37][C:38]=2[O:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Reactant: Ic1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc4c(c3)OCO4)c2)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(3-(tert-butoxycarbonyloxy)phenyl)benzoate 0.12 g and cesium carbonate 0.25 g were added 1-iodo-3,4-methylenedioxybenzene 0.15 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.4 mg, tris(dibenzylideneacetone)dipalladium(0) 2.9 mg and palladium acetate 1.4 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.4 mg, tris(dibenzylideneacetone)dipalladium(0) 2.9 mg and palladium acetate 1.4 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-(tert-butoxycarbonyloxy)phenyl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(F)c(F)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1nc2cc(F)c(F)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Difluoro-benzene-1,2-diamine (4.98 g; 34.5 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.48 g; 51.9 mmoles) were suspended in 6N HCl (8 mL; 48 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a pale orange solid.
Reaction SMILES: C1C2CC3C(=CC=CC=3)C=2C=CC=1C(Cl)=O.CN.[CH3:19][NH:20][C:21]([C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C:25]=2[CH:24]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH3:19][NH:20][CH2:21][C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C:25]=2[CH:24]=1
Reactant: CNC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: CN
Agent: O=C(Cl)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCc1ccc2c(c1)Cc1ccccc1-2

Procedure:
A solution of fluorene-2-carbonyl chloride (prepared from fluorene-2-carboxylic acid and oxalyl chloride) in THF is added to aqueous methylamine (2 molar equivalents) to prepare N-methyl fluorene-2-carboxamide. Reduction of the amide using LiAlH4 in ether provides 2-((methylamino)methyl)fluorene. The amine is protected by reaction with di-tert-butyl dicarbonate to provide 24N-tBOC—N-methylamino)methyl)fluorene.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:3](=[O:5])[C:2](=[O:1])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)[CH3:44]
Reactant: O=C(O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Reactant: CCOC(=O)CNCC(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To 1.12 g (2.6 mmol) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid in 50 ml of methylene chloride containing 2 drops of anhydrous DMF stirred and cooled in an ice bath was added 1.1 ml (13 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 1.5 hours. The solvent was removed at reduced pressure and the resultant solid acid chloride was dissolved in 50 ml of methylene chloride and added dropwise to a stirred, ice bath cooled solution of 0.7 ml (5.25 mmol) of diethyl iminodiacetate and 0.7 ml (5.25 mmol) of triethylamine in 15 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 hours and then was concentrated at reduced pressure. The resultant crude product was triturated with methanol and filtered to give 1.32 g (84% yield, mp 55°-56°) of N-(2-ethoxy-2-oxoethyl)-N-[1,2-dioxo-2-[4-[(12-phenoxydodecyl)oxy] phenyl]ethyl]glycine ethyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:10]=1.[OH-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>CN(C=O)C>[F:30][C:29]([F:31])([F:32])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:14]2[CH:15]=[CH:16][C:11]3=[N:10][C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[N:17][C:12]3=[CH:13]2)=[CH:23][CH:24]=1
Reactant: Fc1cccc(-c2nc3ccncc3[nH]2)c1F
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nc3ccn(Cc4ccc(OC(F)(F)F)cc4)cc-3n2)c1F
Yield: 1116.7 %

Procedure:
First, 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine (20 g, 86.6 mmole) was added to 430 mL of DMF. Some of the solid material did not dissolve. To this solution was added 43 mL of a 10% NaOH (w/v) solution. With vigorous stirring, the un-dissolved material went into solution. The resulting solution was divided into 30 equal portions of 16.3 mL, 3 mmole of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine so as to fit into a microwave reaction vessel. To each reaction vessel was added of 1-(chloromethyl)4-(trifluoromethoxy)benzene (693 mg, 3 mmole). Each reaction mixture was microwaved for 1 minute at 110° C. Following the completion of all the microwave reactions, all of the reaction vessels were combined (one was lost due to breakage of the vessel) into three batches for workup. For each batch, DMF was removed by vacuum, and the resulting material was washed three times with deionized water. The resulting crude material was dissolved in CH2Cl2, purified using a 330 g SiO2 column (Redisep (Isco) 0% to 0%/5 min to 10%/B/30 nin to 20%/5 min), and the resulting material was re-crystallized from ethanol/H2O. The three batches yielded 14 g, 33.5 mmole of 5-(4-(trifluoromethoxy)benzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine. 1H 300 Mhz (CD3OD) sigma 5.79 (s, 2p); 7.25-7.35 (m, 1p); 7.37 (d, 2p); 7.38-7.42 (m, 2p); 7.55 (d, 2p); 7.88-7.95 (m, 1p); 8.25 (d, 1p); and 9.05 (s, 1p). LC/MS M/z=406.23.