Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH:11]2[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(O)C.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>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][CH:11]1[C:10]2[C:15](=[N:16][CH:17]=[C:8]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 26 %

Procedure:
Na2CO3 (2N, 53 μL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (9.0 mg) (1 eq), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4:1, v/v, 2 mL). The reaction was heated at 90° C. for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z=436 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J=9.1 and 13.3 Hz, 1H), 2.98 (dd, J=6.4 and 13.3H, 1H), 3.08-3.18 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.70 (m, 5H), 5.18 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.16 (d, J=1 Hz, 1H), 7.50 (dd, J=2.5 and 8.8 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(C3C=CCCC3)c[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A suspension of N-tert-butyl-3-(2-cyclohexen-1-yl)-1H-indole-6-sulfonamide (2.82 g, 8.48 mmol) and 20% palladium hydroxide/carbon (300 mg) in methanol (30 ml) was stirred at room temperature for 4 hr under a hydrogen atmosphere of 1 atm. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Hexane was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide (2.29 g, yield 82.0%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH:9]([CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: ClCc1cccnc1
Reactant: COCOc1ccc(CC#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(C(C#N)Cc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
The solution of 2.3 g of diisopropylamine in 30 ml of dry tetrahydrofuran was cooled to -35 to -40° C., followed by addition of 1.5M n-butyl lithium in 15 ml hexane in solution, and stirred for 30 minutes, to produce lithium diisopropylamide. To the solution was added the solution of 2.0 g of 4-methoxymethyloxybenzyl cyanide in 15 ml of dry tetrahydrofuran at -78° C., and stirred at the same temperature for 30 minutes, followed by addition of 3-picolyl chloride hydrochloride (1.9 g) at -78° C., and stirred overnight to room temperature. The reaction solution was poured into saturated aqueous sodium chloride solution, which was then extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, followed by the distillation of the solvent to obtain residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform-methanol (50:1 v/v) to produce 0.67 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile.
Reaction SMILES: [CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:23][S:24]SC>>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([S:24][CH3:23])[C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Reactant: CSSC
Product: CCCCCCCCCCc1ccc2cc(SC)c(OC)cc2c1
Yield: 93 %

Procedure:
7-Decyl-3-methylthio-2-methoxynaphthalene (compound (4)-12) was synthesized from 7-decyl-2-methoxynaphthalene (compound (3)-12) and dimethyl disulfide by the same method as that in Example 14 (yield of 93%, recrystallized from hexane to obtain yellow crystals).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1S.[CH2:17]([O:29]S([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC=O)=O>O>[O:29]1[C:3]2[CH:4]=[CH:5][C:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[N:1]=[CH:17]1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Nc1c(S)ccc2c1ccc1ccccc12
Agent: O=COC=O
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ccc1c2ccc2ocnc21
Yield: 71 %

Procedure:
5 mmol of 1-amino phenanthren-2-thiol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of formic anhydride was added for 5 minutes. A precipitation product was obtained in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain phenanthro oxazole at a yield of 71%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH3:12][O:13][CH2:14][CH2:15]Br>>[CH3:10][O:9][C:5]1[C:4]([O:11][CH2:15][CH2:14][O:13][CH3:12])=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COCCBr
Reactant: COc1cccc(CO)c1O
Product: COCCOc1c(CO)cccc1OC

Procedure:
Analogously to Method F, 2.44 g of 2-hydroxymethyl-6-methoxyphenol and 2.56 g of 2-bromoethyl methyl ether are reacted and the title compound is obtained as a colourless oil. Rf=0.22 (1:1 EtOAc-heptane); Rt=2.91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.Cl[Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][Si:24](Cl)([CH3:26])[CH3:25].[Na+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][Si:21]2([CH3:29])[CH3:28])=[N:6][CH:7]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
In a 500 mL three-necked flask, 5-bromopyridin-2-amine (5 g, 28.9 mmol) was combined with THF (80 ml) to give a light yellow solution. Cooled to −78° C. and n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added via syringe. The reaction was stirred at −78° C. for 1 hr, then 1,2-bis(chlorodimethylsilyl)ethane (6.22 g, 28.9 mmol) was added dropwise over 15 min. After stirring for 90 min at −78° C., n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added. The reaction was allowed to warm to 25° C. and stirred for 2 hr. The reaction mixture was diluted with 50 mL sat NaCl and extracted with diethyl ether (2×200 mL). The organic layers were combined, washed with H2O (1×25 mL), sat NaCl (1×25 mL), dried over MgSO4 and concentrated in vacuo. The crude brown oil was purified by vacuum distillation (1 mm Hg, 170° C.). The product solidified upon cooling to give 4.89 g (54%) of the title compound as a white crystalline solid. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.15 (d, J=2.6 Hz, 1H), 7.47 (dd, J=8.9, 2.5 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 0.83 (s, 4H), 0.24-0.38 (m, 12H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 1.35 g (5.233 mmol) of the product of Example 50 dissolved in 20 mL of chloroform and 1.5 mL of pyridine was added 1.02 g (5.233 mmol) of 4-fluorobenzenesulfonyl chloride and the resulting mixture was stirred overnight at room temperature. The chloroform was removed in vacuo and the residue was diluted with ether and washed with water, 5% HCl solution and saturated sodium bicarbonate solution and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether/hexanes (1:1) and the solid was collected by filtration and dried in vacuo to provide 1.50 g (69%) of the sulfonamide as a white solid. Electrospray Mass Spec: 416.9 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C:13]2[C:21]3[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH:30]5[CH2:33][CH2:32][CH2:31]5)[CH2:24][CH2:23]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[CH:30]1([N:29]([CH2:28][CH:25]2[CH2:24][CH2:23][N:22]([C:20]3[C:21]4[C:13]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[CH:14][S:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:27][CH2:26]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)CBr
Reactant: c1ccc(-c2csc3ncnc(N4CCC(CNC5CCC5)CC4)c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CN(CC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1)C1CCC1
Reaction time: 2 h
Yield: 62.2 %

Procedure:
Methyl bromoacetate (15 μL, 0.158 mmol) was added dropwise to a stirred suspension of N—[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]cyclobutanamine (50 mg, 0.132 mmol) and cesium carbonate (51 mg, 0.158 mmol) in dry DMF (4 mL) at room temperature. The reaction was allowed to stir for 2 h, then water and ethyl acetate were added and the organic layer separated. The aqueous layer was further extracted with ethyl acetate (×3). The organic layers were combined, washed with water, dried by passage through a hydrophobic frit and concentrated in vacuo to give methyl 2-[cyclobutyl-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]amino]acetate as a colourless oil (37 mg). LCMS RT=3.20. M+1=451.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](=[O:18])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4].[CH3:24][Mg]Br>O1CCCC1>[CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([OH:18])([CH3:24])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCOc1nccc2nc(C(C)=O)c3ccc(F)cc3c12
Solvent: C1CCOC1
Product: CCCCOc1nccc2nc(C(C)(C)O)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)ethanone (59 mg, 0.19 mmol) in tetrahydrofuran (2.0 ml) was added methylmagnesium bromide (1.4 M in toluene/THF 75:25; 0.202 ml, 0.283 mmol) dropwise at −78° C. The cooling bath was removed, and the resulting suspension was allowed to warm to room temperature. The reaction mixture was stirred for 30 minutes, and then quenched with saturated aqueous ammonium chloride (5 mL). Water was added, and the mixture extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to a crude solid that was adsorbed on to silica gel and purified by column chromatography on silica gel eluting with an EtOAc/hexanes gradient to afford 2-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)propan-2-ol. LRMS (ESI) calc'd for (C19H21FN2O2) [M+H]+, 329.2; found 329.1.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1>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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][CH2:35][O:36][CH:37]6[CH2:42][CH2:41][CH2:40][CH2:39][O:38]6)[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCOC1CCCCO1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 32.3 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 ml) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradiation of microwave. Filtered, concentrated and purified by pre-TLC (EtOAc) to give 130 mg of 256. Yield=32%. 1H NMR (CDCl3, 400 MHz): δ8.44-8.42 (m, 1H, ArH), 7.81 (s, 1H), 7.58 (s, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.19 (s, 1H), 4.51-4.95 (m, 1H), 4.45-4.44 (t, 1H), 4.39-4.38 (m, 2H), 4.38-4.37 (m, 2H), 4.07-4.04 (m, 2H), 4.00-4.97 (m, 1H), 3.63-3.54 (m, 2H), 3.40-3.36 (m, 1H), 2.49 (s, 3H), 1.76-1.60 (m, 4H), 1.48-1.47 (m, 2H) LC-MS: m/z=504 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(F)c1
Agent: C
Product: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reaction time: 1 h

Procedure:
To stirred 90° C. polyphosphoric acid (150 g) was added 10.72 g (7.65 mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid extracted with methylene chloride. The dried (MgSO4) solution was filtered and the solvent removed to yield a brown solid. Recrystallization from ethanol-hexane (1:3) returned a greenish yellow solid that was chromatographed on silica gel (methylene chloride) to yield 4.83 g (30%) of yellow 4-amino-3'-fluorobenzophone, mp 98°-100° C. 1H NMR (300 MHz, CDCl3): 4.21 (s, 2H, NH2) 6.66-6.70 (m, 2H, aromatic) 7.23-7.26 (m, 1H, aromatic) 7.39-7.51 (m, 3H, aromatic) 7.69-7.72 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.B1C2CCCC1CCC2.[OH-:24].[Na+].OO.Cl.[NH4+].[Cl-]>O.C1COCC1>[OH:24][CH2:1][CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:3]1
Reactant: [OH-]
Reactant: C=C1CC(COCc2ccccc2)C1
Agent: B1C2CCCC1CCC2
Agent: Cl
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: OCC1CC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
In a 10 mL flask with 1-methylene-3-benzyloxymethyl-cyclobutane (1.54 g, 8.19 mmol) inside, dry THF 11 mL was added under argon to give a colorless solution. Then cool this to 0° C., 9-BBN (0.5 M in THF, 27.4 mL, 13.7 mmol) was added drop by drop. This was allowed to warm up to ambient temperature and was left stirring for 22 hr, after which time the reaction mixture was cooled to 0° C. and H2O (0.9 mL), 3 N NaOH (2.7 mL) and 30% H2O2 (2.8 mL) were added successively. After stirring for 1 hr, 2 N HCl and saturated NH4Cl were added. The mixture was extracted with EtOAc and the separated organic phase was dried over MgSO4 and solvent evaporation gave the crude oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give a colorless oil (cis/trans=211, 1.44 g, 85%, Rf=0.16 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 1.52-1.60 (m), 1.86-1.90 (m), 2.12-2.19 (m), 2.36-2.64 (m), 3.39-3.41 (d, J=8), 3.49-3.51 (d, J=8), 3.54-3.56 (d, J=8), 3.64-3.66 (d, J=8), 4.51 (s), 4.53 (s), 7.2-7.4 (m). MS (FAB): expected for C13H18O2 (M+H)+ 207.28. Found 207.13807.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CN(C=O)C>C1COCC1.O>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (80% in oil, 3.2 g, 104 mmol) in 100 ml of THF, there is slowly added a solution of 2-(1-adamantyl)-4-bromophenol (29 g, 95 mmol) in 200 ml of THF. The mixture is stirred until the evolution of gas ceases at which point 27.8 g (23 ml, 104 mmol) of 1-iododecane and 100 ml of DMF are added. The mixture is stirred for 12 hours at ambient temperature, poured into water, extracted with ether, dried and the solvents evaporated. The resulting residue is purified by passage through a silica column (eluant: heptane), yielding 40.7 g (96%) of 2-(1-adamantyl)-4-bromo-1-decyloxybenzene. Melting point: 69°-70° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:14][N:13]=[C:12]([CH:15]([OH:31])[CH:16]([O:29][CH3:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)=[CH:4][C:3]=1[O:32][CH3:33].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:1][C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]([C:10]2[O:14][N:13]=[C:12]([C:15](=[O:31])[CH:16]([O:29][CH3:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2nc(C(O)C(OC)c3ccc(N4CCOCC4)cc3)no2)cc(OC)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(-c2nc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)no2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.8 %

Procedure:
To a solution of 1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinophenyl)ethanol (0.18 g, 0.35 mmol) in anhydr CH2Cl2 (4 mL) under argon was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.198 g, 0.47 mmol). After stirring at room temperature for 50 min, the mixture was diluted with Et2O, saturated aqueous NaHCO3 and 20% Na2S2O3. The layers were separated and the organic layer was washed with saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (40-50% EtOAc-hexanes) gave the product as a bright yellow solid (0.1249 g, 70% yield). MS: m/z 518.1 [M+H]+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:40])[C:24]=1[NH:25][C:26]1[C:35]2[C:30](=[C:31](O)[C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[O:29][C:28](=[O:39])[CH:27]=1>>[CH:13]1([CH2:12][O:11][C:31]2[C:32]([O:36][CH3:37])=[CH:33][CH:34]=[C:35]3[C:30]=2[O:29][C:28](=[O:39])[CH:27]=[C:26]3[NH:25][C:24]2[C:23]([Cl:40])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:18])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC1CCCC1

Procedure:
The title compound was prepared from cyclopentylmethyl 4-methylbenzenesulfonate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 3.91 (s, 3H), 3.84 (d, 2H), 2.28 (m, 1H), 1.80-1.35 (m, 8H); MS (ESI): 434.9.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[O:21][CH3:22])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(N(C)C)=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.[Pd].O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:24]5[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][CH2:34][CH2:35]6)=[CH:36][CH:37]=5)[N:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[O:21][CH3:22])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc2nc(N)nn2c1-c1ccc2c(c1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1ccc2nc(Nc3ccc(OCCN4CCCC4)cc3)nn2c1-c1ccc2c(c1)OCCO2
Temperature: 150 °C

Procedure:
In a microwave vial, 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.05 g, 0.17 mmol), 1-[2-(4-bromophenoxy)ethyl]-pyrrolidine (0.068 g, 0.251 mmol), bis(dibenzylideneacetone)palladium (0.005 g, 0.008 mmol), Xantphos (0.01 g, 0.017 mmol) and sodium tert-butoxide (0.033 g, 0.335 mmol) were added successively. Dioxane (1.2 mL) and dimethylacetamide (2 drops) were added and the vial was sealed and heated in the microwave (150° C., 10 min). The crude was purified using an SCX cartridge, by washing with methanol and releasing the compound with 2M ammonia in methanol. After concentration under reduced pressure, the crude was purified by preparatory LCMS. LCMS Method: 2: RT: 2.52 min, MI: 488 [M+1].