Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.B1C2CCCC1CCC2.FC(F)(F)S(O[C:24]1[CH2:38][C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@H:36](/[CH:47]=[CH:48]/[C@@H:49]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:50][C@H:51]([CH3:56])[CH2:52][CH2:53][CH2:54][CH3:55])[C:25]=1[S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O-][Si]([O-])=O.[Mg+2]>O1CCCC1>[CH2:1]([C:24]1[CH2:38][C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@H:36](/[CH:47]=[CH:48]/[C@@H:49]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:60])[CH3:59])[CH2:50][C@H:51]([CH3:56])[CH2:52][CH2:53][CH2:54][CH3:55])[C:25]=1[S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OS(=O)(=O)C(F)(F)F)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: C=Cc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: O=[Si]([O-])[O-]
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(CCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.4 %

Procedure:
Styrene (150 μl, 1.0 mmol) in tetrahydrofuran (3 mL) was ice-cooled, then 9-BBN, (0.5M THF solution, 2.1 mL, 1.05 mmol) was added. This was agitated for 6 hours while gradually raising the reaction temperature to room temperature. Further, to this were added methyl (11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (233 mg, 0.3 mmol), bistriphenylphosphinepalladiumchloride (70 mg, 0.1 mmol), and tripotassium phosphate (255 mg, 1.2 mmol) in tetrahydrofuran (5 mL) suspension. The reaction mixture was agitated at 60° C. for 15 hours. The reaction solution was cooled, then subjected to Florisil column chromotography to remove the metal complexes. The obtained solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (2 to 4% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (104 mg, 48%).
Reaction SMILES: [Na+:1].[Cl-].C(N(CC(O)=O)CC(O)=O)C[N:5](CC(O)=O)[CH2:6][C:7]([OH:9])=[O:8].CC(CC(C1C=CC(OCCOCCO)=CC=1)(C)C)(C)C.C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4CC[C@@]3(C)[C@@H]2CC1)CCC([O-])=O.[Na+].C(N)(=O)C=C.[CH2:79]([OH:86])[C:80]([NH2:85])([CH2:83][OH:84])[CH2:81][OH:82].[CH3:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][O:99][S:100]([O-:103])(=[O:102])=[O:101].[Na+].CN(CCN(C)C)C>>[CH2:79]([OH:86])[C:80]([NH2:85])([CH2:83][OH:84])[CH2:81][OH:82].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][O:99][S:100]([O-:103])(=[O:102])=[O:101].[Na+:1]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: C=CC(N)=O
Agent: CC(C)(C)CC(C)(C)c1ccc(OCCOCCO)cc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Product: NCC(=O)O
Reaction time: 0.17 h

Procedure:
Western blotting was performed with the compound of the example 64 of the present invention. A375P cell line was lysed by using RIPA buffer solution (50 mM tris pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.25% sodium deoxycholate) containing phosphatase inhibitor (Phosphatase inhibitor cocktail I & II) and protease inhibitor (Complete, Mini, EDTA-free; Roche Applied Science), and centrifuged at 13000 rpm for 10 min. Whole protein was stained with Bio-Rad agent (bio-rad #500-0006) and quantitated by comparing with BSA (positive control). 12% gel was prepared by using 30% acrylamide, 1.5 M Tris (pH 8.8), 10% SDS solution, 10% PAS solution and TEMED. After loading 100 ug of protein per one lane of gel, proteins were isolated by sodiumdodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE, 250 mM Tris base, 2.5 M Glycine, 0.1% SDS, 140V, electrophoresis for 2 h), and transferred to nitrocellulose filter at 200 mA for 2 h. The results are weakly reacted with an antibody[Rabbit anti-Map Kinase (Zymed #61-7400) and phosphor-p44/42 MAP kinase (Thr202/Tyr204) (Cell signaling #9101)] at 4° C. for a day. Further, it is washed with TBST buffer solution containing 0.05% tween20 at 4 times every 5 minutes. The results are weakly reacted with secondary antibody[anti-rabbit IgG (Amersham #NA934V)] for one hour at room temperature, and washed by the same manner. Protein bands were identified with imaging apparatus (Gelliance). The results is shown in FIG. 1.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[C:16]3[C:17]4[C:11]([C:12](=[O:18])[O:13]2)=[CH:10][C:9]([NH2:19])=[CH:8][C:7]=4[O:6][C:5](=[O:20])[C:4]=3[CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=O.C(Cl)(Cl)Cl.CO>O1CCCC1>[N:28]1([CH:26]=[N:19][C:9]2[CH:8]=[C:7]3[C:17]4[C:16]5[C:4]([C:5](=[O:20])[O:6]3)=[CH:3][C:2]([N:1]=[CH:26][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:15][C:14]=5[O:13][C:12](=[O:18])[C:11]=4[CH:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=CN1CCCC1
Reactant: Nc1cc2oc(=O)c3cc(N)cc4oc(=O)c(c1)c2c43
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1oc2cc(N=CN3CCCC3)cc3c(=O)oc4cc(N=CN5CCCC5)cc1c4c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A suspension of 2,7-diamino-5,10-dioxo-4,5,9,10-tetrahydro-4,9-dioxapyrene (500 mg) in tetrahyrofuran (4 ml) was added to a mixture of phosphorus oxychloride (0.7 ml) and N-formylpyrrolidine (2 ml) and tetrahydrofuran (4 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 80° C. for 1 hour and worked up as described in Example 1, paragraph 1. Yield 68%, melting point 275° C. (decomposition) (CHCl3 /methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:21][C:22](=O)/[CH:23]=[C:24](\[NH:26][C:27](=O)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)/[CH3:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:22](=[O:21])[CH:23]=[C:24]([CH3:25])[N:26]=[C:27]2[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCN(C)CC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (0.63 g, 3.01 mmol) in DCM (15 mL) was added trimethylaluminium (5.3 mL, 10.6 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (0.80 g, 2.99 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 12 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.94 g, 73%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[O:13]C.O>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[OH:13]
Reactant: COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)c(O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
56 g of 4-(2,4-dichlorophenoxy)-3-methoxybenzonitrile are dissolved in 120 ml of dichloromethane. At 0°, a 1M solution of borontribromide in dichloromethane is added slowly in 4 portions of 6 ml each. The reaction mixture is then stirred for 2 days at room temperature. After renewed cooling to 0°, water is added carefully until no reaction is observed any more. The reaction mixture is then washed with water, a saturated aqueous solution of sodium bicarbonate and finally with brine. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from ether/hexane to yield 4-(2,4-dichlorophenoxy)-3-hydroxybenzonitrile.
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[CH:22][C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1>C(OC(=O)C)(=O)C>[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[C:22]([N+:5]([O-:8])=[O:6])[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2c1ccccc1
Yield: 48.1 %

Procedure:
The mixed solution of acetic anhydride (3 ml) and acetic acid (3 ml) was cooled and nitric acid (3 ml) was added cautiously with stirring. Then a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydrobenzofuran (3.7 g, 13.9 mmol) in acetic anhydride (3 ml) was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 9:1) and crystallized from methanol to obtain the desired compound (2.08 g, yield: 48.1%), m.p. 155°-156° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>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].O1CCOCC1>[CH2:34]([NH:41][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (150 mg, 0.28 mmol), benzylamine (42 mg, 0.39 mmol), Pd2(dba)3 (16 mg, 10% mmol), DavePhos (22 mg, 20% mmol), t-BuONa (37 mg, 0.39 mmol) and dioxane (10 mL). The mixture was stirred at 130° C. under an atmosphere of N2 for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: MeOH, 100:1) to give [3-(6-benzylamino-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 90 mg, 57%).
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[CH2:8][O:9][C@@H:10]1[O:15][C@@H:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:13][CH2:12][CH2:11]1>C(OCC)C>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:6]([Cl:5])[C:7]=1[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cccc(Cl)c1CO[C@H]1CCC[C@H](Cn2ccnc2)O1
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: Clc1cccc(Cl)c1COC1CCCC(Cn2ccnc2)O1
Yield: 97803.5 %

Procedure:
When 0.2 ml of 69% w/v aqueous nitric acid was added to a solution of 865 mg of trans-1-[6-(2,6-dichlorobenzyloxy)tetrahydropyran-2-ylmethyl]imidazole in 10 ml of diethyl ether, the solution became turbid and an oily layer separated. After decanting off the ethereal layer, more diethyl ether was added to the residue to aid crystallization and the precipitated crystals were filtered, to give 846 g of the title product. Further recrystallization of these crystals from a mixture of acetone and ethyl acetate gave the title product in the form of colourless crystals melting at 117° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[NH4+].[Cl-]>C1COCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[C:1]#[CH:2])[CH:9]=[C:8]([O:7][CH3:6])[CH:21]=1
Reactant: [Li]CCCC
Reactant: COc1cc(OC)cc(C(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)(c1ccccc1)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
The following method was adapted from a literature procedure.vii Anhydrous THF (50 mL) was cooled to −78° C. Purified acetylene gas was gently bubbled through the THF for 1 hour. A 2.5M solution of n-butyllithium in THF (8.2 mL, 20.5 mmol) was then added drop-wise and the mixture was stirred vigorously for 20 minutes. 3,5-Dimethoxybenzophenone (5.0 g, 20.5 mmol) was dissolved in 10 mL of anhydrous THF and the solution was slowly dropped into the reaction flask. The mixture was stirred vigorously for 20 minutes at −78° C. before being allowed to slowly warm to room temperature. A 5% aqueous solution of NH4Cl (60 mL) was added and the mixture stirred for 30 minutes. The product was extracted with ether (3×100 mL) and the combined organic layers were washed with brine (100 mL) and water (75 mL) before being dried with anhydrous magnesium sulfate. The filtrate was dried in vacuo to afford 1-(3,5-dimethoxyphenyl)-1-phenylprop-2-yn-1-ol as a yellow oil in 95% yield. 1H NMR (CDCl3): δ 7.62 (d, 3JH-H=7.2 Hz, 2H), 7.33 (t, 3JH-H=6.4 Hz, 2H), 7.29 (d, 3JH-H=7.2 Hz, 1H), 6.79 (d, 3JH-H=2.4 Hz, 2H), 6.37 (t, 3JH-H=2.4 Hz, 2H), 3.76 (s, 6H), 3.16 (s, 1H), 2.85 (s, 1H). 13C{1H} NMR (CDCl3): δ 160.68, 146.99, 144.35, 128.39, 127.99, 126.03, 104.60, 99.84, 86.45 (C2), 75.56 (C1), 74.33, 55.46. HR-MS (FAB+) Calculated for C17H17O3, 269.1172. found, 269.1178.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([OH:40])[CH:30]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Cl[CH2:50][CH2:51][O:52][CH:53]1[CH2:55][CH2:54]1>CN(C=O)C>[CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([O:40][CH2:50][CH2:51][O:52][CH:53]3[CH2:55][CH2:54]3)[CH:30]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: ClCCOC1CC1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc(OCCOC2CC2)c1
Temperature: 100 °C

Procedure:
To a solution of trans-tert-butyl 3-({cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1.0 eq., Example 92) in DMF (0.1 M) was added cesium carbonate (2 eq.), sodium iodide (0.05 eq.) and (2-chloroethoxy)cyclopropane (3 eq.). The reaction mixture was heated at 100° C. for 22 h. After cooling to RT, the reaction was quenched with sat. aq. ammonium chloride and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 95:5 (v/v) CH2Cl2:MeOH) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:16]([NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 0.441 g, 2.12 mmol) is dissolved in dry N,N-dimethylformamide (8 mL) in a 50 mL round bottom flask under an inert atmosphere. A 2.12 M solution of octadecylisocyanate (2.12 mmol) in dry N,N-dimethylformamide (1 mL) is then added dropwise. The residual octadecylisocyanate solution is quantitatively transferred with 2 portions of N,N′-dimethylformamide (1 mL each) and the reaction is stirred overnight at room temperature. The reaction is then heated to 100° C. for 22 h, and then cooled to room temperature to give a white slurry. The solid is then vacuum filtered, washed with fresh N,N-dimethylformamide followed by deionized water. The filtrate is then concentrated by rotary evaporation to give a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15](OCC)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH3:22]>C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([NH2:22])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)COc1ccc(OCCn2ccnc2)cc1
Reactant: N
Solvent: CCO
Product: NC(=O)COc1ccc(OCCn2ccnc2)cc1
Reaction time: 20 h

Procedure:
A mixture of ethyl 4-[2-(1-imidazolyl)ethoxy]phenoxyacetate free base (1.0 g), ethanol (10 ml) and concentrated ammonia solution (20 ml) was allowed to stand at room temperature for 20 hours to give a clear solution. The solution was evaporated and the residue was crystallized twice from 2-butanone to give 4-[2-(1-imidazolyl)ethoxy]phenoxyacetamide (0.38 g), m.p. 123°-124° C. Found: C, 59.70; H, 5.77; N, 16.26. C13H15N3O3 requires: C, 59.76; H, 5.79; N, 16.08%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:20]#[C:21]Br.O>C1COCC1.C(OCC)(=O)C>[O:7]([CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:21]([NH2:20])=[N:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H](CO)CCOc1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@H](CCOc2ccccc2)CO1
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a stirred mixture of (S)-2-amino-4-phenoxy-butan-1-ol (175 mg) and K2CO3 (200 mg) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (123 mg) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) yielded the title compound as a white solid, (62 mg, 31%); MS (ISP): 207.1 ((M+H)+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[S:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[S:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccc(Cl)s1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
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: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(C=O)s2)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 5 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (848 mg) and 5-chlorothiophene-2-carboaldehyde (764 mg) were suspended in a mixed solvent of toluene (20 mL) and THF (15 mL), and to the suspension 2 M sodium carbonate (8 mL) was added. Tetrakis(triphenylphosphine)palladium(0) (231 mg) was added to the mixture under an argon atmosphere, and the mixture was stirred at 90° C. for 5 hours as it is. After allowing the reaction mixture to cool, ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:17].[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.CC([O-])=O.[K+]>>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[O:13][C:14]3[C:4]([C:5](=[O:17])[C:6]=2[CH:11]=1)=[CH:3][C:2]([C:24]1[C:19]([F:18])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][CH:15]=3
Reactant: OB(O)c1cccnc1F
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: CC(=O)[O-]
Agent: [K+]
Product: O=c1c2cc(-c3cccnc3F)ccc2oc2cnc(Cl)cc12
Temperature: 120 °C

Procedure:
A vial was charged with 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3 g, 9.66 mmol), 2-fluoropyridin-3-ylboronic acid (1.497 g, 10.63 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(H) (0.684 g, 0.966 mmol), and KOAc (1.510 mL, 24.15 mmol). The vial was evacuated and backfilled with nitrogen (this procedure was repeated twice). ACN (20 mL), dioxane (30 mL) and water (3 mL) were added, and the vial was sealed and the reaction mixture was heated to 120° C. for 4 h. The reaction mixture was cooled to RT. Upon addition of EtOAc, a solid precipitated which was filtered off and dried under vacuum to provide 3-Chloro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one as a tan solid.