Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:28]([O:30][C:31](=[O:37])[C:32](OCC)=[O:33])[CH3:29]>C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH:26]=[C:32]([OH:33])[C:31]([O:30][CH2:28][CH3:29])=[O:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
Sodium metal (1.35 g, 58 mmol) was cut into small pieces, rinsed with hexane to remove mineral oil, and added portion wise to anhydrous EtOH (100 ml) under a nitrogen atmosphere over a period of 20 min. The reaction mixture was stirred for a further 10 min until all sodium had reacted. 1-[2,4-bis(benzyloxy)-5-chlorophenyl]ethanone (10 g, 27.3 mmol) was added portion wise over 5 min, and the resulting suspension was then stirred for further 5 min at RT. Diethyloxalate (6 ml, 43 mmol) was added, resulting in a thick yellow coloured precipitate. The reaction mixture was heated to reflux for 4 h, affording a dark homogeneous solution, which, upon cooling, produced a solid mass to which acetic acid (6 ml) was added. The mixture was triturated to afford a yellow solid, which was filtered, washed sequentially with water, EtOH, and Et2O, and then dried under vacuo to afford the title compound ethyl 4-(2,4-bis(benzyloxy)-5-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate (12.4 g, 98%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.N([O-])=O.[Na+].[CH3:24][CH2:25][O:26][C:27]([S-:29])=[S:28].[K+]>Cl.O>[C:27](=[S:28])([O:26][CH2:25][CH3:24])[S:29][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)Sc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
Reaction of 4-fluoro-nitrobenzene with 4-trifluoromethoxyphenol in the presence of KOtBu as described in Example 74A, followed by reduction of the nitro group (hydrogen, 10% Pd/C) gave 4-(4-trifluoromethoxyphenoxy)-aniline. The aniline (4.58 g, 17 mmol) was dissolved in conc. HCl (3.1 mL) and ice (4.5 g) cooled to −5 C., then treated with a solution of NaNO2 (1.17 g, 17 mmol) in water (7mL) which was added dropwise. The cold soltion was added to an aqueous (7 mL) solution of potassium xanthate (5.46 g, 34 mmol) and the resulting mixture was heated at 70 C for 2 h, then allowed to cool to rt and partitioned between EtOAc and water. The organic extract was dried (MgSO4), filt ered and concentrated to give the title compound
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=O)C.N>CO>[Cl:15][C:9]1[C:8]2[C:13](=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1
Agent: N
Solvent: CO
Product: Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1
Yield: 77.6 %

Procedure:
A mixture of 7-acetoxy4-chloro-5-cyclopentyloxyquinazoline (1 g), a saturated methanolic ammonia solution (10 ml) and methanol (10 ml) was stirred at ambient temperature for 30 minutes. The mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with water and dried under vacuum to give 4-chloro-5-cyclopentyloxy-7-hydroxyquinazoline (0.67 g); NMR Spectrum: (DMSOd6) 1.6–1.75 (m, 2H), 1.75–1.85 (m, 2H), 1.85–2.05 (m, 4H), 5.0 (m, 1H), 6.72 (d, 1H), 6.8 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 265.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][N:21]=[CH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=3)[CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Yield: 93.7 %

Procedure:
A mixture of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was dissolved in hot water. Cold 2N hydrochloric acid (1.0 mL) was added dropwise and the product was allowed to crystallize and was filtered, washed with water and dried to give 0.45 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 260° C. with decomposition.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:48][CH:49]1[C@H:53]2[C@H:54](OC3CCCCO3)[N:55](C(OC(C)(C)C)=O)[C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 94.4 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15f (190 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16f (105 mg, 0.17 mmol, 96%) as a solid: [α]20D=+1330° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.32-1.58 (m, 8H, 14-H, 14′-H, 15-H, 15′-H), 1.78-1.92 (m, 4H, 13-H, 13′-H), 1.93-2.10 (m, 4H, 2-H, 2′-H), 2.26-2.38 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.89 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.15 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.2; 29.6; 46.6; 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.2, 164.67; IR (neat): 3326, 2934, 1599, 1505, 1455, 1431, 1382, 1261, 1216, 1092, 1019 cm−1; MS (FAB) m/z (relative intensity) 667 ([M+2×MeOH]+., 3), 635 ([M+MeOH]+., 8), 603 (M+., 100).
Reaction SMILES: [F-].[Na+].F[C:4]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]>CN(C)C=O>[CH:16]1([N:15]2[C:19]3[C:5](=[CH:4][C:22]([F:23])=[C:21]([F:24])[C:20]=3[F:25])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 90 %

Procedure:
21.2 g of sodium fluoride are added to a solution of 107.8 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate in 400 ml of anhydrous dimethylformamide. The reaction mixture is then stirred under reflux for 2 hours and, while hot, poured onto ice. The precipitate is filtered off with suction, thoroughly washed with water and dried over calcium chloride at 100° C. in vacuo. 91.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 167°-168° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([CH:5]=[O:6])([CH3:4])[CH3:3].[NH2:7][C:8]1[C:9](O)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].C>>[C:2]([C:5]1[O:6][C:9]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=[CH:17][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: CC(C)(C)C=O
Agent: C
Product: COC(=O)c1cccc2nc(C(C)(C)C)oc12
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of pivaldehyde (1.65 mL, 15.4 mmol), methyl 3-amino-2-hydroxybenzoate (501 mg, 3.0 mmol) and Darco KB-B (375 mg) in xylenes (8 mL) was heated under an oxygen atmosphere at 120° C. for 12 h. The reaction mixture was cooled to room temperature, filtered through a celite pad. The filtrate was concentrated and the crude material was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate) to afford the desired methyl 2-tert-butylbenzoxazole-7-carboxylate (417 mg, 60%) as a light orange oil: 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J=7.8, 0.9 Hz, 1H), 7.88 (dd, J=7.8, 0.9 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 4.01 (s, 3H), 1.54 (s, 9H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:24][C@@:15]2([C:25]([O:27]CC)=[O:26])[NH:14][C:13](=[O:30])[C@@H:12]2[CH2:31][C@@H:32]([O:34][C:35]([N:37]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][C:43]=4[F:46])[CH2:38]3)=[O:36])[CH2:33][N:11]2[C:10]1=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:24][C@@:15]2([C:25]([OH:27])=[O:26])[NH:14][C:13](=[O:30])[C@@H:12]2[CH2:31][C@@H:32]([O:34][C:35]([N:37]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][C:43]=4[F:46])[CH2:38]3)=[O:36])[CH2:33][N:11]2[C:10]1=[O:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCOC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\COCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCOCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecine-14a-carboxylate (0.18 g, 0.27 mmol) in THF (2 mL) was added 0.1 N NaOH solution (6.64 ml, 0.62 mmol) in H2O. The reaction was stirred at rt for 26 hr. Water (5 mL) and ether (15 mL) was added. The aqueous layer was separated and acidified by saturated potassium hydrogen sulfate solution to pH=2-3. The aqueous layer was extracted with EA (2×15 mL), washed with brine and dried over sodium sulfate. After removal of solvent, it gave (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecine-14a-carboxylic acid as white solid (0.15 g, 92%). MS: Calcd.: 630. Found: [M+H]+ 631. 1H NMR (400 MHz, d6-DMSO) δ 12.29 (s, 1H), 8.59 (d, J=13.2 Hz, 1H), 7.36 (m, 1H), 7.10-7.20 (m, 3H), 5.59 (m, 1H), 5.50 (m, 1H), 5.30 (s, 1H), 4.66 (s, 4H), 4.51 (m, 1H), 4.41 (m, 1H), 4.23 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.50 (m, 1H), 3.37 (m, 2H), 2.35 (m, 1H), 1.78 (m, 2H), 1.51 (m, 2H), 1.37 (m, 2H), 1.24 (m, 2H), 1.08 & 1.09 (s, 9H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[N:18]3[CH:19]=[C:20]([C@@H:23]([N:28]4[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]4)[C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=1)[CH:10]=[CH:9]2)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[N:18]3[CH:19]=[C:20]([C@@H:23]([N:28]4[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]4)[C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=1)[CH:10]=[CH:9]2)[CH3:2]
Reactant: CCSc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Solvent: O=C(O)C(F)(F)F
Product: CCSc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Yield: 35.3 %

Procedure:
tert-butyl (S)-1-((R)-1-(3-(8-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (55 mg, 0.096 mmol) was stirred in TFA for 30 minutes. The reaction was concentrated to dryness, and the residue was diluted in 1 mL of methanol and added dropwise into 4N HCl in ether. The resulting precipitate was filtered and dried under vacuum to yield (S)-1-((R)-1-(3-(8-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (16 mg, 35% yield) hydrochloride as a solid. LCMS APCI (+) m/z 473 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrC1C=CC=CC=1.[Li]>CCOCC>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH2:2][CH2:3]2)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]c1ccccc1
Reactant: O=C(O)c1cccc2c1NCC2
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cccc2c1NCC2
Temperature: 25 °C

Procedure:
A stirred mixture of 0.165 mole (25 g.) of indoline-7-carboxylic acid and 800 ml. of dry ether was treated dropwise with 0.435 mole of phenyllithium which was prepared from 157 g. (0.435 mole) of bromobenzene, 6.94 g. (0.87 mole) of lithium wire and 500 ml. of dry ether. After addition of the phenyllithium, the reaction mixture was refluxed for three hours and then poured onto ice. After warming to room temperature, the mixture was filtered and the ether layer was separated from the aqueous layer. After washing the ether extract with 1N hydrochloric acid, the product was extracted into 12 N hydrochloric acid. Neutralization of the acidic extract caused precipitation of crude product. The product melted at 119°-122°C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[CH:51]=[CH:50][N:49]=1.[CH2:62]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][CH2:64][NH:63]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:61][O:60][C:54]1[CH:53]=[C:52]2[C:57](=[CH:56][C:55]=1[O:58][CH3:59])[C:48]([N:63]1[CH2:64][CH2:65][C:66]3[C:71](=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:62]1)=[N:49][CH:50]=[CH:51]2
Reactant: COc1cc2ccnc(Cl)c2cc1OC
Reactant: c1ccc2c(c1)CCNC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ccnc(N3CCc4ccccc4C3)c2cc1OC
Yield: 87.1 %

Procedure:
Palladium acetate (25 mg 0.112 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (209 mg, 0.335 mmol) were heated to 80° C. in toluene (25 mL) for 20 min. To the mixture was added 500 mg (2.24 mmol) of 1-chloro-6,7-dimethoxy-isoquinoline, 298 mg (2.24 mmol) of tetrahydroisoquinoline, and 4.47 mL (4.47 mmol) of a 1.0 M solution of potassium tert-butoxide in THF. After stirring at reflux for 4 h, the mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated. Silica gel chromatography (4:1 hexanes/EtOAc) provided 625 mg (87%) of the title compound as a yellow oil. The hydrochloride salt (387 mg) was obtained after treatment with concd. HCl in isopropanol and recrystallization from EtOH/MeOH.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([NH:15][C:16]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:17][O:18][C:19](=[O:21])[CH3:20])(=[O:14])[CH3:13].CCOCC.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[C:12]([NH:15][C:16]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:22][O:23][C:24](=[O:26])[CH3:25])(=[O:14])[CH3:13]
Reactant: CCCCCCC(O)CCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCC(=O)CCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Pyridinium chlorochromate (301.5 mg) was added to a solution of 2-acetamido-1,3-diacetoxy-2-(8-hydroxytetradecyl)-propane (300 mg) in dichloromethane (19 ml) and the mixture was stirred at room temperature for 2 hours in a stream of nitrogen. Ether (38 ml) and magnesium sulfate (appropriate amount) were added thereto and the mixture was stirred for 10 minutes. The reaction mixture was suction-filtered and the filtrate was concentrated. The concentrate was extracted with ethyl acetate and the ethyl acetate layer was washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate solution and saturated brine in order. The resultant mixture was dried over magnesium sulfate. The solvent was distilled away to give the subject compound (290 mg).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:43][O:42][C:24]1[CH:23]=[C:22]([CH:41]=[CH:40][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:21][O:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (700 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (930 mg), potassium carbonate (750 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (1.35 g, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:4].B(Br)(Br)Br>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:4]
Reactant: COc1ccc(Sc2ccc(CCNC(=O)C(F)(F)F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCCc1ccc(Sc2ccc(O)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
Under nitrogen at 4° C., to a solution of 2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]-acetamide (1.5 g) in dichloromethane (15 ml) was added 1M boron tribromide in dichloromethane (10.5 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate. After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 2,2,2-trifluoro-N-[2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]acetamide (1.42 g).
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34]([N:7]1[CH:8]2[CH2:9][CH2:10][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)=[O:35]
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: COCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-methoxyethyl chloroformate (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[ClH:28]>CO>[ClH:28].[NH:12]1[CH2:11][CH2:10][CH:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:2](=[O:1])[CH:7]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3cccnc3)c(=O)c2)CC1
Agent: Cl
Solvent: CO
Product: O=c1cc(OC2CCNCC2)ccn1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of tert-butyl 4-(2-oxo-1-(pyridin-3-yl)-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (142 mg, 0.382 mmol), hydrogen chloride (4.0 M in 1,4-dioaxne, 1.5 mL, Aldrich) in MeOH (1.5 mL) was stirred at room temperature for 45 min and then concentrated to give the product (115 mg) as a light orange solid. The material was used in the next step without further purification. MS (ESI) 272 (M+H).