Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: OB(O)c1ccccc1F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Product: Fc1ccccc1-c1ccc2[nH]ccc2n1
Temperature: 120 °C
Yield: 95.9 %

Procedure:
A mixture of 5-chloro-1H-pyrrolo[3,2-b]pyridine (150 mg, 0.983 mmol, Matrix Scientific), 2-fluorophenylboronic acid (275 mg, 1.966 mmol, Aldrich) and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (80 mg, 0.098 mmol, Strem) was capped, degassed and backfilled with argon (3×). Toluene (2 mL), EtOH (2 mL) and Na2CO3, 2.0 M (0.983 mL, 1.966 mmol) were added, and the reaction was heated to 120° C. in a microwave for 45 min. The solution was diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 1-4% MeOH/DCM), affording 5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (200 mg, 96%). MS (ESI, pos. ion) m/z: 213.1 (M+1).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].ClC1C=CC=CN=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N+:27]([C:30]([N+:34]([O-:36])=[O:35])([CH3:33])[CH2:31][OH:32])([O-:29])=[O:28].O(CC=C)S(C(F)(F)F)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[N+:27]([C:30]([N+:34]([O-:36])=[O:35])([CH3:33])[CH2:31][O:32][CH2:3][CH:2]=[CH2:1])([O-:29])=[O:28]
Reactant: C=CCO
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Agent: C=CCOS(=O)(=O)C(F)(F)F
Agent: Clc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=CCOCC(C)([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A solution of allyl alcohol (16 g, 276 mmol) and 2-chloropyridine (32 g, 282 mmol) in methylene chloride (100 ml) was added over 30 min to a stirred solution of trifluoromethanesulfonic anhydride (78 g, 277 mmol) in methylene chloride (200 ml) at 0° C. The mixture was stirred in an ice bath for 3 h, and then filtered cold to remove the salt byproduct. The brown allyl triflate solution was stored in a freezer for use in the following reaction. A solution of 2,2-dinitropropanol (24 g, 160 mmol) in methylene chloride (100 ml) was added, with ice bath cooling, over 15 min to a stirred mixture of one-half of the allyl triflate solution and anhydrous sodium sulfate (50 g). The ice bath was removed. After the mixture was stirred at room temperature for 17 h, sodium sulfate (40 g) and half of the remaining allyl triflate solution were added. After another 8 his of stirring at ambient temperature, another 40 g portion of sodium sulfate and the remaining allyl triflate solution were added, and stirring was continued for 17 h. The mixture was filtered. The solution was washed with saturated sodium bicarbonate solution and with water. The solution was dried over magnesium sulfate and solvent was removed under vacuum. The brown liquid residue was distilled to give 25.7 g of allyl 2,2-dinitropropyl ether, by 50° C./0.1 mm Hg, 84% yield based on dinitropropanol: HNMR (acetone-d6): 2.20 (s, 3H), 4.15 (t of d, 2H), 4.37 (s, 2H), 5.22 (AB quartet, of d, 1H), 5.30 (AB quartet of d, 1H), 5.90 (m, 1H) ppm; IR (neat): 2890 (m), 1573 (br, vs), 1469 (m), 1445 (m), 1424 (m), 1401 (m), 1383 (m), 1349 (m), 1328 (s), 1273 (w), 1230 (w), 1195 (m), 1099 (br, s), 989 (s), 939 (s), 869 (m), 848 (m), 776 (w), 736 (w) cm−1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:31][CH2:30][C:18]4([CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:31][CH2:30][C:18]4([CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)C4)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(Nc2nccc(NC3CCC4(CCNC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To a solution of tert-butyl 8-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.51 g, 1.19 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (5 mL, 2.83 M) and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and adjusted to pH=8 with saturated Na2CO3 solution, then extracted with DCM (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.17 g, 44%).
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.NCCCCCO.O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([NH:30][C:31](=[O:32])[C:26]=12)=[O:29].P(Br)(Br)[Br:37]>C1(C)C=CC=CC=1.O>[Br:37][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([NH:30][C:31](=[O:32])[C:26]=12)=[O:29]
Reactant: BrP(Br)Br
Reactant: O=C1NC(=O)c2c(CCCCCO)cccc21
Agent: NCCCCCO
Agent: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)c2c(CCCCCBr)cccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Phthalic anhydride (43.0 g, 0.29 mole) and 5-aminopentanol (29.9 g, 0.29 mole) in 250 ml dry toluene (dried over 4A sieves) were heated to reflux in a 120° C. oil bath with stirring for three hours. The system was equipped with a Dean-Stark trap for the azeotropic removal of water (5.3 ml). Upon TLC confirmation of complete formation of the intermediate, 5-hydroxypentylphthalimide (Rf =0.66 (A)), phosphorous tribromide (18.2 ml, 0.19 mole) in 20 ml dry toluene was added dropwise to the hot reaction mixture and the mixture was stirred for 1.5 hours at 100° C. After removal of an orange precipitate by filtration through a pad of Celite, the filtrate was concentrated by rotary evaporation, and the resulting oil was crystallized from absolute ethanol as white plates. Yield: 64.7 g (75.3%). Mp 59.5°-66.0° C. TLC: Rf =0.78 (A). MW calc. 295.10, found 295. Anal. calc. for C13H14NO2Br: C, 52.72; H, 4.76; N, 4.73; Br, 26.98. Found: C, 53.17; H, 4.91; N, 4.62; Br, 27.14. HPLC 100%. 1H NMR (CDCl3) 1.50 (2H, m), 1.72 (2H, m), 1.92 (2H, m), 3.40 (2H, t, 7 Hz), 3.70 (2H, t, 7 Hz), 7.72 (2H, m) and 7.90 (2H, m) for AA'BB"system.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][O:34][CH3:35])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][O:34][CH3:35])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:37]([CH3:36])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:14])=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 4-(cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoic acid (98 mg), ethyl 3-(methylamino)propanoate (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg), hydroxybenzotriazole monohydrate (37 mg) and triethylamine (33 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (93 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2>O1CCCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
Methyl 5-bromo-2,3-dihydro-1H-indole-7-carboxylate (6.5 g, 25 mmol) was dissolved in tetrahydrofuran (100 mL). Activated manganese dioxide (5 μm particle size, 22 g, 0.25 mol) was added and the mixture stirred at room temperature for 16 hours. A further 22 g of activated manganese dioxide was added and the reaction stirred for 96 hours. The reaction was then filtered through celite and concentrated in vacuo to give the title compound (5.1 g) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:28])([F:27])[C:21]1([CH3:26])[CH2:25][CH2:24][CH2:23][NH:22]1.Cl>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:21]1([C:20]([F:28])([F:27])[F:19])[CH3:26])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C(F)(F)F)CCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C(F)(F)F)CCCN1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 8.83 g (0.05 mol) of 2,6-difluorobenzoyl chloride in 10 ml of tetrahydrofuran (THF), to which 5.6 g (0.055 mol) of triethylamine had been added, was added dropwise to a solution of 7.65 g (0.05 mol) of 2-trifluoromethyl-2-methylpyrrolidine in 25 ml of tetrahydrofuran (THF). The reaction is exothermic, and slow dropwise addition prevented the temperature from rising above +35° C. Stirring was continued for one hour at room temperature, and the mixture was then poured into 250 ml of ice-water and acidified using dilute hydrochloric acid, and the precipitate obtained was filtered off with suction, washed thoroughly with water and dried. 9.96 g (68% yield of theory) of N-(2,6-difluorobenzoyl)-2-trifluoromethyl-2-methyl-pyrrolidine of melting point 119°-120° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH:27]([C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][C:31]1[CH:41]=[CH:42][CH:43]=[C:29]([C:27]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Br:26])[C:6]([N:11]4[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:19])[NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)[CH2:13][CH2:12]4)=[C:7]3[N:8]=2)[CH:30]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 5 h
Yield: 27.5 %

Procedure:
To 2-[4-(2-Amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.1 g, 0.22 mmol) in ethanol (5 ml) was added tert-butyl N-(3 formylbenzyl)carbamate (69 mg, 0.29 mmol) and 1M aq. Na2S2O4 (900 μL, 0.9 mmol). The reaction mixture was stirred at 80° C. for 16 h. tert-Butyl N-(3 formylbenzyl)carbamate (20 mg, 0.08 mmol) and 1M aq. Na2S2O4 (200 μL, 0.2 mmol) were added and the reaction mixture was stirred for another 5 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (100% dichloromethane to dichloromethane/ethyl acetate 1:1+1% methanol to 2% methanol in ethyl acetate). The isolated product was further triturated in ether, filtered, and dried in vacuo to give the title compound as a pale yellow solid (0.038 g, 27%); 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, CH3 Boc), 2.78 (broad s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, CH2CO), 3.70 (broad s, 4H, piperazine N(CH2)2), 4.22 (d, J=6.23 Hz, 2H, CH2NHBOC), 7.24 (d, 1H, J=3.60 Hz, thiazole 4-H or 5-H), 7.37 (d, J=7.21 Hz, 1H) and 8.02 (d, J=7.21 Hz, 1H) (4-ArH, and 6-ArH), 7.47 (m, 1H, 5-ArH), 7.49 (d, J=4.12 Hz, 1H, thiazole 4-H or 5-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.54 (s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:31]=[CH:30][C:23]([O:24][CH:25]2[CH2:29][CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][CH:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:33])[F:32])=[CH:31][CH:30]=2)[CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 42 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A6) and 3-(4-trifluoromethyl-phenoxy)-pyrrolidine (Example 25(b)). The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as a light brown solid (yield 42%). MS (m/e): 488.1 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)C#C.C1C2C(=CC=CC=2)C=CC=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.C(=S)=S>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:14]1[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: COc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: S=C=S
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-methyl-4'-methoxybenzophenone was prepared by the Friedel-Crafts reaction of ortho-toluoyl chloride and anisole using aluminum chloride as a catalyst and carbon disulfide as the solvent. 11.1 grams (0.05 mole) of the resulting benzophenone was converted to the propargyl alcohol using the method described in Example 1, Step 2. The crude product was mixed with 6 grams of 2-naphthol and 0.1 gram of p-toluene sulfonic acid in 200 milliliters of benzene and the mixture stirred overnight at room temperature. The resultant reaction mixture was poured into an equal volume of aqueous 5 percent sodium hydroxide to remove unreacted naphthol. The organic layer was washed with water and the benzene solvent removed on a rotary evaporator. The resulting oil residue was column chromatographed on silica using a 1:1 mixture of chloroform and hexane as elutant. The photochromic fractions were combined and the product crystallized from a mixture of hexane and diethyl ether. The product (4.8 grams) had a melting range of 131-133° C. NMR analysis of the product confirmed it to be 3(2-methylphenyl)-3-(4-methoxyphenyl)-3H-naphtho[2,1-b]pyran.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23](=[O:24])[N:22](COCC[Si](C)(C)C)[N:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C(Cl)Cl.C(O)(C(F)(F)F)=O.O.CCO.CCN(C(C)C)C(C)C>CO.C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23](=[O:24])[NH:22][N:21]=[CH:20]4)=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ncn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]ncn1-c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 82d (108 mg, 0.246 mmol) was treated with 5 mL of DCM-TFA-water (30:10:1) and stirred at room temperature for 1 h. EtOH (1 mL) was added and the mixture was concentrated to a pale yellow resin. The resulting material in DCM (10 mL) was treated with solid NaHCO3 (2 g), stirred 20 min, filtered, and concentrated to give a white solid which was purified by flash column chromatography on silica gel (0-25% MeOH-EtOAc) to afford a white solid. A portion (68.1 mg) of this material in MeOH (70 mL) and CHCl3 (20 mL) was treated with DIEA (229 μL, 1.32 mmol), refluxed for 2.5 h, and then concentrated to give a white solid which was purified by flash column chromatography on silica gel (0-25% MeOH-EtOAc) to afford the title compound 65 as a white solid. 1H-NMR (CDCl3-MeOH (3:1), 400 MHz): δ 8.15 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (ddd, J=8.4, 7.0, 1.5 Hz, 1H), 7.67-7.70 (m, 2H), 7.58-7.63 (m, 2H), 7.52-7.58 (m, 1H), 7.36-7.40 (m, 2H), 7.29 (s, 1H), 4.12-4.17 (m, 4H), 3.81-3.86 (m, 4H), 3.38-3.44 (m, 2H), 3.27-3.33 ppm (m, 2H). Mass spectrum (LCMS, ESI pos.): Calcd. for C29H26N8O2, 519.2 (M+H). found 519.0.
Reaction SMILES: N1C=CC=CC=1.ClCCl.[C:10]([O:14][C:15]([NH:17][C@H:18]([CH2:23][OH:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>CS(C)=O.O>[C:10]([O:14][C:15]([NH:17][C@@H:18]([C@@H:19]([CH3:20])[CH2:21][CH3:22])[CH:23]=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of pyridine--sulfur trioxide complex (5.1 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) was added dropwise a solution of (S)-N-(tert-butoxycarbonyl)-isoleucinol (1.4 g, 6.5 mmol) and triethylamine (3.2 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) under an argon gas stream and ice-cooling. After stirring for 30 minutes, the reaction solution was poured into water, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous citric acid solution, an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanal (1.3 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10](I)[N:5]2[N:4]=1)[CH3:2].[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.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]>[CH2:1]([C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]2[N:4]=1)[CH3:2]
Reactant: OB(O)Oc1ccccc1
Reactant: CCc1cc2c(C=O)ccc(I)n2n1
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1cc2c(C=O)ccc(-c3ccccc3)n2n1
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 95.2 %

Procedure:
The compound of Example 130 (50.0 mg), phenylboric acid (22.4 mg), tris(dibenzylideneacetone)dipalladium (3.1 mg), tri-n-butylphosphine (17.0 μL) and cesium carbonate (65.3 mg) were suspended in dioxane in an argon atmosphere. The suspension was stirred at 80° C. for 6.5 hours. Subsequently, the reaction mixture was diluted with methylene chloride and filtered through Celite. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a yellow oil (38.7 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[Br:29][CH2:30][C:31](O)=[O:32]>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC.CCOC(C)=O>[Br:29][CH2:30][C:31]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])=[O:32]
Reactant: O=C(O)CBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CC(=O)CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A mixture of 100 mg of cholesterol and 40 mg of bromoacetic acid (1.1 eq) was dissolved in 10 mL of anhydrous dichloromethane. Then 44 μl (1.1 eq) of DIPC(N,N-diisopropylcarbodiimide) and 1.5 mg (0.05 eq) of DMAP (4-dimethylaminopyridine) were added. The solution was left stirring at room temperature for 48 h and analyzed by TLC using a mixture of n-hexane/EtOAc 10/1 as solvent systems. The solvent was evaporated and the reaction product was purified by silica gel flash chromatography in n-hexane/dichloromethane 1/1. The fractions containing the product were pooled, evaporated and then lyophilized in water/acetonitrile 20/80. The purified product was analyzed by NMR. Yield: 73%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.3 %

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (200 mg, 0.673 mmol) was dissolved in THF (5 mL) and morpholine (0.088 mL, 1.01 mmol) was added. The mixture stirred overnight at room temperature and was then filtered and concentrated to afford the title compound (223 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.79 (d, 2H), 7.36 (d, 2H), 3.73 (t, 4H), 3.55 (s, 2H), 2.47 (t, 4H).