Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([C:15]#[CH:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>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.[Cu](I)I.C1COCC1.C(N(CC)CC)C>[CH:10]1([C:15]#[C:16][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: C#CC1CCCC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(Cl)nc(C#CC2CCCC2)n1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
2,6-Dichloropyrimidin-4-amine (0.2 g, 1.22 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.043 mmol) and copper iodide (14 mg, 0.07 mmol) were introduced in a flask. A mixture of THF-triethylamine 2:3 (5 mL) was added and the system was inertized 3 times with vacuum/argon cycles. Finally, cyclopentyl acetylene (0.16 mL, 1.34 mmol) was added and the resulting mixture was heated at 100° C. overnight. The reaction crude was cooled at room temperature and filtered over Celite®. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.15 g of the title compound, impurified with its regioisomer.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (75 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (19 μL, 0.24 mmol) and triethylamine (37 □L, 0.26 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then loaded directly onto a pre-wetted Biotage 25M column and purified by flash chromatography (0-5% MeOH/CH2Cl2) to give the title compound as a white solid, 77 mg, 83%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.58-8.67 (2 H, m), 7.59-7.69 (2 H, m), 6.97-7.13 (4 H, m), 6.49 (1 H, s), 4.84-4.98 (1 H, m), 4.45 (2 H, dd, J=8.97, 6.44 Hz), 4.05 (2 H, t, J=8.34 Hz), 4.01 (2 H, s,) 3.05 (3 H, s); m/z (APCI+) for C19H19N4O2SF 387.1 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:20]([N:23]([CH:29]([CH3:31])[CH3:30])[C:24](=[O:28])[O:25][CH2:26][I:27])([CH3:22])[CH3:21]>C(#N)C>[I-:27].[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:1]([C:2]2[CH:3]=[N+:4]([CH2:26][O:25][C:24](=[O:28])[N:23]([CH:29]([CH3:31])[CH3:30])[CH:20]([CH3:22])[CH3:21])[CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:11][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CC(C)N(C(=O)OCI)C(C)C
Reactant: CC(=O)Nc1ccc(OC(=O)c2cccnc2)cc1
Solvent: CC#N
Product: CC(=O)Nc1ccc(OC(=O)c2ccc[n+](COC(=O)N(C(C)C)C(C)C)c2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a solution of 4-acetamidophenyl nicotinate [297], (0.05 g, 1.95 mmol, 1.0 eq) in acetonitrile (4 ml) was added iodomethyl diisopropylcarbamate [6304] (0.055 g, 1.95 mmol, 1.0 eq). The resulting reaction mixture was stirred overnight at RT. The reaction was monitored by TLC. Acetonitrile was removed under vacuum and the resulting crude mixture was washed with diethyl ether (10 ml) to give pale yellow solid product 3-((4-acetamidophenoxy)carbonyl)-1-(((diisopropylcarbamoyl)oxy)methyl)pyridin-1-ium iodide [298] (0.086 g, 81%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].C(O)(=S)C.[OH-].[Na+].[N+:12]([C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]([O:23][CH:24]([CH:26]2[CH:29](OC(=O)C)[NH:28][C:27]2=[O:34])[CH3:25])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>O1CCOCC1.O.ClCCl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([O:23][CH:24]([CH:26]2[CH:29]([S:3][C:1](=[O:4])[CH3:2])[NH:28][C:27]2=[O:34])[CH3:25])=[O:22])=[CH:35][CH:36]=1)([O-:14])=[O:13]
Reactant: CC([O-])=S
Reactant: CC(=O)OC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium thioacetate, prepared by treating a solution of thioacetic acid (3.24 g) in dioxane (8 ml) and water (21.5 ml) with 1N aqueous sodium hydroxide, was added to a solution of 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (15.0 g) in dioxane (56 ml) at 0° to 10° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes, diluted with ice-cooled dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetylthio-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16](=[N:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.B.N1C=CC=CC=1.Cl>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1
Reactant: CC(=NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Agent: B
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a suspension of 2-chloro-8-(1-hydroximinoethyl)phenoxathiin (C.A. 66, 2519a, 1967) (425 mg, 1.456 mmol) in ethanol (12 mL) and THF (5 mL) at room temperature there was added pyridine-borane (271 mg, 0.3 mL, 2.92 mmol) and 4M ethanolic HCl (1.1 mL, 4.4 mmole); the mixture was stirred at room temperature overnight, there was added more pyridine-borane (0.35 mL) and 4M ethanolic HCl (2 mL) and stirring was continued for 2 hours. The solvents were evaporated, the residue diluted with water and ethyl acetate and basified with 1N aqueous NaOH. From the organic phase a crude product was obtained which was chromatographed on silica gel, eluting with a 1:1 mixture of ethyl acetate-hexane, to afford the title product (344 mg) as a white solid, m.p.: 103°-105° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:28][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 278 mg (0.75 mmol) of 1,4-dimethyl-6-hexadecyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of chloroform was added 108 mg (0.38 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 5 mL of sat aq NaHCO3. The mixture was extracted with chloroform and the combined organic layer was washed with brine and dried over MgSO4. The concentrated residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave the product as a white solid: yield 331 mg (98%); nip 49-50° C.; silica gel TLC Rf 0.78 (8:1:1 hexanes/ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25-1.31 (m, 28H), 1.66 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.55 (t, 2H, j=8.0 Hz), 2.80 (t, 2H, J=8.4 Hz), 2.90 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3), δ 14.1, 19.5, 22.7, 25.2, 28.7, 29.4, 29.57, 29.61, 29.65, 29.68, 29.71, 29.71, 29.71, 29.71, 29.71, 29.71, 31.9, 33.0, 38.1, 52.4, 110.9, 120.3, 141.1, 156.8 and 161.8; mass spectrum, m/z 451.3 and 453.2 (M+H)+ (theoretical 451.3 and 453.3); mass spectrum (APCI), m/z 451.2680 and 453.2697 (M+H)+ (C25H44N2Br requires 451.2688 and 453.2667).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]2[N:18]=[CH:19][N:20]([CH:21]([CH3:23])[CH3:22])[C:4]=2[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=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.O.C(O)C>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:5]3[N:18]=[CH:19][N:20]([CH:21]([CH3:23])[CH3:22])[C:4]=3[CH:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)cc21
Reactant: OB(O)c1cncc(F)c1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)cc21
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A 5 ml microwave reaction vial was charged with 4-(2-(6-chloro-1-isopropyl-1H-imidazo[4,5-c]pyridin-4-ylamino)ethyl)phenol (c): (17 mg, 0.051 mmol), 5-fluoropyridin-3-ylboronic acid (72 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol). To this mixture was added toluene (1 ml), ethanol (0.5 ml) and aqueous sodium carbonate solution (2M, 0.5 ml). The vial was sealed and the reaction mixture was stirred at 140° C. under microwave irradiation for 2 hours. Water was added to the cooled mixture, which was extracted with ethyl acetate (5 ml×3). The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27]>[OH-].[Na+]>[C:1]([NH:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
140 mg of benzoyl chloride were added tc a solution of 255 mg of 5'-amino-2',5'-dideoxy-5-ethyluridine in 3 ml of 0.33M sodium hydroxide solution and the mixture was shaken vigorously for 5 minutes. The mixture was filtered and the solid was washed with 5 ml of water and 5 ml of diethyl ether, and recrystallized from ethanol to give 140 mg of 5'-benzamido-2',5'-dideoxy-5-ethyluridine of melting point 246°-247° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(OCN1C2N=CN=C(C3C=NN([CH:37]([O:39][CH2:40][CH3:41])[CH3:38])C=3)C=2C=C1)(=O)C(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:37]([O:39][CH2:40][CH2:41][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:38]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, condenser and N2 inlet was charged with 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17, 1.42 kg, 7.32 mol), toluene (9.5 L) and ethyl vinyl ether (18, 790.5 g, 1050 mL, 10.98 mol, 1.50 equiv). A 4 M HCl in dioxane (50 mL) was added via an addition funnel over 10 minutes and the resulting reaction mixture was heated at 35-40° C. for 7 hr to give a clear homogeneous solution. When the reaction was shown to be complete by GC, solid NaHCO3 (130 g) was added and the mixture was stirred for 1 hr before being filtered. The filtrate was concentrated under reduced pressure. Heptane (200 mL) was added to the residue to affect crystallization. The solid was collected by filtration and dried in a vacuum oven to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 1.896 Kg, 1.948 Kg theoretical, 97.3%) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O.Cl>>[OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: Cc1ccc(C(=O)CCC(=O)O)c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)c1ccc(C)cc1O

Procedure:
3-(2-Hydroxy-4-methylbenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1(i), to give methyl 3-(2-hydroxy-4-methylbenzoyl)propionate, m.p. 61°-63°.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([F:20])[CH2:17][C@@H:16]1[CH2:21][OH:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([F:20])[CH2:17][C@@H:16]1[CH:21]=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add triethylamine (6.6 mL, 47.7 mmol) and sulfurtrioxide-pyridine complex (3.8 g, 23.9 mmol) to an ice cold solution of 4-(R)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g, 11.9 mmol) in DMSO (12 mL). Stir 30 min, then warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that is used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: BrCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g (0.199 mol) of 11-bromo-1-undecanol (Aldrich) was dissolved in 500 ml of dichloromethane, and the mixture was cooled to 0° C. 22.15 ml (0.242 mol) of dihydropyran were added dropwise over a period of two hours; the reaction was started by addition of a few crystals of p-toluenesulphonic acid at the beginning of the addition. After the addition was complete, the reaction mixture was stirred for 15 min and stopped by addition of 0.5 g of NaHCO3. After evaporation of the dichloromethane, the pale yellow syrup obtained was dissolved in ethyl acetate and purified by filtration through silica gel. Yield=65.3 g (98%).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl>C(O)CCC.CO>[NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Reactant: CC(C)NCC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
4-Anilino-2,5-dichloropyrimidine (Method 7, 241 ma, 1.0 mmol) was dissolved in n-butanol (20 ml) and methanol (4 ml). 4-[2-Hydroxy-3-(isopropylamino)propoxy]aniline (obtained as described in Pharmazie 1980, 35, 278; 202 mg, 0.9 mmol) and ethereal hydrogen chloride (1.0M; 2 ml, 2.0 mmol) were added and the solution was heated at 100° C. for 20 hours, allowed to cool to ambient temperature and then concentrated to a volume of 5 ml. The solution was loaded on a Varian Mega Bond Elut column and the column was eluted with 0-4% 2.0M methanolic ammonia solution in DCM. Concentration of the appropriate fractions and recrystallization of the residue from acetonitrile gave the product as a white solid (159 mg, 41%). NMR: 1.0 (d, 6H), 2.5-2.6 (m, 1H), 2.65-2.75 (m, 2H), 3.8-3.95 (m, 3H), 4.9 (br s, 1H), 6.8 (d, 2H), 7.1 (t, 1H), 7.35 (t, 2H), 7.45 (d, 2H), 7.65 (d, 2H), 8.1 (s, 1H), 8.7 (s, 1H), 9.1 (s, 1H); MS (MH+): 428, 430.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc2ccccc2c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 391.18 g/mol.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2(C3C=CC=CC=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37]>CN(C=O)C>[C:3]1([C:9]2[C:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C1=C(c2ccccc2)N=NC1(c1ccccc1)c1ccccc1
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCCCC
Product: c1ccc(-c2n[nH]c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 0.83 h
Yield: 181.1 %

Procedure:
A mixture of sodium hydride (50% dispersion, 0.2 g, 4 mmol, prewashed with hexane) and 3,3,5-triphenyl-3H-pyrazole (1.00 g, 3.4 mmol) in DMF (15mL) was heated to 110° C. under an atmosphere of nitrogen. After 50 minutes, the solution was cooled to room temperature and 11-bromoundecene (0.81 g, 3.7 mmol) added. The mixture was stirred at room temperature overnight, poured onto water and extracted with diethyl ether. The combined extracts were washed with water (3×), and saturated sodium chloride solution, dried and the solvent removed. The residue was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (9:1) containing 1% triethyl amine to give 3,4,5-triphenyl-1H-pyrazole -1-undecene (1.51 g, 100%) as an oil. MS(CI): m/e=448 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH2:35][CH3:36])=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[CH2:35]([C@H:26]1[CH2:27][N:28]([CH:31]2[CH2:32][O:33][CH2:34]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:39]4[CH2:51][CH2:50][N:42]5[C:43]6[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=6[CH:49]=[C:41]5[C:40]4=[O:52])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1)[CH3:36]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
A mixture of 131a (150 mg, 0.21 mmol) and LiOH (50 mg, 2.1 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 131 (26 mg, 25%) as a white solid. LCMS: [M+H]+ 665. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0, 1H), 8.50 (d, J=5.0, 1H), 7.93 (d, J=2.5, 1H), 7.83 (d, J=1.5, 2H), 7.38 (d, J=5.0, 1H), 7.27 (d, J=5.0, 1H), 6.90 (s, 1H), 6.83 (d, J=8.5, 1H), 4.73-4.64 (m, 5H), 4.50 (s, 1H), 4.33-4.31 (m, 1H), 4.20-4.16 (m, 2H), 3.88-3.86 (m, 1H), 3.73 (s, 3H), 3.53-3.51 (m, 1H), 3.33 (s, 1H), 3.13 (t, J=5.0, 2H), 2.61-2.56 (m, 4H), 2.45 (d, J=4.0, 2H), 2.37 (s, 1H), 1.91-1.79 (m, 7H), 1.39-1.40 (m, 1H), 0.83 (t, J=7.0, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[C:3]=1[Br:10].C1COCC1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ccc(Br)c(Br)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1c(F)ccc(Br)c1Br
Temperature: 40 °C
Reaction time: 40 h
Yield: 79.4 %

Procedure:
A thick-walled glass vessel was charged with 1,2-dibromo-4-fluoro-3-iodobenzene (8.31 g, 21.88 mmol), Pd(PPh3)2Cl2 (0.768 g, 1.094 mmol), and CuI (0.292 g, 1.532 mmol) and sealed with a rubber septum. Anhyd THF (30 mL) and DIPA (30.8 mL, 219 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic bath. Ethynyltrimethylsilane (3.40 mL, 24.07 mmol) was added via syringe and the septum was replaced with a PTFE bushing. The mixture was stirred in an oil bath at 40° C. After 40 h, the mixture was cooled, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed (satd NH4Cl×2, water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording ((2,3-dibromo-6-fluorophenyl)ethynyl)trimethylsilane (6.08 g, 17.37 mmol, 79% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=8.9, 5.4 Hz, 1H), 6.95 (dd, J=8.9, 8.1 Hz, 1H), 0.29 (s, 9H); MS (GCMS EI) m/z 348 ([M]+, Br isotopes, 18%), 350 ([M]+, Br isotopes, 34%), 352 ([M]+, Br isotopes, 18%), 333 ([M-CH3]+, Br isotopes, 56%), 335 ([M-CH3]+, Br isotopes, 100%), 337 ([M-CH3]+, Br isotopes, 54%).