Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S@@:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:27][C:28]1[CH:36]=[C:32]([C:33]([N:9]=[S@:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: COC(=O)CCCC[S@](=N)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of (S)-Methyl 5-(S-phenylsulfonimidoyl)pentanoate (475 mg, 1.86 mmol) in anhydrous DMF (6 mL) at room temperature under nitrogen atmosphere was added diisopropylethylamine (0.65 mL), 5-bromonicotinic acid (0.38 g), and (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (0.81 g). The resulting reaction mixture was stirred for about 15 min at room temperature and then poured into saturated aqueous NaHCO3. The aqueous was extracted with EtOAc (1×), which was then washed with saturated aqueous NaHCO3 and brine (v:v 1:1, 2×), brine (1×), and dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. A column chromatography (EtOAc-Hex 1:2) rendered the title compound as slightly yellow colored solid in amount of (616 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][C:15]([NH2:19])([CH3:18])[CH2:16][NH2:17]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][CH2:16][C:15]([CH3:18])([NH2:19])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(N)CN
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(Cl)nc(NCC(C)(C)N)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-1,2-diamine (365 μL, 3.52 mmol) in methanol (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and stirred for 30 minutes. The formed solid was collected by filtration and dried in vacuo to afford 500 mg of the desired product as a white solid (yield was 80.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([C:23](=[O:33])[C:24]#[C:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([C:23](=[O:33])[C:24]#[C:25][C:26]([OH:28])=[O:27])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8]
Reactant: COc1cc(C(=O)C#CC(=O)OC(C)(C)C)ccc1OCC(=O)Nc1nc2ccccc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)C#CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonylpropioloyl)phenoxymethylcarbonylamino]benzothiazole (0.5 g) in methylene chloride (30 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at room temperature for 4 hours. The mixture is concentrated, and to the residue is added methylene chloride. The mixture is stirred, and the precipitated crystals are collected by filtration, and recrystallized from dichloromethane-trifluoroacetic acid to give 2-[2-methoxy-4-(3-carboxypropioloyl)phenoxymethylcarbonylamino]-benzothiazole (0.26 g) as brown powder.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([CH2:31][O:32][C:33]2[N:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[N:35][C:34]=2[N:42]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:50][O:51][C:52](=[O:59])[C@H:53]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH2:54]>>[CH3:50][O:51][C:52](=[O:59])[C@@H:53]([NH:54][C:39]([C:37]1[CH:36]=[N:35][C:34]([N:42]2[CH2:47][CH2:46][C:45]([F:48])([F:49])[CH2:44][CH2:43]2)=[C:33]([O:32][CH2:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:38]=1)=[O:40])[CH2:55][CH:56]([CH3:58])[CH3:57]
Reactant: O=C(O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-cyclopentylmethoxy-5-(4,4-difluoro-piperidin-1-yl)-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 469.1 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCI
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a mechanically stirred solution of 10-bromodecanoic acid (50 g, 0.2 mol) in 1 L of acetone under nitrogen was added sodium iodide (238.7 g, 1.59 mol) and the resulting heterogeneous reaction mixture was allowed to stir at room temperature for 18 h. The thick reaction mixture was filtered through a pad of Celite 521, concentrated in vacuo to one-fifth volume and diluted with 1 L of brine. This was extracted with 4×250 mL of hexanes. The combined organic extracts were washed with 2×250 mL of freshly prepared 10% aqueous sodium thiosulfate, dried over sodium sulfate, concentrated in vacuo and vacuum dried to give iodo acid 2 (57.5 g, 98%) as a white solid:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9].[CH2:12](Br)[CH:13]=[CH2:14].O>CN(C)C=O>[CH3:9][C@H:8]([O:10][CH2:14][CH:13]=[CH2:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:11])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)CCC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO[C@@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72 mmol) and dimethylformamide (100 mL) were charged to a 250 mL three-necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added a solution of (2S)-6-methylheptan-2-ol (3.1 g, 24 mmol) in dimethylformamide (10 mL). This reaction mixture was stirred at room temperature for 1 hr then allyl bromide (8.6 g, 72 mmol) was added dropwise over 10 minutes ensuring the reaction temperature did not rise significantly (41° C. was observed). The reaction mixture was stirred for a further 20 minutes until the reaction was complete. To the reaction mixture was added water (10 mL) and the resultant mixture was extracted with methyltert-butyl ether (2×100 mL). The combined organic phase was dried over magnesium sulphate and the solvent remove in vacuo to yield a yellow oil which was chromatographed over silica gel (hexane/methyltert-butyl ether) to give 3-{[(1S)-1,5-dimethylhexyl]oxy}prop-1-ene as a sl. yellow oil (2.7 g, 15.8 mmol, chemical yield 66%).
Reaction SMILES: N[C@H](C(O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+].C1(CC(Cl)=O)C=CC=CC=1.[C:25]1([CH2:31][C:32]([NH:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(O)C(C)C>[CH2:3]([O:41][C:40](=[O:42])[C@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:34][C:32](=[O:33])[CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)CO
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
L-Leucine (Aldrich) (0.114 g, 0.869 mmols) was taken-up in dioxane (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification. N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHCl3 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]([NH:37][NH2:38])=[N:20][C:21]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:22]([Cl:30])[C:23]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>C(O)(=O)C>[Cl:17][C:18]1[C:19]([N:37]=[N:38][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][C:21]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:22]([Cl:30])[C:23]=1[O:24][CH2:25][C:26]([F:27])([F:28])[F:29]
Reactant: NNc1nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c1Cl
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c2Cl)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (30 ml) and 9,10-phenanthrenequinone (1.25 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 3,5-dichloro-2-hydrazino-4,6-bis(2,2,2-trifluoroethoxy)pyridine (2.5 g) was added in 15 minutes. After stirring at 100 to 105° C. for two hours, the heating was stopped and the reaction mixture was left to cool and filtrated. The filtrated crystals were stirred for 30 minutes in methanol (100 ml), and then filtrated and dried to give intended crystals (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:19])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1ccc(Cl)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 2-chloro-5-[(methylthio)methyl]pyridine (A) (7.60 g, 40 mmol) in chloroform (100 mL) cooled in ice-water bath was added a solution of 70-75% m-chloroperbenzoic acid (mCPBA, 10.51 g, ca 44 mmol) in chloroform (110 mL) over a period of 1.5 h under stirring. The stirring was continued for another 1 h at 0° C. Methanol (12 mL) was added to the mixture, which was then bubbled with ammonia gas to precipitate the benzoic acid and the extra mCPBA if any. TLC showed there was small amount of unreacted starting material in the reaction mixture. Most of the ammonium salt was removed by filtration. The filtrate was concentrated before it was loaded onto a Et3N-treated silica gel plug, which was eluted with 10% MeOH in CH2Cl2 to give 7.6 g of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) in 92% yield as a colorless oil that turned into a white solid upon drying in vacuo (m.p. 72-74° C.). LC-MS (ELSD): mass calcd for C7H8ClNOS [M+H]+ 190.67. Found: 190.21.
Reaction SMILES: CS(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH:14][O:15]C)[C:8]=1[F:17].C(=O)(O)[O-].[Na+].[BH4-].[Na+]>O.O1CCCC1>[Br:6][C:7]1[C:8]([F:17])=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COC=Cc1cccc(Br)c1F
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonic acid (0.4 mL) was added to a mixture of 1-bromo-2-fluoro-3-(2-methoxyvinyl)benzene [Example 16, Step i)] (1.8 g), tetrahydrofuran (15 mL) and water (1.5 mL) and sealed into a microwave tube. The reaction was heated to 80° C., over a period of 90 min in the microwave reactor. Sodium bicarbonate (654 mg) was added portionwise and the mixture was stirred for 10 min. Sodium borohydride (295 mg) was added portionwise (gas evolution) and the mixture was stirred for 30 min. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with DCM (3×30 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in isohexane to afford the subtitled compound (1.26 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 7.47-7.40 (m, 1H), 7.23-7.16 (m, 1H), 6.97 (t, J=7.8 Hz, 1H), 3.88 (q, J=6.2 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H), 1.43 (t, J=5.7 Hz, 1H).
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].O.CO.[O-:14][C:15]#[N:16].[K+]>C(O)(=O)C>[NH2:16][C:15]([N:8]1[CH2:9][CH2:10][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:6][CH2:7]1)=[O:14]
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)N1CCC(O[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
7.1 g. 4-Nitroxypiperidine are dissolved in 60 ml. water and 30 ml. methanol and mixed with 16.2 g. potassium cyanate. After the dropwise addition of 12 ml. glacial acetic acid, stirring is continued at ambient temperature for 4 hours. The inorganic salts are precipitated out by the addition of 100 ml. ethyl acetate. After suction filtration, the aqueous phase is separated off and the organic phase is dried with anhydrous sodium sulphate. After suction filtration, the filtrate is evaporated in a vacuum. The residue is triturated with diethyl ether and the crystals are filtered off with suction. There are obtained 8.3 g. of the title compound, i.e. 89% of theory; m.p. 110°-111° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]1([NH:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][C:19](Br)=[C:20]([O:25][CH3:26])[CH:21]=3)[N:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+]>CCOCC.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]>[CH:8]1([NH:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][C:19]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:20]([O:25][CH3:26])[CH:21]=3)[N:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc2ncc(NC3CCCCC3)nc2cc1Br
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc2ncc(NC3CCCCC3)nc2cc1N1CCOCC1
Temperature: 80 °C

Procedure:
This preparation is based on an adaptation of the method described by Buchwald, et al, J. Am. Chem. Soc., 1996, 118, 7215. To a toluene solution of 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline (0.1 g, 0.3 mmol) under argon is added morpholine (0.1 g, 0.3 mmol), sodium tert-butoxide (0.04 g, 0.42 mmol), S-(−)-BINAP (cat., 0.001 g), and bis(dibenzylideneacetone)-palladium (cat., 0.001 g). The reaction mixture is heated to 80° C. overnight. The mixture is cooled, diluted with Et2O, filtered, concentrated, and chromatographed (50% EtOAc/hexanes). The product is recrystallized from EtOAc/hexanes to provide, in two crops, to provide a yellow solid (m.p. 194-196° C.). Anal. Calcd. for C19H26N4O2: C, 66.64; H, 7.65; N, 16.36; Found: C, 66.60; H, 7.60; N, 16.51.
Reaction SMILES: C(OC1N=CC([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([Br:32])[CH:17]=2)=CC=1)C1C=CC=CC=1.C(OC1N=CC(N)=CC=1)C1C=CC=CC=1.BrC1C=C(OCC2C=CC(OC)=CC=2)C=C(Br)C=1.CC([O-])(C)C.[Na+]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:32][C:18]1[CH:17]=[C:16]([NH2:15])[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:19]=1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3ccc(OCc4ccccc4)nc3)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Product: COc1ccc(COc2cc(N)cc(Br)c2)cc1
Temperature: 120 °C
Yield: 47 %

Procedure:
(6-benzyloxy-pyridin-3-yl)-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-amine. A dry tube was charged with 6-benzyloxy-pyridin-3-ylamine (68 mg, 0.34 mmol), 1,3-dibromo-5-(4-methoxy-benzyloxy)-benzene (126 mg, 0.34 mmol), NaOtBu (46 mg, 0.48 mmol), Pd2(dba)3 (3.1 mg, 0.0034 mmol), BINAP (6.3 mg, 0.01 mmol) and degassed toluene (2 mL). The tube was heated in a microwave reactor at 120° C. for 1 h. After cooling down to room temperature, the reaction mixture was loaded directly on Celite®. Chromatographic purification afforded 6-benzyloxy-pyridin-3-yl)-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-amine as a yellow oil (78.8 mg, 47%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([C:8]#[C:9][Sn](CCCC)(CCCC)CCCC)[CH2:6][CH:5]([O:23][CH3:24])[O:4]1.I[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([C:9]#[C:8][CH:7]2[CH2:6][CH:5]([O:23][CH3:24])[O:4][CH:3]2[O:2][CH3:1])=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(I)cc1
Reactant: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC1CC(C#Cc2ccc(C#N)cc2)C(OC)O1
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 102.3 %

Procedure:
A mixture of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran (1.86 g, 4.18 mmol), 4-iodobenzonitrile (1.15 g, 5.02 mmol), and tetrakis(triphenylphosphine) palladium(0) (145 mg, 0.125 mmol) in toluene (25 mL) was heated at 100° C. After 5.5 hours, the resultant red solution was allowed to cool, and the solvent was removed under reduced pressure. Flash column chromatography twice with 10% EtOAc/hex provided 1.10 g (100%) of 3-[2-(4-cyanophenyl)-ethynyl]-2,5-dimethoxy-tetrahydrofuran as an orange oil. A mixture of diastereomers was observed by 1H NMR, which was used without further purification. 1H NMR (CDCl3): 3.12 (ddd, J=2.8, 6.6, 9.0 Hz), 2.57 (ddd, J=5.6, 9.3, 13.4 Hz), 2.08 (dd, J=2.5, 4.7 Hz), 2.04 (dd, J=3.1, 4.3 Hz). IR: 2227, 1603, 1216, 1102, 1012, 841 cm-1. Anal. Calculated for C15H15NO3.0.1 EtOAc: C, 69.51; H, 5.98; N, 5.26. Found: C, 69.52; H, 5.76; N, 5.32.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH:27]2[O:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:22]([CH3:33])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:28]1[CH2:29][CH2:30][CH2:31][O:32][CH:27]1[C:23]1[C:22]([CH3:33])=[CH:21][C:20]([C:17]2[S:16][C:14]3[C:13]([N:18]=2)=[CH:12][CH:11]=[C:10]([C:7]2([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]2)[N:15]=3)=[CH:25][C:24]=1[CH3:26]
Reactant: Cc1cc(Br)cc(C)c1C1OCCCO1
Reactant: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C1OCCCO1
Temperature: 190 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (23.2 mg, 92 μmol), 2-(4-bromo-2,6-dimethylphenyl)-1,3-dioxane (25 mg, 92 μmol), PdCl2(AmPhos)2 (4.8 mg, 7.7 μmol), and cesium carbonate (90 mg, 276 μmol) in DMF (1.0 mL) was heated (microwave) at 190° C. under argon for 30 min, then at 200° C. for 30 min. The reaction mixture was then partitioned between EtOAc (40 mL) and water (10 mL). The organic layer was separated and sequentially washed with water (2×10 mL) and brine (10 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-70% EtOAc/Hex,) furnished 2-(4-(1,3-dioxan-2-yl)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine as a yellow solid. MS (ESI) m/z: Calculated: 442.2; Observed: 443.2 (M++1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.[C:20](O)(=[O:40])[CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:20]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1)(=[O:40])[CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39]
Reactant: NCCNC(=O)c1cccnc1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
The TFA salt of N-(2-aminoethyl)nicotinamide (1.6 g, 5.7 mmol) was taken up in CH3CN (15 mL) along with (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (1.7 g, 5.7 mmol), HATU (2.4 g, 6.3 mmol) and DIEA (3 mL, 17 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH—CH2Cl2) afforded N-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethyl)nicotinamide (1.6 g, 62%). MS calculated for C28H39N3O2: 449.3; found: [M+H]+450.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][N:4]=1.[O:11]1CCOCC1>O>[F:10][C:6]1[C:7]([I:9])=[CH:8][C:3](=[O:11])[NH:4][CH:5]=1
Reactant: C1COCCO1
Reactant: Fc1cc(I)c(F)cn1
Agent: Cl
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 50 %

Procedure:
Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness and the residue was triturated in water (20 mL). The solids were collected via filtration and washed with water (2×30 mL) and hexanes (3×30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1H) 7.68 (d, J=2.34 Hz, 1H) 11.50 (br. s., 1H).