Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:24][CH2:25]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-4-piperidinyl)carbamate (92 mg) in chloroform (1.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml) and the reaction stirred at rt for 1 h. More 4N HCl in 1,4-dioxane (0.5 ml) was added and the reaction stirred at rt for 0.5 h then the solvents removed. The residue was dissolved in MeOH (25 ml) and treated with Amberlyst A21 basic resin until the pH was 6. The residue was filtered off and the solvent removed; the residue was subjected to column chromatography on silica gel eluting with 0-20% methanol-DCM to afford the free base of the title compound (67 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:32]=[O:33])C>C1COCC1>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:32]([OH:33])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccc(Cl)c(Cl)c2C1O
Yield: 83 %

Procedure:
In a similar manner to Step 2 of Example 16, 3,4-dichloro-N-(1-methyl-1-phenylethyl)benzamide (2.85 g, 9.25 mmol) was dissolved in THF (114 mL), and the solution was treated with TMEDA (4.50 mL, 29.6 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 29.3 mL, 29.6 mmol) and DMF (1.60 mL, 20.4 mmol), followed by purification by slurry using diisopropylether to obtain 4,5-dichloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.58 g, yield 83%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)[CH:32]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:30]=1
Reactant: COCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Temperature: 150 °C

Procedure:
A microwave flask was charged with 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (705 mg, 1.71 mmol, following the general procedures described in these Examples), 1-[3-methoxymethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (570 mg, 1.71 mmol), and K2CO3 (591 mg, 4.28 mmol). Dioxane (13 ml) and water (3.2 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (140 mg, 0.17 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a reparatory funnel and shaken with water (60 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×50 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 24% ethyl acetate in hexanes to afford 492 mg of 1-[2-(3-Methoxymethoxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a red-brown viscous oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[NH:3]1.[H-].[Na+].[CH3:23]I>CN(C)C=O.O>[CH3:23][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]21[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]=[N:19][CH:20]=[C:13]21
Reactant: CI
Reactant: N#Cc1ccc2c(c1)C(=O)NC21CCCn2cncc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2cc(C#N)ccc2C12CCCn1cncc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 mmol of 3′-oxo-2′,3′,6,7-tetrahydro-5H-spiro[imidazo[1,5-a]pyridine-8,1′-isoindole]-5′-carbonitrile (Example 13) in 5 ml of N,N-dimethylformamide is treated with 1.2 mmol of sodium hydride (60% dispersion in oil). The reaction mixture is stirred for 20 minutes at room temperature, and then 1.2 mmol of methyl iodide are added. The reaction mixture is stirred for 20 minutes at room temperature, then diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)=[C:20]([F:27])[CH:19]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2F)cc1
Yield: 57 %

Procedure:
In accordance with Example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, and (4-bromo-2-fluorophenyl)boronic acid instead of (4-bromophenyl)boronic acid, the title compound (yield 57%) was afforded as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][C:14]([CH3:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][C:14]([CH3:20])([OH:15])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)COc1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)COc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-[3-(Benzyloxy)phenoxy]acetone (1.77 g) was dissolved in THF (20 mL), and, a solution of 0.97M methyl magnesium bromide in THF (9.0 mL) was added dropwise thereto with cooling in an ice bath under nitrogen flow. The reaction mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-85/15) to obtain 1-[3-(benzyloxy)phenoxy]-2-methylpropan-2-ol (997 mg).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](Cl)Cl.CO>>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: ClCCl
Reactant: Cc1cccc(C(=O)O)c1I
Solvent: CO
Product: COC(=O)c1cccc(C)c1I

Procedure:
2-iodo-3-methylbenzoic acid (595 mg, 2.27 mmol) was dissolved in DCM/MeOH=1/1 (5 ml) at 0° C., then TMS-CH2N2 (2M in Et2O, 1.4 ml, 2.8 mmol) was added. After 1.5 hours at RT solvents were evaporated. Yield 630 mg yellow oil.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:26]([O-:28])=[O:27])[C:17]([I:25])=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C=O)C>[C:22]([NH:21][C:18]1[C:17]([I:25])=[C:16]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:27])[C:15]([I:29])=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[C:19]=1[I:20])(=[O:24])[CH3:23]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 40 °C
Reaction time: 65 h

Procedure:
1-Chloroethyl ethyl carbonate (1.68 g, 11.0 mmol) was added at room temperature to a solution of potassium 3,5-di(acetylamino)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 mmol) and sodium iodide (0.30 g, 2.0 mmol) in dry DMF (100 ml). After stirring at 60° C. for 2 hours and at 40° C. for 65 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 2.45 g Purity by HPLC: 98.5% 1H-NMR(DMSO-d6): delta=1.24(CH2CH3); 1.63(CHCH3); 2.02(COCH3); 4.20(CH2CH3); 6.93(CHCH3); 10.03 ppm (NH). FAB/MS: 731 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:5][CH:6]=1.C([Li])(C)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:4]2[O:5][CH:6]=[C:2]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2cc(Br)co2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1coc(CN2CCN(C)CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
A stirred mixture of 1-((4-bromofuran-2-yl)methyl)-4-methylpiperazine (2.10 g, 8.10 mmol) and THF (50 mL) was cooled to −78° C. in a dry ice/acetone bath. tert-Butyllithium (7.60 mL, 12.2 mmol; 1.6 M in pentane) was added and the reaction mixture was stirred for 30 minutes. Next, tributylchlorostannane (2.09 ml, 7.70 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction was quenched by addition of pH 7 phosphate buffer (20 mL) and warming to room temperature. The mixture was extracted with diethyl ether, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column, eluting with 1:1 EtOAc/hexanes (500 mL), 2:1 EtOAc/hexanes (500 mL), then EtOAc (1 L) to provide a product mixture as a light yellow oil (0.77 g, 86:14 ratio of 1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine to 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine by 1H-NMR). The mixture was carried forward without separation at this step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C@@H:17]12[C:26](=[O:27])[O:25][C:23](=[O:24])[C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>C(OCC)C>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:26]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[C:23]([OH:25])=[O:24])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)[C@H]2CCCC[C@H]2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution containing 5.68 g (0.03 mole) of 4-amino-2,6-di-t-butylphenol in 200 ml of diethyl ether was added dropwise to a solution of 4.62 g (0.03 mole) of cis-1,2-cyclohexanedicarboxylic anhydride in 200 ml of diethyl ether. The reaction mixture was stirred at room temperature for about sixteen hours. The resulting precipitate was collected, rinsed with a mixture of diethyl ether and hexane, and dried to give 8.1 g of a solid. This material was recrystallized from a mixture of ethyl acetate and hexane to give 7.3 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl)carbamoyl]-cis-cyclohexanecarboxylic acid, m.p. 181°-184° C. Analysis: Calculated for C22H33NO4 : %C, 70.4, %H, 8.9; %N, 3.7; Found: %C, 70.1; %H, 8.7; %N, 3.6.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: COC(=O)C(CC1CCC(=O)CC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid methyl ester (590 mg, 1.58 mmol) in methanol (7.0 mL) and water (3.0 mL) was treated with lithium hydroxide (980 mg, 31.6 mmol). The reaction mixture was stirred at 25° C. for 2 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was diluted with water (25 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was then acidified to pH=3 with a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (550 mg, 97%) as a colorless gum: EI-HRMS m/e calcd for C16H19ClO5S (M+Na)+ 381.0534, found 381.0537.
Reaction SMILES: [F:1][C:2]([C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:24]([CH3:35])[CH:23]=1)([F:21])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20]>O1CCCC1.[OH-].[Na+]>[F:1][C:2]([C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([CH3:35])[CH:23]=1)([F:21])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH3:20]
Reactant: CCOC(=O)COc1ccc(C(F)(F)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl [4-(1,1-difluoro-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propyl)-2-methylphenoxy]acetate (example 1, 0.028 g) in tetrahydrofuran (4 ml) and 2M aqueous sodium hydroxide (4 ml) was stirred at 60° C. for 2 hours. The solvent was evaporated and the residue partitioned between ether and water; the aqueous layer was acidified using 10% w/v aqueous citric acid and then extracted thrice with ethyl acetate. The combined ethyl acetate solutions were dried over magnesium sulfate and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O1CCCC1>>[CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:9])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)c1ccccc1
Yield: 87 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (1.0 g) and 1N phenylmagnesium bromide-tetrahydrofuran solution (8.0 mL) to give the title compound (1.2 g, 87%) as a yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: OCCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCCCOc1ccc(Oc2ccccc2OC(F)(F)F)cc1
Temperature: 90 °C

Procedure:
A mixture of 3.13 g of 4-(4-hydroxyphenoxy)butan-1-ol, 4.97 g of 4-(trifluoromethoxy)bromobenzene, and 4.75 g of K2CO3 are placed in a flask and flushed with N2 gas. To this are added 17 ml of pyridine and, after heating to 90° C., 3.42 g of CuO. The reaction mixture is heated at reflux for 2 days, and then cooled and poured into an ice/3N HCl mixture. This mixture is extracted twice with ether; and after separating, the combined ether extracts are washed with saturated NaHCO3, followed by brine, and then dried over MgSO4. Filtration and evaporation yields an oily residue which is purified by flash chromatography on silica gel, using 2:1 hexane/EtOAc as eluant. After evaporation, 4-[4-(4-(trifluoromethoxyphenoxy)phenoxy]butan-1-ol is obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][NH2:21]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:21][CH2:20][C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Reactant: NCc1cccs1
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1cccs1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
10 g of 2-amino-3-cyano-4-chloroquinoline is heated with 19 g of thienylmethylamine at 115° C. for 4 hours. The reaction mixture is cooled to 25° C. and mixed 6 times with 50 ml of water. The crystals are filtered off, washed 2 times with 50 ml of water and dried. The resulting product is recrystallized from 60 ml of N,N-dimethylformamide, to obtain 6.8 g pale yellow title compound, m.p.: 208-209° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:48]=[CH:47][C:10]([CH2:11][N:12]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:13]2[N:18]=[C:17]([C:19]3[C:20]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:21][CH:22]=[C:23]([C:25]([CH3:27])=[CH2:26])[CH:24]=3)[N:16]=[C:15]([CH3:37])[N:14]=2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:25]([C:23]1[CH:24]=[C:19]([C:17]2[N:16]=[C:15]([CH3:37])[N:14]=[C:13]([N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:48][CH:47]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:18]=2)[C:20]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:21][CH:22]=1)([CH3:27])[CH3:26])=[N+:2]=[N-:3]
Reactant: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N=[N+]=[N-])cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A slurry of sodium azide (0.075 g, 1.160 mmol) and N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol) in CHCl3 (1 mL) at −15° C. was treated with a solution of trifluoroacetic acid (0.223 mL, 2.90 mmol) in CHCl3 (1 mL) added via syringe over 10 min. The cooling reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction was sealed and heated at 60° C. After 2 h, the reaction was poured onto ice and basified with 10N NaOH. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(2-azidopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.184 g, 0.291 mmol, 100% yield). m/z (ESI, +ve ion) 633 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.90 (d, J=2.7 Hz, 1H); 8.38 (d, J=2.5 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 7.91 (dd, J=8.8, 2.7 Hz, 1H); 7.18-7.26 (m, 4H); 6.81-6.94 (m, 4H); 6.73 (d, J=8.8 Hz, 1H); 4.90 (s, 2H); 4.81 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.78 (s, 3H); 2.59 (s, 3H); 1.64 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ort/10-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:25]=[O:26])=[C:20](B(O)O)[CH:21]=1>COCCOC.O.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([CH:25]=[O:26])=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Reactant: Brc1ccc(Br)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
A solution of 1,4-dibromobenzene (8.3 g, 35.3 mmol), potassium carbonate (11.3 g, 81 mmol) and 5-chloro-2-formylphenylboronic acid (5 g, 27.1 mmol) in DME (150 mL) and water (30 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(PPh3)4 (0.94 g, 0.814 mmol) was added and the reaction heated to 80° C. overnight. The reaction was cooled to r.t. and evaporated on the rotovap. The residue was diluted in EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (0-15% EtOAc:Hex) to give 4′-bromo-5-chlorobiphenyl-2-carbaldehyde (4.17 g, 14.11 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.28 (m, 2H) 7.42 (d, J=2.01 Hz, 1H) 7.50 (ddd, J=8.41, 2.01, 0.88 Hz, 1H) 7.59-7.69 (m, 2H) 7.98 (d, J=8.53 Hz, 1H) 9.92 (s, 1H).