Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([CH3:25])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=1)=[O:16])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:25]
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(Br)c(OCC(F)(F)F)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and α,α-dimethyl-2-thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e=424.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C1(C)C(C)=CC=CC=1.Cl>C(OCC)C>[ClH:1].[F:29][C:15]([F:14])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=c1cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)[nH]1
Yield: 26.3 %

Procedure:
The compound 1b (6.67 g; 0.033 mol) and 4-(3-trifluoromethylphenyl)piperazine (15.3 g; 0.066 mol) are heated to dryness for 7 hours at 120-130° C. Xylene (40 ml) is added and heated for one additional hour under reflux. After cooling and concentrating to dryness under vacuum, the residue is taken up in water (30 ml) and in ethyl ether (2×100 ml). The organic phases are dried (Na2SO4) and concentrated to dryness under vacuum. The oil obtained is taken up in ethyl ether (50 ml) and then supplemented, dropwise, with hydrochloric acid in ethyl ether (20 ml). A solid is drained which is crystallized from ethanol (50 ml). After filtration, washing with ethyl ether and drying under vacuum at 80° C., the compound 1 (3.77 g) is obtained.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[CH:13]([OH:15])=[O:14]>>[CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[CH:13]([O-:15])=[O:14]
Reactant: O=CO
Agent: O=C=NCCCCCCN=C=O
Product: O=C[O-]
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
About 2 parts by weight silico-formic acid and about 4 parts by weight hexamethylene diisocyanate are mixed and heated to about 50° C while agitating for about 50 minutes thereby producing a hexamethylene diisocyanate silico-formate polymer. About 3% by weight of an activator mixture containing 25% dimethyl ethanolamine and 10% ammonium stearate in water is added to the mixture, mixed well, and heated to about 50° C thereby producing a semi-rigid hexamethylene diisocyanate-silico-formate foam which has expanded to approximately 6 times its original volume.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].CO.[BH4-].[Na+]>C1COCC1>[C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C@@H:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to −50° C. to −55° C. CeCl3.7H2O (16.4 g, 0.044 mol) was added and stirred for 30 min., maintaining the temperature between −50 and −55° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature between −70 and −90° C. The resulting mixture was stirred for 1 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to a residue under vacuum at about 45° C. Methanol (60 mL) was added and the resulting mixture was concentrated. The resulting residue was cooled to RT, water (50 mL) was added and the resulting aqueous mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine solution (50 mL), and concentrated to obtain title compound. Yield: 5 g.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].C(O[C:16](=[O:18])[CH3:17])(=O)C>>[CH3:1][CH:2]([CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:3][C:4]([O:6][C:16](=[O:18])[CH2:17][CH:2]([CH3:1])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(=O)OC(C)=O
Product: CC(CC(=O)OC(=O)CC(C)CC(C)(C)C)CC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A reactor was charged with 633.0 g of 3,5,5-trimethylhexanoic acid (4.00 mol, manufactured by KH Neochem Co., Ltd.) and 817.5 g of acetic anhydride (8.00 mol, manufactured by Wako Pure Chemical Industries, Ltd.), and the resulting mixture was stirred for 1 hour at 120° C. After completing the reaction, the reaction product was distilled at 157° C. to 162° C. under the reduced pressure of 0.4 kPa, to thereby yield 496.4 g of 3,5,5-trimethylhexanoic anhydride.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[CH:33]1([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1.[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:41][C@H:40]([C:39]([O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Temperature: 90 °C
Yield: 48 %

Procedure:
From Intermediate 4H. To a solution of 6-amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(4-fluorobenzoyl)pyridin-2(1H)-one (99 mg, 0.21 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added cyclopentyl L-leucinate (Intermediate 8) (212 mg, 1.06 mmol, 5 eq), sodium iodide (64 mg, 0.43 mmol, 2 eq) and N,N-diisopropylethylamine (0.039 ml, 0.21 mmol, 1 eq). The mixture was heated at 90° C. for 20 hours, before being allowed to cool to room temperature and diluted with EtOAc (25 ml). The solution was washed with water (2×25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2% MeOH in DCM) followed by preparative HPLC afforded the title compound as a yellow solid (64 mg, 48% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:26](O)=[O:27]>>[OH:13][C:4]1[C:5]([C:9]([F:11])([F:10])[F:12])=[CH:6][C:7]([CH:26]=[O:27])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(F)(F)F)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc(C=O)cc(C(F)(F)F)c1O

Procedure:
A solution containing 1.9 g of 2-methoxy-6-trifluoromethylphenol and 1.4 g of hexamethylenetetramine in 20 ml of trifluoroacetic acid was refluxed for 1 h. The solvent was removed in reduced pressure, 50 ml of 1 N hydrochloric acid was added to the residue and the solution was extracted with dichloromethane. Most part of the solvent was evaporated in vacuo and petroleum ether was added, whereupon the product crystallized. Yield 0.7 g (32%), m.p. 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[N:10]([CH2:22][C:21]([CH3:23])=[CH2:20])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)CBr
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=C(C)Cn1c(=O)n(C)c2nc(Cl)ccc21
Temperature: 90 °C

Procedure:
5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3) (1.852 g, 8.16 mmol) and cesium carbonate (7.97 g, 24.47 mmol) were added to a round bottom flask and suspended in NMP (25 mL) under nitrogen. 3-bromo-2-methylprop-1-ene (1.101 g, 8.16 mmol) was added to the suspension and then refluxed at 90° C. overnight. The reaction was then cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine (×5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using normal phase chromatography (0-60% Ethyl Acetate/Hexanes), and the desired fractions were collected to produce the tan solid 5-chloro-3-methyl-1-(2-methylprop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (74-1). MS (M+H)+: observed=238.59, calculated=238.69.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC>[CH2:18]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Oc1cccc2c1NCCC2
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCCCCCCCCCN1CCCc2cccc(O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of 499.2 mg (3.35 mmol) of 1,2,3,4-tetrahydro-8-quinolinol (see Example 7A), 425 mg (5.05 mmol, 1.5 eq.) of sodium bicarbonate, and 780 μl (3.69 mmol, 1.1 eq.) of 98% 1-bromodecane in 10 ml of hexamethylphosphoric triamide under argon was stirred for three hours at room temperature, followed by 44 hours at 50° C. The reaction was diluted with 80 ml of 1:1 ether:petroleum ether and the organic layer was washed with five 40 ml portions of water and 40 ml of brine, dried over sodium sulfate and evaporated to yield 1.04 g of a brown oil. Purification by flash chromatography on 110 g of silica, eluted with 5:95 ethyl acetate:petroleum ether afforded 624.4 mg of the title compound as a colorless oil.
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.[CH2:9]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH2:10]1.S(C#N)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[O:17]=[C:14]1[CH2:15][CH2:16][C:11]2([CH2:10][CH2:9]2)[CH:12]=[C:13]1[C:3]#[N:5]
Reactant: O=C1CCC2(CC1)CC2
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CC2(CCC1=O)CC2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
LDA (1.34 mL, 2.69 mmol, 2.0 M in hexanes) was combined with THF (2.4 mL) and cooled to −78° C. To this mixture was added a solution of spiro[2.5]octan-6-one (0.30 g, 2.4 mmol) in THF (2.4 mL). The resulting mixture was stirred at −78° C. for 20 mins then taken up in a syringe and added to a mixture of tosyl cyanide (0.88 g, 4.8 mmol) in THF (2.4 mL) at −78° C. The reaction mixture was allowed to stir at −78° C. for 45 mins then quenched with 0.5 M NaOH and extracted with EtOAc (2×) The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.[OH-].[Na+]>O>[CH3:26][O:25][C:22]1[C:21]([CH3:27])=[CH:20][N:19]=[C:18]([CH2:17][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)[C:23]=1[CH3:24]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C

Procedure:
21.8 g of 5-(trifluoromethyl)-2-benzimidazolethiol are suspended in 400 ml of alcohol and treated with 22.2 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 8.0 g of sodium hydroxide in 300 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 1.5 l of methylene chloride. The solution is washed firstly with 200 ml of 1.5N sodium hydroxide solution and then 3 x with 700 ml of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 360 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 164°-166°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (2.1 mL, 18.4 mmol) followed by LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (15 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.36 g (1.96 mmol, 85%) of (2S)-2-(4-chlorophenyl)propanoic acid; [α]D=+67° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1H), 7.32–7.23 (m, 4H), 3.72 (q, 1H, J=7.3 Hz), 1.50 (d, 3H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>[Cu]I>[C:1]1([C:7]#[C:8][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cu]I
Product: O=[N+]([O-])c1cccc(C#Cc2ccccc2)c1
Temperature: 56 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Example 1 was repeated except phenylacetylene ##STR9## was employed as the sole alkyne (25 mmols); the amount of CuI was increased to 0.25 mmol; and the reaction temperature was increased to 56° C. After 24 hours, the bromonitrobenzene was totally converted, giving an 84% yield of phenyl-3-nitrophenylacetylene ##STR10## Example 16 shows that it is not predictable (when Ex. 16 is compared with Exs. 13-15) which charge stocks will react with which halogenated arenes.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:4][C:3]=1[C:19]([NH2:21])=[O:20].C(N(CC)CC)C.O.[O:30]1CCC[CH2:31]1>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[C:10]3[C:2]4[NH:1][C:31](=[O:30])[NH:21][C:19](=[O:20])[C:3]=4[S:4][C:5]=3[CH:6]=[N:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: NC(=O)c1sc2cncc(Oc3ccc(Cl)cc3)c2c1N
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c(=O)c2sc3cncc(Oc4ccc(Cl)cc4)c3c2[nH]1
Reaction time: 24 h
Yield: 51 %

Procedure:
To a suspension of Example 131D (70mg, 0.22 mmol) in anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere was added 1,1-carbonyldiimidazole (71mg, 0.44 mmol) and triethylamine (60 [μL, 0.44 mmol). The reaction mixture was stirred at reflux for 48 hours and then ambient temperature for an additional 24 hours. The reaction mixture was poured into a 1:1 solution of water: saturated NH4Cl and the resulting solid collected by filtration. This material was purified by flash chromatography on silica gel eluting with 20% acetone-hexane. The desired fractions were combined, evaporated and slurried in hot EtOAC to obtain title compound (39 mg) in 51% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Yield: 67 %

Procedure:
The title compound was prepared from 3-bromoquinoline (16a) and methyl acrylate using methods as described in the literature for similar compounds (Frank et al., 1978) in 67% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1>[OH:24][C:23]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:25])[CH3:22]
Reactant: Cn1ccc2ccccc21
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(C(C)(C)O)cc2ccccc21
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
5.0 g of 1-methylindole was dissolved in 30 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 30 ml of 1.5 M n-butyllithium hexane solution, at -30° C. in 5 minutes with stirring. The mixture was stirred at 0° C. for 30 minutes. Thereto was dropwise added 4.2 ml of acetone in 10 minutes at the same temperature, and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of ethyl acetate and 50 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1 to 20/1), followed by recrystallization from n-hexane, to obtain 3.25 g (yield: 45%) of 2-(1-hydroxy-1-methylethyl)-1-methylindole as colorless crystals.
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[CH2:14]([C:16]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])([CH:19]=[CH:20][CH2:21][CH3:22])[CH:17]=[O:18])[CH3:15].CC(C)=O>C(O)(C)C>[CH2:14]([C:16]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])([CH:19]=[CH:20][CH2:21][CH3:22])[CH2:17][OH:18])[CH3:15]
Reactant: CCC=CC(C=O)(CC)CC=C(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCC=CC(CC)(CO)CC=C(C)C

Procedure:
Into a 2 liter four-neck flask, provided with stirrer, column, dropping funnel, and thermometer, 0.5 moles of aluminum isopropylate and 1 liter of dry isopropanol are first introduced. To the boiling mixture, a solution of 1 mole 2-ethyl-2-prenyl-3-hexenal, dissolved in 200 ml of dry isopropanol were added drop by drop. At all times, the reaction mixture was kept boiling to the extent that the acetone being formed could be withdrawn by the column. When in the distillate acetone could no longer be detected, the isopropanol was distilled off. Finally, the residue was poured into 250 ml of 20% hydrochloric acid, the phases were separate, and the organic phase was dried with calcium chloride. The desired product was then distilled over a Vigreux column.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][C:13]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[CH:15][C:14]=1[NH:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30].C(=O)([O-])[O-].[Na+].[Na+].CO.C(Cl)Cl>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>[NH2:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:18]2[C:13]([CH3:12])=[C:14]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1cc(Br)cn2ccnc12
Reactant: Cc1c(NC(=O)N2CCCC2)cccc1B1OC(C)(C)C(C)(C)O1
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: ClCCl
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)N2CCCC2)cccc1-c1cc(N)c2nccn2c1
Yield: 62.9 %

Procedure:
The mixture of 105 mg (0.493 mmol) of 6-Bromo-imidazo[1,2-a]pyridin-8-ylamine, 195 mg (0.591 mmol) of Pyrrolidine-1-carboxylic acid [2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide, 157 mg (1.48 mmol) of sodium carbonate, and 57 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 5 mL of 1,2-dimethoxyethane and 2.5 mL of water was heated at 110 C for 30 minutes using microwave. The mixture was partitioned between 50 mL of ethyl acetate and 10 mL of water. The organic layer was dried (MgSO4), and concentrated. Column chromatography (0->10% MeOH/CH2Cl2 in 20 minutes) gave 104 mg (0.310 mmol, 63%) of the title compound.