Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=NC1=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C.O=[C:23]([CH2:26][CH3:27])[C:24]#[N:25].C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(O)C>[C:24]([C:23]1[C:26]([CH3:27])=[CH:4][CH:5]=[CH:6][N:1]=1)#[N:25]
Reactant: O=c1nccc[nH]1
Reactant: CCC(=O)C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: Cc1cccnc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 11.53 g (120 mmol) of 2-pyrimidone and 12.14 g (120 mmol) of triethylamine were dissolved in 50 ml of ethanol, and 11.23 g (110 mmol) of acetic anhydride was added dropwise thereto at 70° C. spending 1 hour. The reaction solution was cooled to room temperature and mixed with 8.31 g (100 mmol) of 2-oxobutyronitrile and 30.43 g (400 mmol) of ammonium acetate, and the resulting reaction solution was allowed to undergo the reaction at 80° C. for 4 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 100 g (600 mmol) of 25% sodium hydroxide aqueous solution and then extracted twice with 40 ml of toluene. By concentrating the organic layer, 7.92 g (yield 67.1%) of the title compound was obtained (purity 99.1%, melting point 85-86° C.).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:17]1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2ccccc2O1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2,3-dibromopropionate (8.05 g, 31.0 mmol, Aldrich) in acetone (35 mL) was added o-aminophenol (3.38 g. 31.0 mmol) and potassium carbonate (5.1 g, 36.9 mmol). The reaction mixture was stirred at reflux under a water condenser for 18 h. Upon cooling to room temperature, the reaction was concentrated in vacuo, and the residue was taken up in water (50 mL) and the product was extracted using EtOAc (3×75 mL). The organic fractions were combined, washed with saturated brine (15 mL), dried over sodium sulfate, and concentrated. Purification of the product by flash column chromatography (30% EtOAc/hexane) afforded the title compound as a yellow oil. MS m/z: 208 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CN(C)CCCl
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (8.0 g) in dry DMF (240 ml) was slowly added NaH (60%)(1.69 g). The reaction was stirred at room temperature for one hour, 2-dimethylaminoethylchloride (4.64 g) was added and stirring was continued for two hours. An additional 4.64 g of 2-dimethylaminoethylchloride was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:16]2[C:13]3[CH:14]=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[N:18]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1F
Temperature: 0 °C

Procedure:
A mixture of 4.44 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-[1-(2-fluorophenyl)ethoxy]thiophene-2-carboxamide in 300 ml THF is cooled to 0° C. At 0° C. 2.31 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred over night.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH2:15][OH:16])[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([N:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH:15]=[O:16])[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(=O)OCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
0.120 g of manganese dioxide was added to a 2-ml dichloromethane solution of 0.061 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-hydroxymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 15 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.055 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (7:3).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].Cl.[NH2:33][C:34]1([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH:33][C:34]1([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]1)=[O:26]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)ccc3C)c(F)c12
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (60 mg, 0.142 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (40.8 mg, 0.142 mmol) in DMF (1 ml) was added PyBOP (74.1 mg, 0.142 mmol) and triethylamine (0.020 ml, 0.142 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 55 mg (59%). LCMS: (ES+) m/z observed=554.2 (M+H)+ of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)benzofuran-3-carboxamide.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])([CH3:3])[CH3:2].[CH:16](O)=[O:17]>>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH:16]=[O:17])=[CH:7][C:6]=1[C:12]([F:13])([F:14])[F:15])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: CC(C)Oc1ccc(N)cc1C(F)(F)F
Product: CC(C)Oc1ccc(NC=O)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 54.8 g of 2B and 200 ml of 98% formic acid was refluxed for one hour, cooled and poured into ice water. The resulting mixture was extracted with ether. The extract was washed, successively, with aqueous soidum bicarbonate and water, dried and the solvent was evaporated under reduced pressure. The residue, a syrup, crystallized from 1/5 v/v ether/hexane to give N-(4-isopropoxy-3-(trifluoromethyl)phenyl)formamide (2C), as a tan solid, mp: 80°-82° C.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([Br:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]1
Reactant: CC(C)(C)C1CN(CC2OCCc3c(Br)cccc32)CCN1C(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl-4-[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (480 mg, 1.2 mmol) in 10 mL of DCM was added 10 mL of 4N HCl/dioxane, and then stirred at room temperature for 2 hours. The solvents was removed under vacuum to afford 1-[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:5]2.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1>C(N(CC)CC)C.[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]#[C:41][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:5]3)=[CH:38][CH:39]=1
Reactant: OCCCCCCOc1ccc2cc(Br)ccc2c1
Reactant: C#Cc1ccc(OCCCCCCOC2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCCCCCOc1ccc2cc(C#Cc3ccc(OCCCCCCOC4CCCCO4)cc3)ccc2c1
Yield: 51.5 %

Procedure:
A degassed mixture of pure 6-(6-bromonaphthalen-2-yloxy)hexan-1-ol (5.88 g), 4-[6-(tetrahydropyran-2-yloxy)hexyloxy]phenyl acetylene (6.05 g), triphenylphosphine (0.21 g), copper(I) iodide (0.04 g) and bis(triphenylphosphine)palladium dichloride (0.14 g) in 60 ml of triethylamine was refluxed for 2 hours under an atmosphere of argon. The reaction mixture was cooled and filtered though celite to give a yellowish solution which was then evaporated to dryness to give a yellow residue, which was purified by chromatography using a silica gel column and cyclohexane/ethyl acetate (2:1, 1:1) as eluent, followed by recrystallisation of the resulting solid from cyclohexane/ethyl acetate (100 ml/3 ml) to give 5.10 g of 6-[6-[4-[6-(tetra-hydropyran-2-yloxy)hexyloxy]phenylethyny]naphthalen-2-yloxy]hexan-1-ol as a white powder.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Br:10])[CH3:2].[Mg].Br[C:13](=[CH2:19])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].CCOCC>O1CCCC1.C1C=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>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Br:10])[CH3:2].[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[CH2:19])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:2]
Reactant: C=C(Br)C[Si](C)(C)C
Agent: [Pd]
Agent: CCSc1ccccc1Br
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C[Si](C)(C)C)c1ccccc1SCC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of the Grignard reagent of 1-ethylmercapto-2-bromobenzene in tetrahydrofuran was prepared in the following way: 1.50 g (6.9 mmol) of 1-ethylmercapto-2-bromobenzene were added to 218 mg (9.0 mmol) of magnesium in 8 ml of anhydrous tetrahydrofuran at room temperature under N2 and was heated to reflux for 1 h. Meanwhile, a solution of 1.20 g (6.2 mmol) of (2-bromoallyl)trimethylsilane and 358 mg (0.31 mmol) of tetrakis(triphenylphosphine)-palladium in 6 ml of dry benzene was stirred at 80° C. under N2 for 30 min. Then it was cooled to 50° C. and to it was added the Grignard reagent described above. The reaction mixture was stirred at 40° C. for 3 h and was poured into 100 ml of ether. It was washed with water (20 ml×2), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with hexane to give [2-(2-ethylmercaptophenyl)allyl trimethylsilane as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH2:35]O)=[C:32]([CH3:34])[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][C:31]2[S:30][C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:24][CH:25]=3)=[N:33][C:32]=2[CH3:34])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(C)(C)C)cc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with [2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-yl]-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as a light yellow solid.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]COCC>>[I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Reactant: CCOCC
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCI)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 12.6 g of 4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 100 mL of Et2O cooled in an ice bath, was added 40 mL of ethereal CH2N2. The mixture was stirred at 0° C. for few minutes, then let stand for 2 hr. A few drops of ACOH were added to decompose excess CH2N2, then the mixture was filtered and stripped to afford 12.6 g (96%) of methyl 4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]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>[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[CH:5]=[CH:4][C:3]=2[NH2:16])=[CH:20][CH2:19]1
Reactant: COc1ccc(-c2ccc(N)c(Br)c2)cn1
Reactant: CC1(C)CC=C(B(O)O)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: [Na+]
Product: COc1ccc(-c2ccc(N)c(C3=CCC(C)(C)CC3)c2)cn1

Procedure:
The title compound was prepared from 2-bromo-4-(6-methoxy-pyridin-3-yl)-phenylamine (as prepared in the previous step, 20 mg, 0.07 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (14 mg, 0.086 mmol), Pd(PPh3)4 (8.0 mg, 0.007 mmol) and 2M Na2CO3 (0.28 mL, 0.56 mmol) according to the procedure in Example 44, step (b) (16 mg, 76%). Mass spectrum (ESI, m/z): Calcd. for C20H24N2O, 309.1 (M+H), found 309.2.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]4[C:24]=3[CH3:25])[CH:10]=[CH:9][C:7]=2[N:8]=1>[Pd].CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH2:22][CH:21]([CH3:23])[CH2:20][CH2:19][N:18]4[C:24]=3[CH3:25])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2n1CCC(C)C2
Reaction time: 6.5 h
Yield: 188 %

Procedure:
10% Palladium on carbon (0.2 g) was added to a mixture of 2-amino-6-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]benzoxazole dihydrochloride (1.0 g) in methanol (70 ml) and the mixture was subjected to catalytic reduction under atmospheric pressure at ambient temperature for 6.5 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give 2-amino-6-[2-(3,7-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole dihydrochloride (0.95 g).
Reaction SMILES: C[C:2]1(C)[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:2][CH:7]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccccn2)c2ccccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 10 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 0.12 ml of bromine were added. The mixture was stirred at room temperature for 1 hour, then at 35° C. for 1 hour and finally at 65° C. for 1 hour. After cooling the mixture was washed with sodium bicarbonate solution, the aqueous washings were extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 230 mg of 6-bromo-3,4-dihydro-2,2-dimethyl)-4-(2-pyridyl)-2H-1-benzopyran of melting point 134-136° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[O:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+].O>C(O)C>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH2:8][O:7][C:6]2[CH:31]=[CH:32][CH:33]=[C:4]([C:1](=[N:35][OH:36])[CH3:2])[CH:5]=2)=[O:26])[CH2:29][CH2:30]1
Reactant: NO
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2cccc(C(C)=O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2cccc(C(C)=NO)c2)cc1
Yield: 85.1 %

Procedure:
To a solution of 5-[(3-acetylphenoxy)methyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (100 mg) obtained in Example 489 in ethanol (4 ml) were added hydroxylamine hydrochloride (78 mg) and sodium acetate (92 mg), and the mixture was heated under reflux for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (88 mg).
Reaction SMILES: OC1C=C2C(C(C)=CC(=O)O2)=CC=1.C1(C2C=CC(O)=CC=2)C=CC=CC=1.[CH:27]1[CH:32]=[C:31]2C([O:35][C:36]3([C:49]4[C:44](=[C:45](Br)[C:46]([OH:51])=[C:47](Br)[CH:48]=4)OC4C3=CC(Br)=C(O)C=4Br)[C:30]2=[CH:29][CH:28]=1)=O.S1C=CC=CC=CC=C1>>[OH:51][C:46]1[CH:45]=[CH:44][C:49]([C:36]([C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[O:35])=[CH:48][CH:47]=1
Reactant: O=C1OC2(c3ccccc31)c1cc(Br)c(O)c(Br)c1Oc1c2cc(Br)c(O)c1Br
Agent: Cc1cc(=O)oc2cc(O)ccc12
Agent: Oc1ccc(-c2ccccc2)cc1
Agent: c1ccccsccc1
Product: O=C(c1ccccc1)c1ccc(O)cc1

Procedure:
7-hydroxy-4-methyl coumarin; 4-phenyl phenol; 2',4',5',7'-tetrabromo fluorescein (C.I. 453802); Thionin; 2-mercapto benzothiozole; 4-diethylamino-4'-(N-ethyl-N-hydroxyethyl)amino benzophenone; and 2(4(N-ethyl-N-hydroxyethyl)aminobenzylidene)inden-1-one.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[C:12](O)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:5]2
Reactant: C=CCCCCCCCCC(=O)O
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCCCCCC(=O)NC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 46 h
Yield: 23 %

Procedure:
An oven-dried 50 mL round bottom flask was charged with 3-aminoquinuclidine dihydrochloride (2 mmol), 10-undecenoic acid (2 mmol), N,N-dimethylaminopyridine (0.3 mmol), diisopropylethylamine (4 mmol), and dry DMF (15 mL). The flask was purged with argon and cooled to 0° C. in an ice bath. Dicyclohexycarbodiimide (2.2 mmol) was then add to the solution, the flask repurged with argon, and the mixture warmed to R.T. and stirred for 46 h. The reaction mixture was concentrated in vacuo and 30 ml diethyl ether added to the residue. The solid was filtered off over Celite and the organic phase concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (3:7) to afford the product as a white solid (23%). Rf=0.44. 1HNMR (400 MHz, CDCl3): δ=5.73 (m, 1H), 4.93 (dd, 1H, 3JHH=17.0 Hz, 4JHH=1.5 Hz), 4.87 (d, 1H, 3JHH=10.3 Hz), 3.71 (m, 1H), 2.10 (t, 2H, 3JHH=7.8 Hz), 1.97 (q, 2H, 3JHH=7.3 Hz), 1.85 (m, 2H), 1.54-1.68 (m, 5H), 1.02-1.34 (m, 15H) ppm. 13CNMR (400 MHz, CDCl3): δ=172.2, 139.1, 114.1, 48.6, 48.0, 37.0, 34.0, 33.7, 33.2, 29.3, 29.2, 29.0, 28.8, 25.9, 25.7, 25.5, 25.0, 24.9 ppm. HRMS-ESI: Calculated [M-C2H2]+: 266.2358. found: 266.2474.