Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1.C(N[CH:29]([CH3:31])[CH3:30])(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([C:7]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:31][CH2:29][CH3:30])=[CH:20][N:19]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Reactant: CC(C)NC(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 92 %

Procedure:
-Non-1-yne (1.0 ml, 6.4 mmol) was added via syringe to degassed mixture of 2-(2',3'-difluoro-4'-octyloxyphenyl)-5-bromopyrimidine 4 (1.27 g, 3.18 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) and copper(I) iodide (29 mg, 0.15 mmol) in diisopropylamine (60 ml) under nitrogen. The mixture was heated under gentle reflux for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (5% ethyl acetate-light petroleum, the sample was preloaded onto silica in dichloromethane) to give the nonynylpyrimidine 38 (1.29 g, 92%) (from MeOH), transitions/° C. K 64.4 (N 63.3) I; νmax /cm-1 (KBr) 2920, 2850, 2220, 1615, 1520, 1470, 1430s, 1295, 1205 and 1090s; δ 0.90 (6 H, m), 1.20-1.55 (18 H, m), 1.64 (2 H, quint, J 7, CH2CH2C≡C), 1.85 (2 H, quint, J 7, OCH2CH2), 2.46 (2 H, t, J 7, CH2C≡C), 4.10 (2 H, t, J 7, OCH2), 6.83 (1H, ddd, J 8, 7 and 2, 5'-H), 7.85 (1H, ddd, J 8, 7 and 2, 6'-H_ an d8.79 (2 H, s, 4- and 6-H), m/z 442 (M+), 330, 288, 287, 274, 273, 247 and 220.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][C:25]=4[F:33])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].ClCCl>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]3[N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:15]=[CH:16][C:17]=23)=[C:25]([F:33])[CH:26]=1)[CH3:32]
Reactant: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Yield: 99 %

Procedure:
A solution of 4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 43; 110 mg) in 20% trifluoroacetic acid/dichloromethane (5 mL) was stirred at room temperature for 3 hours. The solvent was removed to afford 4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (112 mg, 99%) which was used directly in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]([CH2:8]O)([CH3:7])[C:4]([OH:6])=[O:5].[N:10]([CH2:13][CH2:14][O:15][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])=[C:11]=[O:12]>>[C:16]([O:15][CH2:14][CH2:13][NH:10][C:11]([CH2:8][C:3]([CH2:2][C:11](=[O:12])[NH:10][CH2:13][CH2:14][O:15][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])([CH3:7])[C:4]([OH:6])=[O:5])=[O:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC(CO)(CO)C(=O)O
Reactant: C=C(C)C(=O)OCCN=C=O
Product: C=C(C)C(=O)OCCNC(=O)CC(C)(CC(=O)NCCOC(=O)C(=C)C)C(=O)O

Procedure:
2,2-di(N-methacryloxyethyl carbamoylmethyl) propionic acid (PDMA) is synthesized by reacting 2,2-Bis(hydroxymethyl)propionic acid (BHMPA) and two equivalents of Isocyanatoethylmethacrylate (IEM) as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C([O:29]CC)C.Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][CH:5]=[O:29]
Reactant: CCOCC
Reactant: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a cooled (-78° C.) solution of 4.5 g (18.6 mmol) of 4,4-dimethyl-5-t-butyldimethylsilyloxyvaleronitrile in 36 mL of dry CH2Cl2 was added dropwise, over 30 min., 20.4 mL (20.4 mmol;1.1 eq) of a 1.0M solution of diisobutyl-aluminum hydride in CH2Cl2. After stirring for 2 h at -78° C., the cooling bath was removed and the solution allowed to warm to 0° C. To the crude (0° C.) reaction mixture was added 50-60 mL of ethyl ether, followed by the cautious addition of 10% HCl, until the mixture became strongly acidic (pH=1-2). Separation of the layers and three extractions of the aqueous phase with 100 mL ether, drying over MgSO4 and concentrating the combined organic layers gave 3.6 g (79%) of the title compound as a faint yellow oil, sufficiently pure to be used in the next step. TLC: (Silica) Rf 0.28 (CH2Cl2 /pentane 3:7), detection with Purpald.
Reaction SMILES: C([Li])CCC.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)C=CC=CC=1.[CH:34]([C@H:36]1[N:40]([CH3:41])[C:39](=[O:42])[CH2:38][C@H:37]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O.O>C1(C)C=CC=CC=1>[CH3:41][N:40]1[C@H:36]([CH:34]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@H:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][C:39]1=[O:42]
Reactant: Clc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CN1C(=O)C[C@@H](c2ccccc2)[C@H]1C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)C[C@@H](c2ccccc2)[C@H]1C=Cc1cccc(Cl)c1
Reaction time: 0.25 h

Procedure:
32.8 g (77 mmol) of n-butyllithium (15% in hexane) were added dropwise under nitrogen with ice cooling to 36.0 g (77 mmol) of triphenyl-m-chlorobenzylphosphonium bromide in 150 ml of toluene in the course of 20 minutes, and the orange suspension was subsequently stirred for 15 minutes. 15.6 g (77 mmol) of cis-5-formyl-1-methyl-4- phenylpyrrolidin-2-one (German Laid-Open Application DOS 3,537,075 and 3,632,589; J. Org. Chem. 52 (1987), 4352) in 120 ml of toluene were then added dropwise and stirred in at room temperature for 3 hours (color change toward pale yellow). 200 ml of H2O were then added, the mixture was acidified with dilute HCL and filtered with suction, the phases were separated, the aqueous phase was extracted twice more with toluene, and the combined organic phases were washed with H2O, dried and concentrated. The crude product was taken up in 100 ml of methyl t-butyl ether and filtered with suction and cooling to remove precipitated triphenylphosphine oxide. The filtrate was concentrated and purified by column chromatography (silica gel, eluent: 98/2 methylene chloride/methanol); yield: 16.1 g (67%). Judging by a 1H-NMR spectrum, the styryl side chain is 90% in the trans configuration and 10% in the cis configuration.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]#[N:9])[CH3:3].[OH:26]O.[OH-].[Na+].O>CS(C)=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]([NH2:9])=[O:26])[CH3:1]
Reactant: OO
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[BrH:25]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][Br:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 50, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours and quenched at 0° C. with saturated aqueous Na2CO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 0.400 g of the desired product that is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH2:25]C)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:28][NH2:29]>O1CCCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:28][NH2:29])(=[O:3])[NH2:2]
Reactant: CCOc1cc(C(=O)OC)ccc1Nc1nc(SC)nc(Cl)c1C(N)=O
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Nc2nc(SC)nc(NN)c2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Example 11A (1.2 g, 3.1 mmol) in tetrahydrofuran (400 mL) was added hydrazine hydrate (550 mg, 9.4 mmol) and the mixture was stirred at ambient temperature for 12 hours. After concentration, the residue was washed with methanol and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 379 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:4].N#N.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)(C)C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.35 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (79 mg, 0.38 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 112 mg (69%) of 3-[tert-Butyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.50 ppm (m, 2H, Haro); 7.44-7.34 ppm (m, 3H, Haro); 7.27 ppm (s, 1H, Haro); 7.18 ppm (dl, 1H, Haro); 7.14 ppm (d, 1H, Haro); 7.00 ppm (dd, 1H, Haro); 3.93 ppm (s, 3H); 1.56 ppm (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=[C:17]([Cl:30])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.IC.[CH3:33]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:33])=[CH:19][CH:18]=[C:17]([Cl:30])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CN(C)C=O
Reactant: COC(=O)CCC(=O)Nc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)CCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 2 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(3-methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoline (447 mg), iodomethane (0.1 ml) and dimethylformamide (5.0 ml) was added sodium hydride (60% in oil, 44 mg) under ice-water cooling. After stirring for 2 hours at the same temperature, the reaction mixture was diluted with ethyl acetate and washed with water twice. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a column chromatography eluted with chloroform to give 8-[2,6-dichloro-3-[N-(3-methyoxycarbonylpropionyl)-N-methylamino]benzyloxy]-2-methylquinoline (310 mg) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:12]1[N:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[N:20][C:15]2=[N:14][CH:13]=1)CCC>>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[N:16]2[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:23])[F:24])=[N:20][C:15]2=[N:14][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1nccs1
Product: FC(F)(F)c1ccn2c(-c3nccs3)cnc2n1
Yield: 33.3 %

Procedure:
2-Bromothiazole (341 μl, 3.78 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.8 mmol) by the method of Example 1 to give 3-(thiazol-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (162 mg) as an off-white solid: δH (400 MHz, CDCl3) 7.40 (2H, dd, J 4 and 3), 7.93 (1H, d, J 3), 8.48 (1H, s), 10.22 (1H, d, J 8); m/z (ES+) 271 (M++H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[CH:18]1[CH2:20][CH2:19]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30].[F-].[Cs+].COCCOC>O>[CH:18]1([C:8]2[CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=2[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOc1cc(C=O)cc(C2CC2)c1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(C=O)cc(C2CC2)c1-c1ccc(F)c(F)c1
Yield: 58.6 %

Procedure:
(1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.30 g) was added to a mixture of 2-cyclopropyl-6-ethoxy-4-formylphenyl trifluoromethanesulfonate (3.00 g), (3,4-difluorophenyl)boronic acid (5.60 g), cesium fluoride (5.39 g), and DME (15 mL), and the resultant mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.57 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.O>CS(C)=O>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:21]2[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCCOCCO)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(OCCOCCOc2ncc(Cl)cn2)cc1
Yield: 63.5 %

Procedure:
2-[2-(4-Acetamidophenoxy)ethoxy]ethanol (9 g) was dissolved in dry dimethylsulfoxide (60 ml) and granular sodium hydride (0.9 g) was added portionwise to the solution. 2,5-Dichloropyrimidine (5.6 g) was slowly added to the cooled stirred solution and on completion of the addition the mixture was stirred at room temperature for 1 hour. The mixture was poured into water (200 ml) and the solid was collected by filtration. The product was recrystallised from ethanol/water to give 2-{2-[2(4-acetamidophenoxy)ethoxy]ethoxy}-5-chloropyrimidine (8.4 g), m.p. 110° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:27]=[CH:26][C:14]([C:15]([N:17]([CH3:25])[O:18]C3CCCCO3)=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOCC>[OH:18][N:17]([CH3:25])[C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[CH:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:27][CH:26]=1
Reactant: CN(OC1CCCCO1)C(=O)c1ccc(C=CCCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CO
Product: CN(O)C(=O)c1ccc(C=CCCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-(4-phenyl-1-butenyl)-N-methyl-N-(tetrahydropyran-2-yloxy)benzamide (prepared in Example 1 Part E) (500 mg, 1.37 mmol) in 12 ml of CH3OH under argon was added pyridinium 4-toluenesulfonate (344 mg, 1.0 eq.). The mixture was heated to 55° C. and stirred for 2.5 hours. The solution was diluted with ether and washed with 1/2 saturate sodium chloride (20 ml) and brine (10 ml). The organic layer was dried over anhydrous MgSO4 and reduced to yield a light yellow oil which was flash chromatographed on Merck silica gel, eluting with (7:3) Hex:EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 426 mg (85%) as a golden oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH2:37][O:38][C:39]1[CH:45]=[C:44]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:51]4)=[CH:45][C:39]=3[O:38][CH2:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (75 mg, 0.104 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.33 (d, J=6.78 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 7.76 (dd, J=8.52, 1.92 Hz, 1H), 7.64-7.72 (m, 2H), 7.40-7.46 (m, 1H), 7.33-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.90-6.97 (m, 2H), 6.77 (d, J=8.24 Hz, 1H), 6.61 (d, J=5.31 Hz, 1H), 4.08 (q, J=6.96 Hz, 2H), 3.96 (s, 3H), 2.90-3.01 (m, 2H), 2.39-2.45 (m, 1H), 2.20-2.32 (m, 2H), 1.90-2.02 (m, 2H), 1.70-1.79 (m, 2H), 1.58-1.70 (m, 2H), 1.39-1.50 (m, 2H), 1.27 (t, J=6.96 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 718 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:25])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>>[Cl:10][C:4]1[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=[C:2]([NH:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[N:3]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: OCc1cc(Cl)nc(Cl)c1
Product: COc1cc(Nc2cc(CO)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 2,6-dichloropyridin-4-methanol (53 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction was heated for 16 h to reflux. Obtained as a pale-yellow solid (25 mg, 24%) after column chromatography on silica gel using dichloromethane/methanol (9:1 v/v) as eluent.
Reaction SMILES: C([O:3][C:4](=[O:31])[C@H:5]([CH3:30])[CH2:6][C@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:6][C@@H:5]([CH3:30])[C:4]([OH:31])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid. HPLC Retention time 1.23 minutes (condition F); MS 408.3 (M+1); 1H NMR (400 MHz, MeOD-d4) δ ppm 1.16 (d, J=7.07 Hz, 3H), 1.50 (m, 1H), 1.96 (m, 1H), 2.52 (m, 1H), 2.72 (dd, J=7.71 Hz, 7.58 Hz, 1H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1H), 3.64 (d, J=1.26 Hz, 2H), 4.20 (m, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.21 (m, 3H), 7.32 (m, 1H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1H).