Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[N:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[N:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (656 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C1CCN2C(=NCCC2)CC1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of (±)-4-chloro-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (220 mg, 0.77 mmol), 5-hydroxy indole (155 mg, 1.16 mmol) and MeCN (10 mL) is treated with DBU (0.2 mL, 1.16 mmol) and heated at 80° C. for 4 h. The volume is reduced in vacuo and the residue is separated via FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 381.3 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1Cl
Product: N#Cc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1Cl
Yield: 43.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 3-chloro-4-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3′-chloro-4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (42 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br s, 1H) 8.44-8.55 (m, 2H), 8.34 (d, J=1.8 Hz, 1H), 8.28 (dd, J=8.0, 2.0 Hz, 1H), 8.07-8.13 (m, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.56 (dd, J=8.0, 1.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(CCCBr)c1
Reaction time: 12 h
Yield: 84.4 %

Procedure:
Compound 15-1 (1.88 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.64 g) and N-bromosuccinimide (2.46 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1) to give the object product (2.25 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)[CH:7]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Product: COc1ccc(Cl)cc1C1CCNCC1
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of benzyl 4-(5-chloro-2-methoxyphenyl)piperidine-1-carboxylate (Preparation 234, 73 g, 0.2 mol) in concentrated hydrochloric acid (200 ml) was refluxed with stirring for 2 hours before concentrating in vacuo. Water (100 ml), sodium hydroxide (10 M aqueous solution, 20 ml) and chloroform (200 ml) were added to the residue. The aqueous layer was extracted with chloroform (2×200 ml). The combined organic layers were washed with water (200 ml), saturated aqueous sodium chloride solution (200 ml), dried over sodium sulphate, filtered through silica gel (100 g, 40/63 μm) and evaporated in vacuo to afford the title compound as white crystals, 40 g, 89% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.CN(C)[CH:17]=[O:18].[Cl-].[NH4+]>CCCCCC.C(OCC)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: O=Cc1ccc(F)cc1F
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
2,4-Difluorobromobenzene (18.5 g) was added to dry diethyl ether (150 ml), cooled to -75° C. and n-butyllithium (61 5 ml of a 1.55 molar solution in hexane) was added under dry nitrogen over a period of 45 minutes. The mixture was stirred at -70° C. for a further 20 minutes and dry dimethylformamide (7.65 g) was added in dry diethyl ether (30 ml) at -70° C. over a period of 30 minutes. The mixture was stirred for 40 minutes and allowed to warm to -50° C. over a further 15 minutes. A solution of ammonium chloride (30 g) in water (100 ml) was added and the ether layer separated. The aqueous layer was further extracted with diethyl ether (2×50 ml) and the combined ethereal extracts were dried and evaporated to yield a pale yellow oil which was distilled at the water pump to give the desired product (13.0 g) b.p. 52°-55° C. at 14 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]S(C)(=O)=O)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]1([CH2:44]O)[CH2:43][CH2:42]1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:44][CH:41]3[CH2:43][CH2:42]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Reactant: OCC1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To an ice-cooled solution of 3.50 g (6.13 mmol) of the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester and 4.97 ml (4.42 g, 61.33 mmol, 10.0 equiv.) of cyclopropyl carbinol in 25 ml of tetrahydrofuran was added 0.535 g (12.27 mmol, 2.0 equiv.) of sodium hydride dispersion (55% in mineral oil) in portions. The mixture was warmed to 55° C. and stirred for 1.5 h. The reaction mixture was poured into 200 ml of an ice/water mixture, the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution, and the aqueous phase was extracted four times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 1:2 v/v mixture of hexane and ethyl acetate as eluent to yield 3.32 g (6.07 mmol, 99.0% of theory) of the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil; MS: 547 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[CH3:10][Mg]Br>CCOCC>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])([CH3:10])[CH3:8])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Br)s1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)s1
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To the solution of 1-(5-bromothiophen-2-yl)ethanone (2.05 g, 10 mmol, 1 eq) in ether (20 mL) was added methylmagnesium bromide (11 mL, 11 mmol, 1.1 eq) dropwise at ice-bath. After 0.5 h, the reaction mixture was allowed to stand at room temperature for 1.5 h. Then, the reaction was quenched with saturated aqueous NH4Cl, washed with brine, dried (Na2SO4), and evaporated to afford 2-(5-bromothiophen-2-yl)propan-2-ol (1.97 g, 89%). LC-MS (m/z)=211 [M+]H+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:12]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][C:22]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:29][CH2:28]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1cccc(-c2ccccc2)c1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Product: COc1cc(CN2CCN(C(=O)C=Cc3cccc(-c4ccccc4)c3)CC2)cc(OC)c1OC
Yield: 85.1 %

Procedure:
Following a procedure similar to that described in Example 61, but using 0.500 g of 3-phenylcinnamic acid and 0.653 g of 1-(3,4,5-trimethoxybenzyl)piperazine, 0.897 g of the title compound was obtained as a powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1
Reactant: NCCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CCN)cc1
Temperature: 22 °C

Procedure:
To a solution of 2.02 g (10.0 mmol) of 4-(2-aminoethyl)benzoic acid hydrochloride in 25 mL of methanol was added 1.5 mL of H2SO4. The mixture was heated to reflux and became a homogeneous solution after 1 h. The solution was refluxed for about 16 h, cooled to 22° C. and concentrated to about 10 mL by evaporation. The solution was diluted with 100 mL of water, made basic with 1 N NaOH and extracted with 100 mL of dichloromethane (DCM). The aqueous layer was back-extracted with DCM (4×100 mL). The combined extracts were dried (Na2SO4) and evaporated to give methyl 4-(2-aminoethyl)benzoate as a colorless oil. The material was used directly in the subsequent transformation.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N:10]1[CH:14]=[C:13]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)[CH:12]=[N:11]1)C>>[CH3:22][C:17]1([CH3:23])[C:18]([CH3:20])([CH3:21])[O:19][B:15]([C:13]2[CH:12]=[N:11][N:10]([CH:2]3[CH2:6][CH2:5][CH2:4][C:3]3=[O:7])[CH:14]=2)[O:16]1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1CCCC1Cl
Product: CC1(C)OB(c2cnn(C3CCCC3=O)c2)OC1(C)C

Procedure:
Intermediate W-1 was prepared from 2-chlorocyclopentanone (1.06 g, 9 mmol) following the similar procedures of synthesizing intermediate (V), as described above. MS (m/z): 277 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 120 °C
Yield: 37.7 %

Procedure:
A mixture of 8-bromo-1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (124 mg, 0.26 mmol), 4-tributylstannanyl-pyridine (145 mg, 0.39 mmol) and PdCl2(PPh3)2 (37 mg, 0.053 mmol) in 5 mL of DMF was heated at 120° C. for 3.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH) to give 46 mg of the title compound. MS: (+) m/z 470.45 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH3:18])[N:17]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylpheny1)-4-methylimidazole (1.0 g, 0.003 mol), nitric acid (70% w/w 1 ml) and sulphuric acid (98% w/w, lml) was stirred and heated at 75° C. for 4 hours then at 100° C. for 2 hours. After cooling the reaction mixture was added to a mixture of ice and water (20 ml) and the precipitated solid was filtered off. Recrystallisation from toluene gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-5-nitroimidazole (0.66 g), m.p. 316.5°-317.5° C., as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:17][CH:16]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:15][CH:16]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:17]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CC(C(C)(C)O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CC(C(C)(C)O)C3)n(C)c2n1
Temperature: 120 °C
Yield: 35.9 %

Procedure:
A mixture of 2-{1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]azetidin-3-yl}propan-2-ol (84 mg, 0.21 mmol), 2-ethylbenzimidazole (34 mg, 0.23 mmol), Pd2(dba)3 (4.9 mg, 2.5 mol %), Xphos (10.1 mg, 10 mol %) and Cs2CO3 (104 mg, 0.32 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 23 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-20% 2 M NH3/MeOH in DCM) to give 451 (38 mg, 35%) as a yellow solid. LCMS: (Method I): RT 2.53 min; [M+H]+ 505.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.77-7.73 (m, 1 H), 7.27-7.22 (m, 2 H), 4.49-4.24 (m, 4 H), 3.88-3.83 (m, 4 H), 3.76 (s, 3 H), 3.48-3.40 (m, 2 H), 3.38-3.27 (m, 4 H), 3.15-2.95 (m, 2 H), 2.95-2.90 (m, 2 H), 2.55-2.47 (m, 1 H), 1.43 (t, J=7.48 Hz, 3 H), 1.17 (s, 6 H)
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[CH:35]([O:38][C:39]1[C:40](=O)[C:41](=[O:47])[C:42]=1[O:43]C(C)C)([CH3:37])[CH3:36]>CO>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH:2]([NH:1][C:40]3[C:41](=[O:47])[C:42](=[O:43])[C:39]=3[O:38][CH:35]([CH3:37])[CH3:36])[C:3]([O:5][CH3:6])=[O:4])[CH:9]=2)[N:14]=1
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)Nc1c(OC(C)C)c(=O)c1=O
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 (2 TFA salt, 1.51 g) in CH3OH (15 ml) cooled with an ice bath, are added 0.96 ml of DIPEA and 495.6 mg of 3,4-diisopropoxy-3-cyclobutene-1,2-dione. The solution is stirred overnight at Rt. The solution is evaporated and the resulting residue is purified over silica gel using CH2Cl2/CH3OH (99.2/0.8) as eluent to give methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[(2-isopropoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propanoate 116.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)C)c1

Procedure:
4-(2-Methoxycarbonylvinyl)-2,6-diisopropylphenol (Example 1, 350 mg) was dissolved in a solution of ethyl acetate (10 mL) and methanol (10 mL) and hydrogenated at 35 psi over palladium on carbon (Pd/C) for 24 hours. The resulting mixture was filtered and the filtrate was concentrated to provide the title compound; 1H-NMR (CDCl3) δ=1.27 (d, 12H, CH(CH3)2), 2.60 (t, 2H, CH2), 2.87 (t, 2H, CH2), 3.13 (m, 2H, CH(CH3)2), 3.68 (S, 3H, OCH3), 6.87 (S, 2H, ArH).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc(F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight and was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (0.64 g, 65%): mp, 214-216° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.53 (s, 2H), 4.72 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.10-7.16 (m, 2H), 7.29-7.34 (m, 2H), 7.62-7.65 (m, 1H), 7.78-7.81 (m, 2H), 8.67 (t, J=5.9 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.83, 41.17, 48.82, 114.77, 115.05, 121.89, 127.12, 130.81, 130.92, 131.51, 132.24, 132.28, 133.19, 134.67, 139.09, 159.42, 162.62, 166.90, 167.42, 169.78, 170.51, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.05; H, 4.18; N, 9.85; F, 4.48.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.6 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (400 mg, 1.4 mmol), 2-piperidin-4-yl-propan-2-ol (242 mg, 1 7 mmol), and 4 Å molecular sieves (1.5 g) in 1,2-dichloroethane (20 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (593 mg, 2.8 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, (10% MeOH in EtOAc): EtOAc, gradient 0:100 to 20:80) to afford the title compound as an orange solid (344 mg, 60%). 1H NMR (400 MHz, CDCl3): δ 3.98-3.93 (6 H, m), 3.85 (5 H, m), 3.08 (2 H, m), 2.28 (2 H, m), 1.79 (2 H, m), 1.48 (3 H, m), 1.23-1.21 (6 H, m).