Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][O:42][C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (228 mg, 0.488 mmol), methyl 2-(4-aminophenyl)acetate (200 mg, 1.21 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 241 mg, 0.634 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by column chromatography (1-100% of EtOAc/heptane, 12 g Analogix column) to afford chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (209 mg, 69.7%) as an white powder. LCMS (ES+) m/z Calcd for C32H31Cl2F2N3O3+H [M+H)+]: 613.17. found: 614.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([NH2:16])[O:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(OCC)OCC.C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([N:16]=[CH:15][O:14][CH2:13][CH3:12])[O:14][CH:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1occ(-c2ccc(NC(C)=O)cc2)c1C#N
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To a suspension of 4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (7.64 g, 39 mmol) in triethyl orthoformate (306 mL), acetic anhydride (15 mL) was added at room temperature. The mixture was heated (inner temp: 100° C.) in an oil bath for 1 h. The black material was precipitated in the mixture and then filtrated. The filtrated material was purified on a silica gel column (eluted by n-hexane-EtOAc 1:3) to afford 473 mg of 6 as a yellow solid. The filtered solution was concentrated in vacuo to afford 6 (7.44 g) as a dark orange solid.
Reaction SMILES: [Na].Br.[CH2:3]1[C:5]2([CH2:10][NH:9][C:8]([NH2:11])=[N:7][CH2:6]2)[CH2:4]1.[C:12](OCC)(=[O:17])[CH2:13][C:14]([O-])=[O:15]>CO>[OH:17][C:12]1[N:11]=[C:8]2[NH:9][CH2:10][C:5]3([CH2:4][CH2:3]3)[CH2:6][N:7]2[C:14](=[O:15])[CH:13]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: NC1=NCC2(CC2)CN1
Agent: Br
Agent: [Na]
Solvent: CO
Product: O=c1cc(O)nc2n1CC1(CC1)CN2
Temperature: 100 °C
Yield: 60 %

Procedure:
1.1 g of sodium are added in a fractionated way to 15 mL of MeOH. After total dissolution, 1.6 g of 5,7-diazaspiro[2.5]oct-5-en-6-amine hydrobromide solubilized beforehand in 5 mL of MeOH, and then 8 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The obtained oil is taken up in ether. The precipitate is filtered and then the residue is taken up in 7 mL of H2O and acidified with concentrated HCl up to pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 1.5 g (yield=60%) of 8′-hydroxy-1′,2′-dihydro-spiro[cyclopropane-1,3′-pyrimido[1,2-a]pyrimidin]-6′-one are obtained as a beige solid used as such.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[NH4+].[Cl-].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]2[NH:16][N:15]=[N:14][N:7]=2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1Br
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-3,5-dimethylbenzonitrile (1 g) in N,N-dimethylformamide (10 mL) is added NH4Cl (770 mg) and NaN3 (800 mg) and the mixture is heated to 100° C. for 12 hours. After cooling to room temperature the mixture is diluted with water. The formed precipitate is filtered off, washed with water and dried to give the title compound. Yield: 650 mg; Mass spectrum (ESI+): m/z=253 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)nc(OCc3ccc(F)cc3F)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of methyl 4-[(4-hydroxy-2-methyl-6-oxopyrimidin-1(6H)-yl)methyl]benzoate (0.2 g, 0.00073 mol, from step 2), potassium carbonate (0.15 g, 0.001 mol), 2,4 difluorobenzylbromide (0.15 g, 0.00073 mol), and 18-crown-6 (0.011 g) in DMF is stirred at room temperature for 1 h under argon atmosphere. The DMF was distilled in vacuo and the residue is partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase is washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel flash chromatography using 35% EtOAc in hexanes to afford the title compound (0.20 g, 69%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.98 (d 2H, J=8.4 Hz), 7.54 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 6.98 (m, 2H), 5.78 (s, 1H), 5.38 (s, 2H), 5.32 (s, 2H), 3.88 (s, 3H), and 2.44 (s, 3H); ES-HRMS m/z 401.1308 (M+H calcd for C21H19N2O4F2 requires 401.1307). 19F NMR(CD3OD/400 MHz) −111.77 (m), 116.06 (m).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:31]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[O:32])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCN(C)CC3)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 156 mg (0.96 mmol, 1.3 eq.) of 4-methylpiperazine-1-carbonyl chloride were reacted according to General Method 3. Yield: 213 mg (66% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15](OCC)C.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:15][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-Amino-4-trifluoromethyl-benzoic acid were dissolved using 50 ml of diethyl ether and 25 ml of methanol. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.3 g of the title compound, viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)[NH:10][CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>CN(C)C=O.O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([CH:9]([NH:10][CH3:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)=[CH:3][CH:4]=2)[NH:13][CH:14]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cnn(C)c3)cc2)NC)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-N-methylethanamine (157 mg, 0.43 mmol), sodium carbonate (138 mg, 1.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.86 mmol) in N,N-dimethylformamide/water (2:1) (9 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 366.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
5 g of (S)-4-benzyl-2-acetoxymethylmorpholine was dissolved in 10 ml of ethanol. To the solution was added a solution of 1 g of sodium hydroxide dissolved in 5 ml of water with ice cooling. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to 50 ml of ice water and extracted with 50 ml of chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 3.6 g of oily (S)-4-benzyl-2-hydroxymethylmorpholine.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][S:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([N:23]=O)=[C:18]([NH2:25])[N:17]=1.[O:26]1CC[CH2:28][CH2:27]1>CN(C)C=O>[NH2:25][C:18]1[C:19]2[N:23]=[CH:28][C:27](=[O:26])[NH:22][C:20]=2[N:21]=[C:16]([S:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:17]=1
Reactant: C1CCOC1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Temperature: 25 °C

Procedure:
To a solution of triethyl phosphonoacetate (15.0 g) in tetrahydrofuran (60 ml) cooled in an ice bath was added butyllithium (2.5 M in hexanes, 25.6 ml) at a rate such that the internal temperature was maintained below 30° C. To this mixture was then added a solution of the product of Example 2 step (b) (10.0 g) in N,N-dimethylformamide (60 ml). The reaction mixture was heated at reflux for 1 hour, then cooled to room temperature and quenched with acetic acid (6 ml). The solid thus precipitated was isolated by filtration, washed with water, ethanol and diethyl ether, and dried over P2O5 at 50° C. to give the sub-titled product as a pale green solid (9.3 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:29])[C:15]([CH2:25][CH2:26][CH2:27][CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:32](Cl)([CH3:35])(=[O:34])=[O:33].N1C=CC=CC=1>CC(C)=O>[CH2:25]([C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:30]=[CH:31][C:3]([NH:2][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 95.7 %

Procedure:
A solution of Example 33B (0.052 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.054 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17](=[O:18])[NH2:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NCCC(N)=O
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc2c(NCCC(N)=O)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
In 10 ml of DMF, 1.0 g (4.9 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then 668 mg (5.37 mmol) of β-alanineamide hydrochloride and 1.09 g (10.7 mmol) of triethylamine were added thereto under ice cooling. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.05 g (yield: 79.8%) of the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:40](=[O:41])[CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a stirred mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and 2-(1H-indol-3-yl)acetic acid (0.13 g) in dichloromethane (8 ml) containing triethylamine (0.25 ml) was added 2-chloro-1-methylpyridinium iodide (0.22 g) at room temperature under nitrogen atmosphere. After being stirred for 5 hours, the reaction mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid, aqueous saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using chloroform-methanol (50:1) as eluent to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-(1H-indol-3-yl)acetyl]piperazine (0.34 g) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH3:19][C:20]([CH:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH2:21][CH3:22].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:23][C:20]([CH:24]1[CH2:25][CH2:26][CH:27]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:28][CH2:29]1)([CH3:19])[CH2:21][CH3:22]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CCC(C)(C)C1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a mixture of (R)-4-(6-hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 300.0 mg, 1.233 mmol) and 4-(1,1-dimethyl-propyl)-cyclohexanol (252 mg, 1.48 mmol) in tetrahydrofuran (5 mL, 60 mmol) was added triphenylphosphine polymer-bound (1.07 g, 1.97 mmol). After the mixture was stirred at room temperate for 10 min, diisopropyl azodicarboxylate (0.388 mL, 1.97 mmol) was added dropwise. The mixture was stirred at room temperate for 48 hrs. The insoluble material was passed over a CELITE™ bed and washed with ethyl acetate. After the solvent was concentrated, the residue was purified with silica gel column eluted with ethyl acetate in hexanes from 0 to 40% to give 410 mg of white precipitate (R)-4-{6-[4-(1,1-dimethylpropyl)-cyclohexyloxy]-naphthalen-2-yl}-4-methyloxazolidin-2-one (84% yield). MS: m/z=396.30 M+H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[CH:31][C:30]([F:48])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[F:48][C:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])=[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:45])([CH3:46])[CH2:40][C:41]=43)[C:34]2=[O:47])[CH:31]=1
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
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: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
In a 10-mL microwave reaction vessel equipped with a magnetic stirring bar were placed 5-bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one 205b (150 mg, 0.43 mmol), 10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 230a (248 mg, 0.50 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (2 mL). After the reaction mixture was stirred at 125° C. for 10 minutes, it was purified by flash chromatography (dichloromethane:methanol, 3:1) to give 36% (100 mg) of 261a as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCO[CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:35]4[O:36][C:32]([CH:28]=[O:27])=[CH:33][CH:34]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Agent: Cl
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J. Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reacted together in a procedure analogous to Procedure B above for 20 hrs. The reaction mixture was allowed to cool, 1N HCl (50 ml) added and stirred at room temperature for 15 minutes. The reaction was filtered and the residue washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature for a further hour. The dioxane was removed under vacuum, the reaction diluted with water and the solid which precipitated was collected by filtration, and washed with water, iso-hexane and acetone. This precipitate was converted to the free base by partitioning into a mixture of triethylamine, ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent removed under vacuum. The residue was triturated with iso-hexanelethyl acetate to give the product (2.41 g, 52%) as a yellow solid; δH [2H6]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H), 7.82 (2H, d, 2′-H, 6′-H), 7.65-7.42 (6H, m, 5× Ph-H, furan-H), 7.21 (2H, d, 3′-H, 5′-H), 5.26 (2H, s, OCH2); m/z (M+1)+ 423.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[N:38]=[C:37]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:42][CH:41]([CH3:43])[C:40]([NH:39][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:28][CH2:29]2)[N:38]=1)=[O:44]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 82 was prepared from triphenylacetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.81 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.30–7.24 (m, 15H), 6.84 (d, 1H, J=7.2 Hz), 6.33 (br s, 1H), 3.44 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, J=11.6 Hz), 2.57–2.49 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=12.0 Hz), 1.79–1.58 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.