Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]([F:23])([F:22])[F:21])=[C:15]([CH2:33]O)[CH:14]=1.ClC1C=C(C=CC=1)CO.C1C=CC(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:58]([CH2:33][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=1[CH:19]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:20]([F:23])([F:22])[F:21])=[N+:59]=[N-:60]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)(F)F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: OCc1cccc(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
DBU (0.483 mL, 3.23 mmol) was added to a stirred solution of N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.46 g of a 1:1.7 mixture with 3-chlorobenzyl alcohol) and DPPA (0.696 mL, 3.23 mmol) in THF (4 mL) at 0° C. The mixture was warmed to ambient temperature and after 3 h was partitioned between ether and water. The organic layer was washed with 1 M sodium hydroxide solution and brine, dried (Na2SO4) and evaporated to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 0-15% ethyl acetate/hexanes) to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 g) as an oil: 1H NMR (CDCl3, 400 MHz) δ 3.72 (s, 3H), 3.97 (d, J=7.3 Hz, 1H), 4.37 (d, J=14.1 Hz, 1H), 4.48 (d, J=14.1 Hz, 1H), 5.20 (pentet, J=7.1 Hz, 1H), 6.63 (d, J=9.0 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 7.37 (m, 2H), 7.55 (d, J=8.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:38]=1>O1CCOCC1.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>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nc1
Temperature: 110 °C
Yield: 99.8 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.04 mmol) and methyl 6-bromonicotinate (292 mg, 1.35 mmol) in dry 1,4-dioxane (5 mL) was added CsCO3 (1 mL, 2 mmol) and Pd(PPh3)2Cl2 (50 mg). After addition, the mixture was warmed to 110° C. for 30 min under microwave. After TLC showed the starting material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (507 mg, 89%), which was purified by preparative TLC. 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.61 (d, 3H), 2.24 (m, 4H), 2.37 (m, 1H), 2.88 (m, 1H), 4.02 (s, 3H), 5.76 (q, 1H), 7.11 (d, 2H), 7.29-7.47 (m, 6H), 7.78 (m, 1H), 7.82 (m, 2H), 8.38 (d, 1H), 9.31 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C1(N)CCCCC1>C(O)(=O)C>[F:11][C:7]1[CH:8]=[C:9]([F:10])[C:2]([F:1])=[C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])[C:6]=1[F:12]
Reactant: O=Cc1c(F)c(F)cc(F)c1F
Reactant: CC[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: NC1CCCCC1
Product: CC(=Cc1c(F)c(F)cc(F)c1F)[N+](=O)[O-]
Temperature: 80 °C
Yield: 91.1 %

Procedure:
A mixture of 2,3,5,6-tetrafluorobenzaldehyde (25.0 g, 0.14 mol), nitroethane (21.08 g, 0.28 mol), and cyclohexylamine (13.92 g, 0.14 mol) in 150 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to room temperature (rt) and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 30.0 g (91%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 258.0 [M+Na]+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30]C)[N:24]=2)=[CH:16][C@@H:17]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH2:32](I)[CH3:33]>>[Cl:29][C:26]1[C:25](=[O:30])[NH:24][C:23]([CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:32][CH3:33])=[CH:14][CH:13]=2)[CH2:16][C@H:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21]2)=[CH:28][CH:27]=1
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Reactant: CCI
Product: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(=O)[nH]2)cc1

Procedure:
An (R,S) mixture of the title compound was obtained as a colorless amorphous (240 mg) by performing substantially the same reaction as in Examples 1-16(2)(3) and 4-209 and 4-210(2)(3) sequentially except for using (5R)-5-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Example 4-48(1) and using ethyl iodide in place of methyl iodide. This was separated by chiral HPLC (CHIRALCEL OD-H, 40° C., flow rate: 7 mL/min, ethanol:hexane=0:100) to give one diastereomer (A) of the title compound as a colorless amorphous (38 mg) and the other diastereomer (B) of the title compound as a colorless amorphous (35 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:11][CH2:12][S:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][CH2:11][CH2:12][S:13][CH3:14]
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSCCOc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)#[N:22]>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)CNc1ccc(CCN)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CNc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1

Procedure:
920 mg of N-[p-(2-aminoethyl)phenyl]glycine methyl ester sulphate were reacted in analogy to Example 3 with 4-cyanobenzoyl chloride to give N-[p-[2-(p-cyanobenzamido) ethyl]phenyl]glycine methyl ester, melting point 161°-162° C. (from toluene).
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.O.[C:15]1(O)([CH3:24])[CH2:20][CH2:19][CH:18]([C:21]([CH3:23])=[CH2:22])[CH:17]=[CH:16]1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:12]=[C:1]([OH:13])[C:2]([C@@H:17]2[C@@H:18]([C:21]([CH3:23])=[CH2:22])[CH2:19][CH2:20][C:15]([CH3:24])=[CH:16]2)=[C:3]([OH:4])[CH:5]=1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Reactant: CCCCCc1cc(O)cc(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: C=C(C)[C@H]1CCC(C)=C[C@@H]1c1c(O)cc(CCCCC)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
A mixture of olivetol (3.6 g, 20 mmol), zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) and dichloromethane (35 mL) was refluxed for 1 hour. A solution of (−)-p-mentha-2,8-dien-1-ol (3.0 g, 20 mmol) in dichloromethane (10 mL) was added drop-wise over 0.75 hour to the refluxing mixture, and the resultant reaction mixture was mixed for 0.5 hours at reflux. The mixture was cooled to 25° C., ice water (50 mL) was added, and the resultant biphasic mixture stirred for 20 minutes at 0° C. The resultant organic phase was collected, washed with water (2×20 mL) and 5% NaHCO3 (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.0 g of first crude (+)-CBD residue. Analysis (GC) of the first crude (+)-CBD residue indicated that it contained (+)-CBD (46.9%) and abn-(−)-CBD (19.7%). The first crude (+)-CBD residue was purified by column chromatography on silica gel (eluent MTBE/hexane) to provide 2.4 g of a second crude (+)-CBD residue.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C@H:17]([OH:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][C:9]=2[CH:34]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[C:30]([O:29][C:27]([N:15]([CH:11]1[CH2:10][C:9]2[CH:34]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH2:14][CH2:13][CH2:12]1)[CH2:16][C@H:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.6 %

Procedure:
To a solution of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.5 g) in methanol (45 ml) and tetrahydrofuran (15 ml) was added 1N sodium hydroxide aqueous solution. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid solution under ice-cooling. The product was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (4.48 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([NH2:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][C:7]([N:10]3[C:14](=[O:15])[C:13]4[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:16])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1ccc2cc[nH]c2n1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc2cc[nH]c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-6-ylamine (0.12 g, 0.9 mmol) was suspended in acetic acid (1.5 mL), then phthalic anhydride (133 mg, 0.9 mmol) and sodium acetate (118 mg, 1.44 mmol) were added and the mixture heated to 120° C. After 3 h, the mixture was concentrated in vacuo, the residue obtained dissolved in ethyl acetate, and then cooled to 0° C. Ice-water and sodium bicarbonate solution were added then the aqueous layer was extracted with ethyl acetate. The aqueous layer was adjusted to pH 6 with 1M HCl solution and was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate then concentrated in vacuo. Purification by chromatography (silica, 20 to 70% ethyl acetate in hexanes) gave 2-(1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (179 mg, 75%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.91 (br. s., 1H) 8.15 (d, J=7.9 Hz, 1H) 7.90-8.05 (m, 4H) 7.59-7.65 (m, 1H) 7.21 (d, J=7.9 Hz, 1H) 6.54-6.60 (m, 1H); LCMS (EI/CI) m/z: 264 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C:28]1[N:29]=[CH:30][C:25]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4s3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3o2)nc1
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: C1CCOC1
Solvent: O
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)nc2c1
Yield: 84.8 %

Procedure:
Following the procedure for 17, 11 (0.558 g, 2.03 mmol), 16 (0.700 g, 2.07 mmol), tetrakis(triphenylphosphine)palladium(0) (117 mg, 102 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded an insoluble white solid (0.70 g, 84%) after filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:28]=[CH:27][CH:26]=[C:4]([CH2:5][N:6]2[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:7]2)[CH:3]=1
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
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: O
Solvent: C1COCCO1
Product: O=c1n(Cc2cccc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 101A and 59 mg (0.23 mmol) of 2-chloro-phenylboronic acid were dissolved in 2 ml of dioxane. A stream of argon was passed through this solution for 10 min, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was then stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 51 mg (61% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(C)C(C)=CC=C[CH:37]=1.CN(C=O)C.[F-].[K+]>ClCCl>[CH:27]([NH:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:11]1[N:10]([CH3:30])[C:9](=[O:31])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH2:37])[CH:3]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1)([CH3:29])[CH3:28]
Reactant: Cc1ccccc1C
Reactant: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=Cc1cccc(-c2c(-c3ccncc3)nc(N3CCCC3CNC(C)C)n(C)c2=O)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-2-[2-(isopropylamino-methyl)-pyrrolidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.48 g, 1.0 mmol), 50 mL xylene, 5 mL DMF and 0.58 mL tributhyl(vinyl)tin. The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(PPh)4 (58 mg, 0.05 mmol), the mixture was warmed up to 140° C. and stirred for 1 h under nitrogen. The mixture was cooled down to rt, 20 mL 10% KF solution was added and stirred for 30 min. The mixture was diluted with 200 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.28 g as pale yellow solid. MS (ES+): 430 (M+H)+; (ES−): 428 (M−H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[C:11]2[N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:3]1.CN1CCC(=O)CC1.C1(C)C=CC=CC=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CCOC(C)=O>[N:21]1([C:11]2[C@:12]3([CH2:14][CH2:15][C@H:16]4[C@@H:7]([CH2:6][CH2:5][C:4]5[C@:17]4([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=5)[C@@H:8]3[CH2:9][CH:10]=2)[CH3:13])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Agent: CC(C)[O-]
Agent: CN1CCC(=O)CC1
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Yield: 82.8 %

Procedure:
From a mixture of compound 5 (660 mg, 1.70 mmol), 1-methyl-4-piperidone (2.5 mL), and toluene (40 mL) was distilled off ca. 10 mL. Aluminum isopropoxide (521 mg, 2.55 mmol) was then added, and the mixture was refluxed under Ar for 4 h. After cooling, the mixture was diluted with EtOAc (50 mL), washed successively with 5% aqueous NaHCO3 (x3) and brine (x2), and then dried (Na2SO4). The solvent was evaporated, and the crude product was purified by FCC [CH2Cl2/EtOH (25:1)] to give the title compound 6 (544 mg, 82%): mp 201-204° C.; IR(CHCl3) 2946, 2858, 1622, 1611, 1490, 1453, 1376, 1291, 1270, 1228, 1189, 893, 850, 837, 722, 662, 615, 568, 553, 537, 519 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H 18-CH3), 1.24 (s, 3H, 19-CH3), 5.78 (s, 1H, 4-H), 5.99 (s, 1H, 16-H), 7.31 (m, 2H, aromatic-Hs), 7.48 (m, 1H, aromatic-H), 7.81 (s, 1H, aromatic-H), and 7.95 (s, 1H, 21-H). HRMS calcd 409.2250 (C26H30ON2.Na+). found 409.2250.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cn2cccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of pyrrole (2.3 ml) and 60% sodium hydride (1.3 g) in N,N-dimethylformamide (50 ml) was added methyl 3-(bromomethyl)benzoate (5.0 g) under ice-cooling and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated to give methyl 3-(pyrrol-1-yl)methylbenzoate (4.14 g) as an oil.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH2:5]1>C(O)=O>[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:1])[CH2:5]1
Reactant: OO
Reactant: CC1(C)CC=Cc2ccccc21
Solvent: O=CO
Product: CC1(C)CC(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred mixture of 30% hydrogen peroxide (5 ml) and 97% formic acid (20 ml) in a round bottom flask equipped with an additional funnel, thermometer, and an ice water bath was added 1,2-dihydro-1,1-dimethylnaphthalene (4.5 g, 28 mmoles) dropwise at 5° C. under a nitrogen atmosphere. When the addition was complete, the reaction vessel was raised above the cooling bath to allow the reaction temperature to rise to just below 35° C. at which point the flask was immersed again. In this manner the temperature of the reaction was maintained between 30° and 35° C. for 45 minutes. After this time the exothermic phase of the reaction ended and the mixture was allowed to cool to room temperature. A solution of 10% aqueous ferric sulfate was added in portions of a few milliliters each until cloudiness persisted in the stirred mixture and then all solvent was removed under reduced pressure. The viscous brown residue was refluxed with 20% H2SO4 (20 ml) for 4 hours and then cooled, extracted three times with ether (75 ml each), dried over magnesium sulfate, filtered and evaporated to leave a brown oil. This was purified using silica gel column chromatography eluting with ethyl acetate:hexane (7:93) to give 4,4-dimethyl-2-tetralone. (3.4 g, 74%). Overall yield=40%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:18])[N:11]=2.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:13]=[C:12]([CH3:18])[N:11]=2
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Yield: 65.5 %

Procedure:
Heat a solution of 8-(2-bromophenyl)-6-chloro-2-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purine (0.0023 mol, 1.0 g), 1-methyl piperazine (0.0025 mol, 0.25 g, 1.1 equiv.) and triethylamine (0.0025 mol, 0.25 g, 1.1 equiv.) in ethanol (10.0 mL) at 90° C. for 16 h. Concentrate the reaction mixture under reduce pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 97:3 to give 8-(2-Bromo-phenyl)-2-methyl-6-(4-methyl-piperazin-1-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine (0.71 g). Used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:45][CH2:46]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (337 mg, 77%).