Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[CH2:38][C:37](=O)[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:5])[CH2:3][C:37](=[CH2:38])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)[O:4]1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C1CC(C)(C)Oc2ccc(C(=O)OC)cc21
Temperature: -30 °C

Procedure:
Potassium tert-butoxide (96.0 mg, 0.85 mmol) was added to a suspension of triphenylmethylphosphonium bromide (305 mg, 0.85 mmol) in toluene (3.00 mL) while stirring at −30° C. under N2 atmosphere. After stirring for 1 hour at −30° C., a solution of methyl 2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromene-6-carboxylate (100 mg, 0.43 mmol) in toluene (2.00 mL) was added slowly via a syringe. The suspension was stirred for a further 30 minutes at −30° C. and then heated to reflux overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (50.0 mL) and washed with water (10.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-25% EtOAc/hexanes to give the desired product as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][C:13]#[C:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[CH2:20]([O:19][P:15]([C:14]1[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:8]=[C:9]2[CH2:10][CH2:11][CH2:12][C:13]=12)(=[O:22])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: CCOP(=O)(C#CCCC/C=C/c1ccc(Cl)cc1)OCC
Solvent: Clc1ccccc1Cl
Product: CCOP(=O)(OCC)c1c2c(cc3ccc(Cl)cc13)CCC2
Temperature: 225 °C
Reaction time: 2.5 h

Procedure:
To a 0.5-2 mL microwave irradiation vial equipped with a stir bar was added enyne 5i (0.034 g, 0.10 mmol) in o-dichlorobenzene (1.7 mL). The reaction was irradiated with stirring at 225° C. for 150 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6i as an amber oil (0.034 g, quant.).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[NH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:18]([CH3:20])=[O:19].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([NH:17][C:18](=[O:19])[CH3:20])=[CH:26][CH:25]=3)(=[O:29])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 4-acetamino-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.60 g of N-{4-[4-(3-nitro-phenyl)-thiazol-2-ylsulphamoyl]-phenyl}-acetamide separated as yellowish crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[O:26]=[C:25]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:18][CH:17]=[C:16]([C:24]=23)[CH2:15][N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2c[nH]c3nccc(C(=O)O)c23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Yield: 54.3 %

Procedure:
3-((1-(tert-Butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (35 mg, 0.093 mmol), HATU (71 mg, 0.187 mmol), and pyridine (0.023 mL, 0.280 mmol) were stirred in DMF (3 mL) at room temperature for 2 h. The solution was concentrated in vacuo and purified via basic prep HPLC eluting with 10% to 35% B in A and gave 18 mg of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.59 (m, 1H), 7.39-7.49 (m, 1H), 4.98 (d, 2H, J=1.5 Hz), 4.77-4.79 (m, 1H), 4.25-4.28 (m, 2H), 2.87-2.92 (m, 2H), 1.91-1.94 (m, 2H), 1.78-1.90 (m, 2H), 1.48 (s, 9H). [M+H] found 357.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@@H:12]([OH:42])[C@@H:13]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[C:26]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:25]=1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.CCO>[Pd].O>[NH2:10][CH2:11][C@@H:12]([OH:42])[C@@H:13]([NH:21][C:22](=[O:23])[C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[C:26]([N:36]2[CH2:40][CH2:39][CH2:38][C:37]2=[O:41])[CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN)cc(N2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of [(2R,3S)-2-hydroxy-3-({1-[3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-phenyl]-methanoyl}-amino)-4-phenyl-butyl]-carbamic acid benzyl ester (D105) (820 mg, 1.4 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 100 mg, 6% w/w), NH4CO2H (800 mg, 12.7 mmol, 9 equiv), EtOH (25 ml) and H2O (10 ml) was stirred at 60° C. for 1 h. The mixture was then cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the EtOH was removed in vacuo and the residue was partitioned between AcOEt and H2O. The aqueous phase was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give N-((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (420 mg, 66%) as a white solid. [M+H]+=454.0, RT=2.63 min
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:14]2[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:12]3[C:13]=2[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:23]>O>[N+:1]([C:6]1[CH:7]=[C:8]2[C:13]3=[C:14]([C:15]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:23])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=1)([O-:4])=[O:2]
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C1CCCCc2c1n1c3c(cc([N+](=O)[O-])cc23)CCC1
Reaction time: 1 h

Procedure:
Nitric acid (1.2 mL, 22 mmol) was added dropwise to a mixture of 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (2.0 g, 8.9 mmol) and concentrated sulfuric acid (43 mL). The reaction mixture was stirred for 1 hour and then poured into water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography (elution with 12% ethyl acetate-hexanes) to provide 2-nitro-8-oxo-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=[O:34]>>[I:1][CH2:2][C:3]1[N:4]=[C:33]([C:32]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=2)[O:34][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)/C(C)=N/O
Product: COc1ccc(-c2nc(CI)c(C)o2)cc1OC

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3,4-dimethoxybenzaldehyde gave 4-iodomethyl-5-methyl-2-(3,4-dimethoxyphenyl)oxazole.
Reaction SMILES: C(O)C.C1(C)C=CC=CC=1.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]>[H][H].[Pd]>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCC[C@H]1CC[C@H](CCC2CC=C(c3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3)CC2)CC1

Procedure:
To a liquid mixture comprising 250 ml of ethanol and 250 ml of toluene was dissolved 92 g of the (4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexene-1-yl)benzene mentioned above, 5 g of palladium/carbon (5%) was added as catalyst thereto, and they were subjected to a catalytic reduction in hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain a yellow oily product. This product was recrystallized from ethanol to obtain 58.5 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.ClC(OCC)=O>CN(C=O)C.C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a stirred solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.28 g) in DMF (30 ml) was added dropwise a solution of mixed anhydride prepared from N-t-butoxycarbonylglycine (3.912 g), triethylamine (2.371 g) and ethyl chloroformate (2.425 g) in methylene chloride (15 ml) with stirring under ice-cooling. The stirring was continued for 1 hour at the same temperature. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and evaporated in vacuo. The residue was dissolved in methanol (12 ml) and conc. ammonia (1.5 ml) was added thereto. After stirring for 2 hours at room temperature, the resulting precipitates were collected by filtration, washed with methanol, and dried to give 6-[4-[N-(t-butoxycarbonyl)glycylamino]phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.74 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19](O)[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>N1C=CC=CC=1>[C:26]([C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1)([O:25][CH2:23][CH3:24])=[O:27]
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 90 %

Procedure:
Prepared from (2) and ethylchloroformate in pyridine at 0-5° C. Yield 90%, m.p. 187-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].[ClH:34].C(O)C>CO.CN(C)C=O>[ClH:34].[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH:7]([OH:8])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(O)CCN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 Grams of 6-{4-[2-(4-methoxybenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril was suspended in 150 ml of methanol-dimethylformamide [1:1(v/v)] then 0.26 g of sodium borohydride was added thereto at room temperature and stirred for 1 hour. The excess sodium borohydride was decomposed by adding 2M-hydrochloric acid to the reaction mixture, and the solvent was removed by evaporation. The residue was treated with a mixture of water-ethyl acetate, and the organic layer was washed with water, dried then the solvent was removed by evaporation. The residue thus obtained was converted into hydrochloride by adding ethanol-concentrated hydrochloric acid, and the thus obtained hydrochloride was recrystallized from ethanol-water to obtain 0.9 g of 6-{4-[3-(4-methoxyphenyl)-3-hydroxypropyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril monohydrochloride. Melting point: 219°-224° C. (dec.). Colorless powdery substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(OCC)C)[N:9]=[C:10]([CH2:11][CH3:12])[C:3]=12.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>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.O>[CH2:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:20]2[CH:19]=[N:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:8][N:9]=1)[CH3:12]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CCOC(C)n1nc(CC)c2c(Cl)ccnc21
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCc1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 85 °C
Reaction time: 25 h
Yield: 29 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.69 g) was added to a solution of compound (3d) (3.01 g), quinoline-3-boronic acid (2.67 g), and an aqueous sodium carbonate solution (2 M, 23 mL) in ethylene glycol dimethyl ether (30 mL) under a nitrogen atmosphere, followed by stirring at 85° C. for 25 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, 1,4-dioxane (23 mL) and 6 N hydrochloric acid (23 mL) were added to the residue, and the resulting mixture was stirred at room temperature for 90 min. The pH was adjusted to 7 with an aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (3e) (0.942 g, the second stage yield: 29%) as a white solid.
Reaction SMILES: COC1C=CC=CC=1C1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(OC)cc(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 84 %

Procedure:
According to the preparation of 42, 3,5-dimethoxybenzaldehyde (40) (1.2 g, 7.3 mmol) was used to afford 49 (1.7 g, 84.0%) as pale yellow needles.
Reaction SMILES: [C-]#N.[K+].[CH:4]([N:7](C(C)C)CC)(C)C.[CH:13](=[O:15])[CH3:14].Cl.[CH2:17]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:17]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:15][CH:13]([C:4]#[N:7])[CH3:14])=[O:39])=[CH:36][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C#N)cc1
Reaction time: 2 h

Procedure:
A mixture of 1 g. (16.1 m moles) potassium cyanide, 5 ml. diisopropylethylamine and 800 mg. (18.1 m moles) acetaldehyde in 50 ml. tetrahydrofuran is stirred for 2 hours at room temperature. To this solution is added 6.7 g. (16.1 m moles) 4-(hexadecylamino)benzoyl chloride hydrochloride in 50 ml. tetrahydrofuran. After stirring for an additional 2 hours, the solution is diluted with 100 ml. water and extracted with ether. After drying with magnesium sulfate, the ether is evaporated and the residue is crystallized from acetonitrile to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:29][CH3:30])[C:8]2[C:9]([CH2:16][NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=3)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[CH3:35].O>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:41]=[C:36]([CH:34]([N:17]([CH2:16][C:9]2[C:8]([N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:29][CH3:30])=[CH:13][CH:12]=[C:11]([O:14][CH3:15])[N:10]=2)[C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][S:27][CH3:28])=[CH:20][N:19]=2)[CH3:35])[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (168 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL) stirred under ice cooling was added with sodium hydride (50% in oil, 24 mg, 1.4 mmol), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to −78° C., added with a solution of 1-bromo-[3,5-bis(trifluoromethyl)phenyl]ethane (250 mg, 0.78 mmol) obtained in Step 2 in N,N-dimethylformamide (0.5 mL), and the mixture was stirred for 12 hours with warming to room temperature. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (88.1 mg, 34%), as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:23])([C:19]([F:22])([F:21])[F:20])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]([O:16]CC)=O)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12.[NH3:24]>>[F:1][C:2]([F:23])([C:19]([F:21])([F:22])[F:20])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]([NH2:24])=[O:16])[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Reactant: N
Product: NC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12

Procedure:
A solution of the intermediate from Step D (0.3684 g, 1.092 mmol) and ammonia (11.70 mL, 82 mmol, 7 N in MeOH) was heated at 50° C. under N2 in a screw cap vial for 24 h. The reaction mixture was concentrated in vacuo to remove the excess amine to afford the desired product, as a yellow solid. m/z=309.1 (M+H).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:21][CH:22]=2)=[C:13]([CH3:32])[CH:12]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:2]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[S:21][CH:22]=2)=[C:15]([CH3:17])[CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1

Procedure:
A THF solution of benzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 and then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-benzyl-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3 δ 8.70 (d, J=4.9 Hz, 2 H), 7.67 (d, J=4.9 Hz, 2 H), 7.33 (d, J=8.6 Hz, 2 H), 7.10-7.26 (m, 3 H), 6.80 (s, 1 H), 6.24 (s, 1 H), 3.86 (s, 2 H), 2.04 (s, 6 H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][C:11]([F:12])([F:13])[F:14])=[O:25])[CH:19]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: FC(F)(F)CNCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(c1cc(Cl)ncn1)N(CCc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
0.80 g (3.94 mmol) phenethyl-(2,2,2-trifluoroethyl)-amine and 3.9 mL (3.9 mmol) of a 1M sodium hydroxide solution were added dropwise to 0.77 g (4.33 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and concentrated by rotary evaporation i.vac.