Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CS(C)=O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzonitrile (7.828 g, 42.9 mmol) and morpholine (4.49 mL, 51.5 mmol) in DMSO (20.00 mL) was stirred at rt for 1 h, after which time LC-MS indicated a small amount of desired product formed. The reaction was heated to 100° C. After 24 h the reaction was equilibrated to rt and poured into 50 mL ea 1N aq. hydrochloric acid and EtOAc. The resulting orange precipitate was collected by filtration, rinsing with EtOAc, then dried under vacuum. Mass Spectrum (ESI) m/e=234.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[Cl:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 6-(2-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (321 mg, 2.40 mmol) in THF (40 mL) according to method C to yield 435 mg (77%) of yellowish solid: mp 224-226° C.; 1H NMR (DMDO-d6): δ 6.86 (1H, dd, J=8.42 Hz, J=2.41 Hz), 6.96 (1H, d, J=2.44 Hz), 7.30 (1H, d, J=3.19 Hz), 7.33 (1H, d, J=2.65 Hz), 7.62 (1H, dd, J=8.81 Hz, J=1.71 Hz), 7.83 (1H, d, J=8.93 Hz), 7.86 (1H, d, J=1.54 Hz), 8.04 (1H, J=8.76 Hz), 10.04 (1H, s), 10.51 (1H, s); 13C NMR (DMDO-d6): δ 112.24, 114.84, 116.26, 118.79, 121.84, 128.16, 128.24, 128.35, 129.27, 130.03, 130.40, 131.73, 132.38, 133.98, 151.24, 157.70; MS (ESI) m/z 303/305/307 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[ClH:22].[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Br)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethy-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH2:18]([N:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:20])=[O:2])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])[CH3:19]
Reactant: CCN(C(C)(C)C(=O)OC)S(=O)(=O)c1ccccc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C(C)(C)C(=O)O)S(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
methyl-2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanoate (524 mg, 1.75 mmol) was charged, and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropionic acid (490 mg, 1.72 mmol, 98%).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)C)cc1Oc1cccc(C(F)(F)F)n1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A mixture of methyl 4-tert-butyl-2-hydroxybenzoate (0.70 g, 3.4 mmol), 2-fluoro-6-(trifluoromethyl)pyridine (0.55 g, 3.4 mmol), and Cs2CO3 (1.1 g, 3.4 mmol) in DMF (15 mL) was heated at 70° C. for 19 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give methyl 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoate (0.49 g, 41% yield). LC/MS: m/z 354.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCCN1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-morpholinoethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C(Cl)(Cl)(Cl)Cl.C(OCC)C.O>[CH2:22]([N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:23]
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCN(CC)C(=O)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
A 500 ml round bottom flask fitted with an addition funnel and a calcium sulfate drying tube was charged with 8.0 g (0.03 mol) of 4-(4-nitrophenyl)butyric acid in 180 ml of carbon tetrachloride. To this stirred solution was added 16.5 ml (0.19 mol) of oxalyl chloride dropwise. The addition funnel was removed and a condenser was fitted onto the flask. The reaction mixture was refluxed for 3 hours, cooled and the excess oxalyl chloride was evaporated under reduced pressure. Approximately 100 ml of dry diethyl ether was added to the solution which was subsequently cooled in ice. To this cooled solution was added 16.3 g (0.115 mol) of ethylheptylamine dissolved in approximately 60 ml of diethyl ether. The resulting reaction mixture was stirred at room temperature overnight and diluted with a mixture of water and diethyl ether. The aqueous phase was separated and further extracted three times with diethyl ether. The organic extracts were combined, washed with water, hydrochloric acid, water (2×), a 10% aqueous sodium carbonate solution and a saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 12.847 g of N-ethyl-N-heptyl-4-nitrobenzenebutanamide as an oil.
Reaction SMILES: O.O.[Sn](Cl)[Cl:4].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.[ClH:35]>C(O)C>[ClH:4].[ClH:35].[CH2:6]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH3+:27])[CH2:17][CH2:18]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cl[Sn]Cl
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: [NH3+]c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
1 g tin (II) chloride-dihydrate was added to 290 mg (1-benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine in 18 mL ethanol. The reaction was refluxed for 15 min. DMF was added until the reaction was diluted. Then, 5 mL 10 M HCl in ethanol was added, the solvent was removed, 8 mL acetone was added and the mixture was stirred at RT. The precipitate was filtered to give 550 mg of the desired product. Rf: 0.35 (dichlormethane 9: methanol 1: ammonia 0.1), (M+H)+: 296
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:9][C@@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of L-tert-leucine tert-butyl ester hydrochloride (5 g, 22.34 mmol) in DMF (25 mL) was treated with triethylamine (3.1 mL, 22.34 mmol) and the mixture was stirred for 1 hour. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stirred for 3 hours at 25° C. The solvent was concentrated and the reaction was partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate/hexane to give the title compound (5.47 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[CH:4]=O.C(N)CN.C(O)(=O)C.CC1(C)O[C:28](=[O:29])[CH2:27][C:25](=[O:26])[O:24]1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:27]([C:25]([OH:26])=[O:24])[C:28](=[O:29])[N:10]2[CH:11]([CH3:13])[CH3:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)Nc1cccc(Cl)c1C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: NCCN
Product: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
To a solution of 2-chloro-6-(isopropylamino)benzaldehyde (1.1 g, 5.57 mmol, step 3) in methanol (10 mL) was added ethylenediamine (0.186 mL, 2.78 mmol) and acetic acid (0.319 mL, 5.57 mmol). Meldrum's acid (1.6 g, 11.1 mmol) was added to the mixture at 0° C. Then, the mixture was stirred at room temperature for 16 h. The formed precipitate was filtrated and washed with methanol. The filtrate was evaporated and crystallized from methanol to give 200 mg (14%) of the title compound as a white solid.
Reaction SMILES: [C-:1]1([CH:6]=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[N+:14](CC)([O-:16])=[O:15]>C(O)(=O)C>[C-:1]1([C:6]([N+:14]([O-:16])=[O:15])=[CH:12][CH3:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: CC[N+](=O)[O-]
Reactant: O=C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC=C([c-]1cccc1)[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Ferrocenyl-nitropropene is prepared by reacting 2.14 g ferrocenecarboxaldehyde with 2.25 g nitroethane 1.40 g ammoniumacetate and 10 ml of glacial acetic acid during 24 hours at room temperature in the dark. After heating the reaction mixture 2 hours at 100° C. and dilution with 100 ml of ice-water the formed ferrocenyl-nitropropene is extracted with diethylether. The organic solution is washed successively with Na2S2O4 -containing water, with diluted ammonia and finally with water until neutral. After drying and evaporating the diethylether, the residue obtained is recrystalized from methanol. The desired ferrocenyl-nitropropene is obtained in a yield of 80%; m.p. 48° C.; TLC: Rf (diethylamine/diethylether 5/95) 0.86.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]34O[C:17]3([CH:18]([O:35][Si](C(C)(C)C)(C)C)[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:35])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:43][C:44](=[O:49])[C:45]([CH3:47])([CH3:46])[CH3:48])=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(O[Si](C)(C)C(C)(C)C)C21O3
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(=O)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
To a solution of Compound 210 (9.5 g, 13.6 mmol) in wet CHCl3 (150 mL) cooled at zero degrees C was added BF3.OEt2 (8.4 mL, 68.0 mmol) followed by stirring at 25° C. for 10 minutes. The reaction mixture was diluted with CH2Cl2 (400 mL), washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was then dissolved in THF (50 mL) and treated with 48 percent aqueous HBr (5 mL) at 25° C. for 40 minutes with stirring. The reaction mixture was diluted with ethyl ether (400 mL), washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash column chromatography of the residue (silica gel, 33 percent ethyl ether in petroleum ether) gave Compound 211 (2.80 g, 34 percent) and Compound 212 (1.30 g, 18 percent). Compound 211: Rf =0.52 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2970, 1719, 1681, 1606, 1494, 1381, 1307, 1179, 1123, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=8.7 Hz, 1 H, H1), 7.45-7.18 (m, 6 H, H4and aromatic), 6.98 (dd, J=8.7, 2.4 Hz, 1 H, H2), 6.11 (d, J=0.9 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.72 (dd, J=11.1, 1.7 Hz, 1 H, olefinic), 2.90 (dt, J=18.9, 4.5 Hz, 1 H, H9), 2.77-2.53 (m, 3 H, H7 and H9), 2.24-2.12 (m, 2 H, H8), 1.34 (s, 9 H, COC(CH3) ), 0.21 (s, 9 H, Si(CH3)3); MS (FAB+) m/e (rel intensity) 698 (M+Cs, 100), 565 (6); HRMS for C34H35NO5SiCs (M+Cs), calcd 698.1339, found 698.1339.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:8]=1.C1C(=O)N([Cl:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]=1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.3, 40 mg, 0.15 mmol) and NCS (24.6 mg, 0.18 mmol) in CCl4 (20 mL). The resulting mixture was stirred for 2 h at 50° C., then cooled to room temperature and quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 30 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 114.4 %

Procedure:
N-(3-amino-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (11 g, 39.8 mmol) was dissolved in tetrahydrofuran (100 ml), triethylamine (8.3 ml, 59.5 mmol) was added thereto, and the mixture was stirred for 30 minutes. 4-Chloromethyl benzoyl chloride (2.03 g, 10.78 mmol) was added, and the resulting mixture was reacted under reflux for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated and crystallized from methylene chloride to give N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (5.3 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([C:42]([F:45])([F:44])[F:43])[C:24]([F:41])([F:40])[C:25]([F:39])([F:38])[O:26][C:27]([F:37])([F:36])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]([O:26][C:25]([F:38])([F:39])[C:24]([F:40])([F:41])[C:23]([F:22])([F:46])[C:42]([F:43])([F:44])[F:45])([F:37])[F:36])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (6.0g, 21 mmol) and 5-(2-(nonafluorobutoxy)-2,2-difluoroethoxy)-1-bromopentane (12 g, 23 mmol; prepared by combining 1,5-dibromopentane with 2-(nonafluorobutoxy)-2,2-difluoroethanol). After refluxing overnight, the resulting crude product was isolated by filtration and further purified by recrystallization from ethanol, followed by Kugelrohr distillation (b.p. 190-200° C. at 0.1 torr; yield of 6.4 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 37.5 °C

Procedure:
A solution of 1.46 g (5.15 mmol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.32 ml (7.73 mmol) N-ethyldiisopropylamine in 15 ml dichloromethane was cooled in an ice bath and 1.8 g (5.67 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 25 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 2.9 g (quantitative) of the title compound as white crystals.
Reaction SMILES: [Cl:1](O)(=O)(=O)=O.C(OC([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=O)(C)(C)C>O1CCOCC1.O>[ClH:1].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCC1CCCCN1
Product: Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 372.8 %

Procedure:
Perchloric acid (4.96 ml, 57.4 mmol) was added to a solution of 3 (56.02 g, 287 mmol) in dioxane (1124 ml) and H2O (856 ml) and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to half its volume and aqueous saturated NaHCO3 was added. The H2O layer was extracted with CH2Cl2 (2×) and the combined organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification by column chromatography (silica, heptane/EtOAc, 2:3->1:2) yielded 4 (47.45 g, 78%).