Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CC1CCNCC1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)CC1

Procedure:
The product from Example 1C and 4-methylpiperidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][O:8][C:7](=[O:10])[CH:6]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][N:15]=1.CO>O1CCCC1.C(OCC)(=O)C>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:4]([CH2:3][CH2:2][F:1])[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)=[CH:18][CH:19]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1C=C(NCCF)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C=C(N(CCF)Cc2ccc(Cl)nc2)CO1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
1.00 g (6.89 mmol) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one (VI-1) and 0.55 g (13.78 mmol) of a 60% dispersion of sodium hydride in mineral oil in 200 ml of tetrahydrofuran are heated under reflux for 2 h. After cooling to room temperature, 2.23 g (13.78 mmol) of 2-chloro-5-chloromethylpyridine are added, and the mixture is heated under reflux for a further 4 hours. The reaction mixture is cooled to room temperature, and methanol is added. After concentration of the reaction mixture under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (9:1) gives 949 mg (50% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2-fluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([C:21]#[CH:22])(C)C>CN(C=O)C.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.[Cu]I>[C:21]([C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1)#[CH:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmol), trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh3)4 (Aldrich, 29 mg, 0.025 mmol) and CuI (Strem Chemicals, 10 mg, 0.05 mmol) in DMF (10 mL) was stirred at ambient temperature overnight. DMF then was removed under reduced pressure. The residue was treated with tetrabutyl ammonium fluoride (Aldrich, in THF, 1M, 5 mL) at room temperature for 3 h. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) δ 1.42-1.54 (m, 1H), 1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m, 5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H) ppm. MS (DCI/NH3): m/z 228 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:10]2([CH2:13][NH:12][CH2:11]2)[CH2:9][NH:8]1.Cl[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1>C(O)C>[C:20]1([N:19]2[C:15]([N:8]3[CH2:9][C:10]4([CH2:13][NH:12][CH2:11]4)[CH2:7]3)=[N:16][N:17]=[N:18]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: C1NCC12CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(-n2nnnc2N2CC3(CNC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To potassium carbonate (76 mg) taken in ethanol (2.0 mL), a solution of 2,6-diazaspiro[3.3]heptane (220 mg in 2.0 ml of ethanol) was added at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and a solution of 5-chloro-1-phenyl tetrazole (0.1 g) in ethanol (2.0 mL) was added very slowly. The reaction mixture was allowed to stir for 5 hours at room temperature. The reaction mixture was evaporated to give a residue which was partitioned between water (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure gave crude product which was purified by column chromatography using methanol\dichloromethane (1:9) as eluent to afford 2-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[O:13].[F:15][C:16]([F:24])([F:23])[C:17](=O)[CH2:18][C:19](=O)[CH3:20].[CH2:25](O)[CH3:26]>>[CH2:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]2[C:19]([CH3:20])=[CH:18][C:17]([C:16]([F:24])([F:23])[F:15])=[N:14][C:12]2=[O:13])[CH:4]=1)[CH3:26]
Reactant: CCO
Reactant: NC(=O)Nc1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)c1ccc(Cl)c(-n2c(C)cc(C(F)(F)F)nc2=O)c1
Temperature: 85 °C
Yield: 9 %

Procedure:
To a stirred suspension of 4-chloro-3-ureido-benzoic acid (26 g, 121 mmol) in ethanol (375 mL) was added 1,1,1-trifluoro-2,4-pentanedione (28 g, 182 mmol) and concentrated (95%) sulfuric acid (50 mL). The reaction mixture was heated at 85° C. for 6 h. After cooling to room temperature, the mixture was partitioned between water (500 mL) and DCM (1 L) and to this was added 6N aq. NaOH, until pH 9-10 attained. The DCM layer was separated and dried over MgSO4 and filtered. Concentration in vacuo gave an orange oil which was purified via silica gel flash chromatography (eluting with a gradient of 10% to 25% EtOAc in hexanes). The resulting orange solid was further triturated with diethyl ether to give 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid ethyl ester (3.77 g, 9%) as a colorless solid. MS (M+H)+: 360.8, tR=2.670 min (method 1); 1H NMR (CDCl3) δ 8.16 (1H, dd, J=8.4, 2.1 Hz), 8.00 (1H, d, J=1.8 Hz), 7.70 (1H, d, J=8.4 Hz), 6.63 (1H, s), 4.39 (2H, q, J=6.9 Hz), 2.15 (3H, s), 1.39 (3H, t, J=6.9 Hz).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCC2
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(S)cc2c1OCCC2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
238 g of 6-chlorosulphonylchroman-8- carboxylic acid and 645 ml of acetic acid were introduced into a 6-liter round-bottomed flask. The mixture was heated to 80° C. and 384 g of tin was added and the mixture was then cooled to 50° C. 1720 ml of hydrochloric acid (d=1.18) were then poured in dropwise, while maintaining the temperature between 55° and 60° C. first by cooling in an ice bath and then by heating in a water bath. Heating was then continued for 3 hours at 60° C. and the solution was poured into 6 liters of water. The precipitate formed was drained, washed with 1 liter of dilute hydrochloric acid followed by water and then air-dried.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=3)[CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:73][CH2:72]OCCOCCOCCOCCOC1>[Cu].C1(C)C=C(C)C=C(C)C=1>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([N:29]([C:14]2[CH:15]=[C:16]([N:18]([C:49]3[C:50]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:46]=[CH:47][CH:48]=3)[C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH:17]=[C:12]([N:11]([C:2]3[C:72]4[C:73](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:6]=[CH:5][CH:1]=3)[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[CH:13]=2)[C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:32]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Ic1cccc2ccccc12
Reactant: CC(C)(C)c1ccc(Nc2cc(Nc3ccc(C(C)(C)C)cc3)cc(Nc3ccc(C(C)(C)C)cc3)c2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: CC(C)(C)c1ccc(N(c2cc(N(c3ccc(C(C)(C)C)cc3)c3cccc4ccccc34)cc(N(c3ccc(C(C)(C)C)cc3)c3cccc4ccccc34)c2)c2cccc3ccccc23)cc1
Reaction time: 16.5 h
Yield: 124.6 %

Procedure:
2.6 g of 1,3,5-tris(p-tert.-butylphenylamino)benzene, 6.4 g of 1-iodonaphthalene, 6.9 g of potassium carbonate, 1.0 g of copper powder, 0.7 g of 18-crown-6 (or 1,4,7,10,13,16-hexaoxacyclo-octadecane) and 20 mL of mesitylene were placed in a 100 mL capacity flask and the reaction was carried out at a temperature of 170° C. for 16.5 hours under a nitrogen atmosphere. After the reaction, the resultant reaction mixture was extracted with toluene and the toluene solution was subjected to silica gel chromatography to fractionate the reaction product. The reaction product was then purified by recrystallization and then by sublimation to provide 2.8 g of the desired 1,3,5-tris(N-(p-tert.-butylphenyl)-N-(1-naphthyl)amino)-benzene. The yield was 62%.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:8]=1[NH:9][C:10]1[C:11]([CH2:15][C:16]#[N:17])=[CH:12][S:13][CH:14]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:4][C:14]1[S:13][CH:12]=[C:11]([CH2:15][C:16]#[N:17])[C:10]=1[NH:9][C:8]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:7]=1[Cl:6]
Reactant: N#CCc1cscc1Nc1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCc1csc(Cl)c1Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 135 mg of sulfuryl chloride in 5 ml of methylene chloride is added dropwise to a solution of 283 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetonitrile in 20 ml of methylene chloride at -15°. After 10 minutes, a sodium dithionite solution and 3 ml of 2 N sodium hydroxide solution are added. The organic phase is separated off, dried, clarified with bleaching earth (for example Tonsil®) and concentrated. Recrystallization of the residue from methanol yields 5-chloro-4-(2,6-dichloroanilino)-3-thiophenacetonitrile (m. 128° to 128.5°).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]1[C:20](Cl)=[O:21].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:20]([CH:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:21])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
The solution of phenethylamine (344 mg, 2.84 mmol) in 20 ml of CH2Cl2 was first treated with the solution of 1,2,3,4-tetrahydro-2-naphthoyl chloride (2.83 mmol) in 2 ml of CH2Cl2 followed by treatment with 10 ml 10% K2CO3 solution. After stirred at r.t. overnight, the organic layer was separated and washed with 2N HCl, water, sat'd brine and dried over Na2SO4. Filtration and removal of solvent gave N-(2-phenylethyl) 1,2,3,4-tetrahydro-2-naphthoic amide as a white powder (793 mg, 100%); mp 86°-87° C.; Calcd for C19H21NO: C 81.67, H 7.59, N 5.01; Found: C 82.00, H 7.27, N 4.77.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1csc(Br)n1
Reactant: CNc1ccccc1
Product: CCOC(=O)Cc1csc(N(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 2-bromo-4-thiazolylacetate (2.5 g) and N-methylaniline (2.1 g) is stirred at 150°-155° C. for 30 minutes. The resultant solution is treated in the same manner as in Example 1 to give ethyl 2-(N-methyl-anilino)-4-thiazolylacetate (2.5 g).
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C@@H:3]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[NH2:4].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[OH:1][C:2]([CH3:11])([CH3:10])[C@@H:3]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[NH:4][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-hydroxy-N,N-dimethyl-L-valinamide obtained in C) in ethanol (5 mL) was added 4-thioxothiazolidin-2-one (380 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (300 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH2:47][CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1>C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH2:47][CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogen carbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C. for 30 min, 4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.2 g, 48%) as a colorless solid.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#N)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-:16].[K+].[OH2:18]>C(O)C>[CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: [OH-]
Reactant: N#CCc1ccc(C(=O)C2CCC2)cc1
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(C(=O)C2CCC2)cc1

Procedure:
p-(Cyclobutylcarbonyl)phenylacetonitrile (8.1 g) in ethanol (50 ml) was added to potassium hydroxide (6.8 g) in water (50 ml) and the mixture was heated under reflux for 5 hours and cooled. The solution was diluted with water (100 ml), washed with ether (2× 100 ml), acidified to pH 1 with hydrochloric acid and extracted with ether (3× 100 ml). The combined extracts were dried over magnesium sulphate, filtered and evaporated to give a brown oil. This was extracted with a hot mixture of light petroleum (b.p. 60°-80°) and ethyl acetate (9:1) (3× 200 ml). The solid that crystallised from the extracts on cooling was collected. It had m.p. 91°-92.5°.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[N:27]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)/C=C\C(O)=O>COCCOC.O.C(O)C>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:8])=[CH:14][CH:13]=3)[C:33]=12
Reactant: CC1(C)OB(c2ccc(C(=O)c3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone (Intermediate AL) (0.241 g, 0.00078 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.30 g, 0.00068 mol), tetrakis(triphenyl-phosphine)palladium (0.047 g, 0.000041 mol) and sodium carbonate (0.18 g, 0.0017 mol) was heated in a mixture of ethylene glycol dimethyl ether (10 mL) and water (5 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate, the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-{4-[4-amino-1-(4-(4-methylpiperazino)cyclohexy)]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-]-phenyl}(phenyl)methanone as a white solid (0.195 g, 0.0004 mol). It was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.137 g, 0.0018 mol) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaletate as a white solid (0.221 g, 0.0003 mol): 1H NMR (DMSO-d6, 400 MHz) 8.28 (s, 1H), 7.90 (d, 2H), 7.83 (m, 4H), 7.73 (t, 1H), 7.61 (m, 2H), 6.15 (s, 4H), 4.88 (m, 1H), 3.1 (br, 9H), 2.71 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.63 min. MS: MH+496.
Reaction SMILES: CCCCCCC.[CH3:8][CH:9]([OH:11])[CH3:10].[CH3:12][CH2:13][N:14](CC)[CH2:15][CH3:16]>CC(O)C.C1COCC1>[CH3:8][CH:9]([OH:11])[CH3:10].[NH:14]([CH2:15][CH3:16])[CH2:13][CH3:12]
Reactant: CCN(CC)CC
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCNCC

Procedure:
The racemate was resolved by chiral support chromatography. Portions of the racemate (0.2 g dissolved in 10 mL of 3:1 iPrOH/THF) were injected onto a preparative Chiralcel OD™ column equilibrated at 30° C. with 800:200:1 heptane/iPrOH/Et3N. Assignment of absolute configurations to the separated enantiomers was made by comparison of the CD spectra to those of the 10-chloro structures. Analytical HPLC analysis (tR=17.2 min on a Chiralcel™ OD-H at a 0.5 mL min−1 flow rate of 800:200:1 hepane/iPrOH/Et2NH) gave an ee of 97%: UV λmax nm (ε, L·mol−1·cm−1) 284 (4740); CD λmax nm (θ, deg·cm2·dmol−1) 298 (3700), 273 (4400).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-])=O)=[C:21]([CH3:29])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Zn]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:20]=[C:21]([CH3:29])[C:22]([NH2:26])=[C:23]([CH3:25])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc(C)c1N
Reaction time: 3 h

Procedure:
To (3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (9.5 g) in ethanol (150 mL) was added zinc dust (22 g) and acetic acid (13 mL). The reaction mixture was stirred 3 hours and then filtered. The solution was concentrated in vacuo, redissolved in ethyl acetate (100 mL) and extracted with water (2×50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an off white compound. Yield. 6.5 g (78%). LC-MS (m/z) 395 (MH+); tR=3.06, (UV, ELSD) 89%, 96%. 1H NMR (500 MHz, CDCl3): 1.40 (s, 9H), 2.10 (s, 6H), 3.50 (broad, 2H), 4.75 (s, 2H), 6.70 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.N1C=CC=CC=1.Cl.[CH2:42]1C[O:45][CH2:44][CH2:43]1.CN(C=O)C>>[ClH:1].[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:44](=[O:45])[CH:43]=[CH2:42])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Reactant: C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Yield: 45 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.1 mmol) was added to a solution of 6-amino-4[(3-(trifluoromethyl)phenyl)amino]quinazoline (153 mg, 0.5 mmol) acrylic acid (73 mg, 1.0 mmol) and pyridine (206 mg, 2.5 nmmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 15 minutes the reaction mixture was stirred at 25° C. for 1 hour, and then recooled to 0° C. Dilute hydrochloric acid (0.5 M, 10 mL) was added, and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (5 mL) and ether (2×5 mL) and dried in a vacuum oven at 75° C. overnight to give N-[4-[(3-(trifluoromethyl) phenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (87 mg, 45%) as a light greenish solid, mp 195-199° C.