Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[I:25]I.[N+]([O-])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([I:25])=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: II
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(I)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 10 ml of acetic acid are treated with 0.70 g of iodine and the reaction mixture is stirred for 1 hour at room temperature. Subsequently the reaction mixture is treated with 0.67 g of 100% nitric acid and stirred at room temperature for 3 hours. The reaction mixture is poured into 150 ml of ice/water and extracted with 100 ml of ethyl acetate. The organic phase is washed with 150 ml of water, thereafter with 150 ml of aqueous sodium bicarbonate solution and finally with 150 ml of saturated aqueous sodium bisulphite solution. The upper phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride/n-hexane. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-iodo-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 147°-150° C., is obtained.
Reaction SMILES: NC1C=CSN=1.C([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:27]=[CH:26][S:25][N:24]=1)=[S:17])(=O)C1C=CC=CC=1>>[S:25]1[CH:26]=[CH:27][C:23]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([NH2:15])=[S:17])=[N:24]1
Reactant: O=C(NC(=S)NCCCNc1ccsn1)c1ccccc1
Agent: Nc1ccsn1
Product: NC(=S)NCCCNc1ccsn1

Procedure:
By the same procedure, using 3 aminoisothiazole, N-benzoyl-N'-[3-(3-isothiazolylamino)propyl]thiourea is prepared and the benzoyl group is removed to give N-[3-(3-isothiazolylamino)propyl]thiourea.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[C:24]([OH:26])[C:23]([CH3:27])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[C:24]([OH:26])[C:23]([CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(C)cc1O

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2,5-dimethyl-4-hydroxyaniline (40 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.51 (brs, 1H), 8.72 (d, J=8.4 Hz, 1H), 8.63 (d, J=3.6 Hz, 1H), 7.45 (dd, J=7.5, 3.5 Hz, 1H), 7.33 (s, 1H), 7.00 (s, 1H), 6.74 (s, 1H), 6.45 (brs, 1H), 2.25 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][OH:13].C>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC(C)OC(C)C
Product: NS(=O)(=O)OCCOc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by the procedures of Example 16 from sulfamoyl chloride and to 2-(3,4-dichlorophenoxy)ethanol. The tan colored solid obtained was dissolved in isopropyl ether and the solution treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from isopropyl ether to give the title compound, mp 84°-85° C., in 19% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[N:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:34]3[CH:35]=[CH:36][N:31]=[CH:32][N:33]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1ccncn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ccncn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.364 g, 1.25 mmol) in Dichloromethane (DCM) (3 mL) was added triethyloxonium tetrafluoroborate (0.249 g, 1.313 mmol). The solution was then stirred, under argon, for 10 minutes before 4-pyrimidinecarbohydrazide (commercially available from e.g. Anichem, J&W PharmLab or Bepharm, 0.207 g, 1.500 mmol) was added. The solution was then stirred for a further hour before the solvent was concentrated and n-butanol (3.00 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions were evaporated in vacuo. The remaining residue was then further purified by mass-direct automated HPLC, before the solvent was again evaporated in vacuo. The remaining solid was then triturated in ether before being dried in a vacuum oven to yield the product in 0.132 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](Br)[CH:3]=1.C([Li])CCC.[N:15]1[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C@:19]23[CH2:20][O:21][CH2:22][CH2:23][C@H:18]2[CH2:17][O:16][NH:15]3)[CH:3]=1
Reactant: C1CC2CON=C2CO1
Reactant: Fc1ccc(Br)cc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1[C@]12COCC[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:22])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][N:24](C=O)C>C(#N)C>[CH3:22][C:5]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:2]([CH3:1])[NH:3][C:4]=1[C:23]#[N:24]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Solvent: CC#N
Product: Cc1[nH]c(C#N)c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of 2,4-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (128.0 mg, 0.402 mmol) and N-chlorosulfonylisocyanide (43.7 μl, 0.502 mmol) in acetonitrile (2.0 ml) was stirred at 25° C. for 1 hour. DMF (31.1 μl, 0.402 mmol) was then added and the resulting mixture was stirred for an additional 16 h at room temperature. The reaction was quenched with water (100 ml) and extracted with dichloromethane (100 ml×2). The organic layers were combined, filtered, and evaporated to give an oil. The oil was purified by column chromatography (0 to 50% ethyl acetate in hexanes) to give 3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-2-carbonitrile (49.6 mg, 0.144 mmol, 35.9% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH2:21]([NH2:24])[CH2:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[CH:7]=[C:2]([NH:24][CH2:21][CH2:22][CH3:23])[C:3]4[CH:19]=[N:18][N:17]([CH3:20])[C:4]=4[N:5]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCCNc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 190 °C
Yield: 11.7 %

Procedure:
A solution of 4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.04 g, 0.14 mmol) in acetonitrile (2 mL) was treated with propylamine (0.041 g, 0.7 mmol) in the presence of p-toluenesulfonic acid monohydrate (0.03 g, 0.14 mmol). The reaction mixture was heated at 190° C. in microwave for 2 h. Solvent were removed and the crude material was purified by mass directed purification to obtain 5 mg of 103 as a white solid. 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.11 (d, J=1.2, 1H), 7.63 (t, J=7.4, 2H), 7.50 (t, J=7.2, 1H), 6.72 (s, 1H), 4.04 (t, J=22.1, 3H), 3.40 (dd, J=20.2, 13.0, 2H), 1.79 (dd, J=14.5, 7.1, 2H), 1.07 (t, J=7.4, 3H). MS (ESI) m/z 307.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 4-(methyloxy)phenylmagnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1587 g, 0.866 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.273 g, 89.0%). EI-MS m/z 354 (M+H) Rt (1.74 min).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8]CC)=[O:7]>CO.O>[CH3:3][CH:4]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydroxide (0.19 g, 4.8 mmol) was added to a solution of ethyl 3-methyl-3-pyridin-4-ylpropanoate (Method 8; 0.501 g, 2.6 mmol) in MeOH (10 ml) and water (5 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue shaken with 1 M hydrochloric acid (4.8 ml). The solvent was removed in vacuo to leave a colourless solid. M/z 164 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:63])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[C@@H:51]([CH3:62])[CH2:50]3)[CH:43]=2)[CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[C:39]([F:63])=[CH:38][CH:37]=4)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino) carbonyl]benzoic acid (0.0452 g, 0.10 mmol) in DCM (1.0 mL) was added 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazine carboxylate (0.0414 g, 0.10 mmol), HBTU (0.0569 g, 0.15 mmol), and Et3N (0.0281 mL, 0.20 mmol). This mixture was stirred at room temperature for 1 h, concentrated, and purified using a Gilson HPLC (with TFA). TFA (1 drop in each tube ˜12 mL), was added to Fractions containing product and solvent was concentrated using a GeneVav EZ-2 evaporator. The compound was purified again using a Gilson HPLC (with TFA) and evaporating the solvent using a GeneVav EZ-2 evaporator. Then product was basified with an amine cartridge to afford 0.0234 g (31%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.33 (d, J=6.78 Hz, 3 H) 1.41 (t, J=7.53 Hz, 3 H) 1.50 (t, J=7.15 Hz, 3 H) 1.80-1.97 (m, 2 H) 2.06-2.15 (m, J=13.05 Hz, 2 H) 2.57-2.69 (m, 1 H) 2.75-2.88 (m, J=15.06 Hz, 1 H) 3.11-3.20 (m, 2 H) 3.33-3.39 (m, 3 H) 3.46-3.56 (m, J=13.80 Hz, 2 H) 3.64-3.74 (m, 2 H) 4.00-4.10 (m, J=3.01 Hz, 4 H) 4.31-4.42 (m, 1 H) 4.47 (q, J=7.19 Hz, 2 H) 4.58-4.64 (m, 2 H) 4.70-4.77 (m, 2 H) 7.18 (dd, J=10.54, 8.53 Hz, 1 H) 7.37-7.42 (m, 1 H) 7.43-7.47 (m, 1 H) 7.48-7.54 (m, 2 H) 7.54-7.59 (m, 1 H) 7.62-7.66 (m, 1 H) 7.93-8.01 (m, 4 H) 8.30 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:5][C@H:4]([CH2:6][OH:7])[C@H:3]([CH2:8][OH:9])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CO.O>[OH:9][CH2:8][C@H:3]1[C@@H:4]([CH2:6][OH:7])[CH2:5][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CNC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
(cis)-3,4-Pyrrolidinediyldimethanol (970 mg, 7.4 mmol) was dissolved in a mixture of MeOH (20 mL) and water (7 mL) and cooled to 0° C. Na2CO3 (1.96 g, 19 mmol) was added followed by benzyl chloroformate (1.15 mL, 8.1 mmol) and the resulting solution was stirred for 4 hours, maintaining the temperature at 0° C. The reaction was concentrated under reduced pressure to remove most of the methanol, and the remaining aqueous solution was extracted twice with EtOAc. The combined organics were washed with brine and dried over sodium sulfate before being concentrated in vacuo. RP-HPLC yielded phenylmethyl (cis)-3,4-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (450 mg, 22%, 1.7 mmol). LCMS: (M+H)+: 266.1.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:26][CH3:27])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]([CH2:26][CH3:27])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.9 %

Procedure:
A solution containing the product from Example 36D (0.154 g, 0.410 mmol) in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL), stirred at 25° C. for 16 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.153 g) as the trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C@@:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:28]([F:31])([F:30])[F:29])[C:25](Cl)=[O:26]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:10]([O:21][C:25](=[O:26])[C@:24]([O:23][CH3:22])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:28]([F:30])([F:31])[F:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(Cc2ccccc2)CCC1Cc1ccccc1
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Product: CO[C@@](C(=O)O[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Cc1ccccc1)(c1ccccc1)C(F)(F)F
Yield: 29 %

Procedure:
The title compound was prepared from (3SR,4SR)-1,4-dibenzyl-piperidin-3-ol and (S)-(+) -alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride in 29% yield as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:7])[N:15]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)[CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2ncnc(N3CCC(NCc4ccccn4)CC3)c2cc1OC
Reactant: CCCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)N(Cc1ccccn1)C1CCN(c2ncnc3cc(OC)c(OC)cc23)CC1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
##STR23## n-Butyl isocyanate (1 g) was added slowly to a stirred solution of 4-[4 -(2-pyridylmethylamino)piperidino]-6,7-dimethoxyquinazoline, (1.4 g) prepared as in part A above, in dry chloroform, followed by standing at room temperature for 30 minutes. The solution was evaporated to dryness in vacuo to give a yellow oil which crystallized on trituration with ether. Recrystallization from ethyl acetate gave 4-[4-{3-n-butyl-1-(2-pyridylmethyl)ureido}piperidino]6,7-dimethoxyquinazoline (1.2 g) as pale yellow crystals, m.p. 162°-4° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>C(OCC)(=O)C>[CH:18]1([NH:17][C:16]([NH:15][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The copolymer was fed into a round-bottomed flask and dissolved in a half amount (25 to 30 mL) of ethyl acetate. Next, N-hydroxysuccinimide and DCC were added thereto followed by dissolution in the residual ethylacetate. The obtained mixture was immersed in ice-water at 4° C. and stirred with a stirrer for 2 hours. Subsequently, it was introduced into a thermostat at 25° C. and stirred therein overnight. The solution was filtered and thus dicyclohexyl urea formed as a by product was removed therefrom. After concentrating under reduced pressure, the residue was purified with diethyl ether. The product thus obtained was taken up by filtration and dried under reduced pressure. The succinylated copolymer thus obtained was stored in a freezer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:24][N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[O:29]1[CH2:30][CH2:31][CH2:32][O:33][CH:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:23][CH:24]=1
Reactant: Brc1ccc(C2OCCCO2)cn1
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-h]pyridine (1) (13.33 g, 79 mmol) in THF (204 mL) at −5° C./−10° C. was added n-BuLi (2.5 M in hexanes, 31.6 mL, 79 mmol) over 50 min. After 30 min, a solution of zinc chloride in ether (1M, 79 mL, 79 mmol) was added at −5° C./0° C. over 50 min and the reaction mixture was allowed to warm-up to r.t. After 45 min, 2-bromo-5-(1,3-dioxan-2-yl)pyridine (316) (15.98 g, 65.5 mmol) and palladium tetrakistriphenylphosphine (2.27 g, 1.964 mmol) in THF (28 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t., and concentrated. The residue was diluted with DCM (600 mL), H2O (500 mL) and NH4OH (100 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL); the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MTBE (150 mL), to afford intermediate 317 (12.796 g, 59% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.66-8.65 (m, 2H), 8.43 (d, J=0.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=5.0, 0.6 Hz, 1H), 5.68 (s, 1H), 4.19 (dd, J=11.6, 4.8 Hz, 2H), 3.99 (t, J=11.4 Hz, 2H), 2.07-2.01 (m, 1H), 1.49 (d, J=13.2 Hz, 1H). MS (m/z): 333.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:11]=[CH:10][N:9]=1.[CH3:28][C:29]1([CH3:42])[O:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:31][O:30]1>CN(C=O)C>[CH3:28][C:29]1([CH3:42])[O:30][CH2:31][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:8]3[C:13]([CH3:14])=[C:12]([O:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]5[N:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:18][CH2:17]4)[N:11]=[CH:10][N:9]=3)=[CH:37][CH:36]=2)[CH2:33][O:34]1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Reactant: Cc1c(Cl)ncnc1OC1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(C3COC(C)(C)OC3)cc2)ncnc1OC1CCN(c2ncccn2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
Cesium carbonate (2.97 mg, 0.00914 moles) was added to a solution 4-chloro-5-methyl-6-(1-(pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine (1.39 gm, 0.00457 moles) and 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (950 mg, 0.00457 moles) in dry DMF (10 ml) and the reaction mixture was stirred at 60° C. for 12 hours. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product so obtained was purified by column chromatography (silica gel) using 22% ethyl acetate in hexane as eluent to obtain 1.5 gm product as white solid.