Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenyl-phosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:18]=[C:14]([C:15](O)=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl.C(OC)(C)(C)C>C1COCC1>[OH:16][CH2:15][C:14]1[CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=1[OH:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: B
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(O)c(CO)c1
Temperature: 15 °C
Reaction time: 7 h
Yield: 76.2 %

Procedure:
To a BH3.THF solution (110 mL, 1M, 110 mmoles) was added dropwise a solution of 5-nitro-salicylic acid (10.0 g, 54.6 mmoles) in 930 mL THF. After a few milliliters, the reaction mixture was cooled with ice to maintain a temperature of about 15° C. The clear brown solution was warmed to room temperature and stirred for an additional 7 hours. During this time a precipitate formed. BH3.THF (20 ml, 20 mmoles) was added and stirring was continued overnight. The mixture was cooled to 5° C. and carefully hydrolyzed with 1 M HCl (100 mL). Methyl tert-butyl ether (MTBE) (100 mL) was added, the phases were separated and the aqueous layer was extracted with MTBE (2×70 mL). The combined organic layers were dried over MgSO4 (10 g), filtered and evaporated to give 10.5 g of a pale ochre solid. This solid was recrystallized from 65 mL toluene to give 7.033 g (76%) of 2-hydroxymethyl-4-nitrophenol as a pale ochre solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]2[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]2=[O:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=c1[nH]c(=O)n(COCCO)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCn2cc(F)c(=O)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
1-(2-Hydroxyethoxy)methyl-5-fluorouracil (1 g) obtained in Example 1 was dissolved in pyridine (5 ml) and to the solution was added p-toluenesulfonylchloride (1.12 g) under cooling in an ice bath, and then the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was poured into ice-water and the resulting oil was extracted with chloroform (30 ml). The chloroform layer was washed with hydrochloric acid and then with water, and dried over magnesium sulfate to give crystalline 1-(2-p-toluenesulfonyloxyethoxy)methyl-5-fluorouracil (1.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cn1c(NS(=O)(=O)c2ccccc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2cccc(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 120 °C

Procedure:
To a solution of N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide (100 mg, 0.35 mmol) in DMF (2 mL) was added 1-bromomethyl-3-trifluoromethyl-benzene (166.4 mg, 0.70 mmol) and potassium carbonate (48 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-(1-methyl-1H-benzimidazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide (1st compound to elute off the column) MS 446 (M+1)+
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][N:11]=1
Reactant: CC1(c2cnc(CO)o2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cnc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl]-methanol (35 mg, 0.19 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with Et3N (0.03 mL, 0.25 mmol) followed by DMAP (2.3 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at rt for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole as a yellow oil. A solution of this crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole (38 mg, 0.19 mmol) in acetone (1.0 mL) was treated with 5-nitro-1H-pyrazole (21 mg, 0.19 mmol) and TBA bromide (12 mg, 0.04 mmol) followed by K2CO3 (77 mg, 0.56 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:6 hept-EA)=0.15. LC-MS-conditions 02: tR=0.83 min; [M+H]+=281.05.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37].[H][H]>CO.[Pd]>[C:13]([OH:15])(=[O:14])[CH3:12].[C:36]([OH:39])(=[O:38])[CH3:37].[C:13]([OH:15])(=[O:14])[CH3:12].[NH2:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC1CCN(c2ccncc2)CC1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of step (iii) (1.34 g) and acetic acid (0.48 ml) in methanol under argon was added 10% Pd on C (100 mg). The mixture was covered with a blanket of hydrogen and stirred at room temperature for 4 hr. The catalyst was then removed by filtration through a pad of kieselguhr and the pH of the filtrate was adjusted to 4 by addition of acetic acid. To this mixture, under argon, was then added a further quantity of 10% Pd on C (100 mg)., it was covered again with hydrogen and stirred at room temperature for 3 days. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. Toluene (100 ml) was then added to the residue and the solvents were again removed in vacuo to give tert. butyl (S)-2-amino-5-[1-(4-pyridyl)piperidin-4-yl]aminopentanoate, triacetate salt (1.68 g) as a yellow gum: NMR (d6 -DMSO+CD3CO2D) δ1.49 (9H, s), 1.70 (6H, m), 2.23 (2H, m), 3.03 (2H, m), 3.25 (2H, m), 3.50 (1H, m), 3.96 (1H, m), 4.30 (2H, m), 7.18 (2H, d), 8.20 (2H, d); m/Z 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH2:24]([Mg]Cl)[CH2:25][CH3:26]>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:23])([CH2:24][CH2:25][CH3:26])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CCC[Mg]Cl
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
MgBr diethyl etherate (10.5 g, 40.2 mmol) was added to a solution of the above-mentioned ethanone (6.0 g, 16.8 mmol) in dichloromethane (DCM, 65 ml) and the mixture stirred at room temperature for about 90 min. This mixture was then cooled to about 0° C. and n-propylmagnesium chloride (22.8 ml of a 2 M solution in THF, 45.6 mmol) was added dropwise. After stirring for about two hours, the mixture was allowed to warm to room temperature and was then quenched by addition of a saturated ammonium chloride solution. The organic components were extracted three times with DCM, the organic phases combined, washed again with saturated ammonium chloride solution, dried and the solvents evaporated. Addition of diisopropyl ether resulted in precipitation of the unreacted starting material, which was filtered off. The filtrate was then purified using reverse phase chromatography, to give the product as a light brown colored solid (2.5 g, 36%, HPLC2 Rt=1.26 min, masse=392).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][C:11]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C1CCC(c2ccc(Cl)nc2)O1
Product: NC(=O)CCC(O)c1ccc(Cl)nc1
Temperature: 45 °C

Procedure:
3.6 g of 5-(6-chloropyridin-3-yl)tetrahydrofuran-2-one (prepared as described in Example 15) was dissolved in 30 ml of 25 percent aqueous ammonia solution and the mixture was heated at 45° C. for 1.5 hours. The solution was evaporated in vacuo. The oily residue (4.65 g) was dried in vacuo over phosphorus pentoxide. The product yield was 3.9 g (approximately 100%) of rubber-like product. Other data concerning the product was:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OCC2C=CC=CC=2)[CH2:30]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Product: N[C@H]1CCCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)C1
Yield: 20 %

Procedure:
Following the procedures of Example 144, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl piperidin-3-ylcarbamate were reacted. The reaction mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 20.0 mg (20%) of 161 over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO): 9.30 (s, 1H), 9.21 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 8.48 (m, 1H), 7.66 (s, 1H) 7.53 (m, 1H), 7.46 (s, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.37 (m, 1H), 4.29 (d, J=12.6 Hz, 1H), 3.06-2.97 (m, 1H), 2.79 (d, J=7.6 Hz, 2H), 1.94 (m, 1H), 1.80 (m, 1H), 1.61 (d, J=9.5 Hz, 1H), 1.34 (m, 1H)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].O=O.[CH3:11]O>[Fe]>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Oc1ccc(O)cc1
Agent: [Fe]
Agent: O=O
Product: COc1ccc(O)cc1
Reaction time: 4.5 h

Procedure:
After being filtered, washed with methanol and dried, the resin contains 1.0 milliequivalent of iron per gram of resin. 2.0 g of the catalyst prepared in this manner are fed into the autoclave together with 5.0 g of hydroquinone and 40 cm3 of methanol. The autoclave is pressurised to 5 kg/cm2 with O2 and kept at 105° for 4.5 hours. 4.1 g of hydroquinone monomethyl ether are obtained (conversion 80%, selectivity 91%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[F:13][C:14]([F:48])([F:47])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[N:18]=[C:17]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]3[CH:38]=[C:39]([S:43](Cl)(=[O:45])=[O:44])[CH:40]=[CH:41][CH:42]=3)[CH:32]=2)[N:16]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:43]([C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([C:33]2[CH:32]=[C:31]([C:17]3[N:16]=[C:15]([C:14]([F:13])([F:47])[F:48])[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=4)[N:18]=3)[CH:36]=[CH:35][N:34]=2)[CH:38]=1)(=[O:44])=[O:45]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.066 g, 1.08 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.156 g, 76%). MS (ISP) 569.2 [(M+H)+]; mp 192.5° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CCOc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CCOc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxyphenylboronic acid in a manner analogous to Example 2c (0.42 g, 71%). MS=274 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(O[C:14]([S-])=[S:15])C.[K+].Cl>N1C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc2oc(=S)[nH]c2c1
Temperature: 0 °C
Yield: 46 %

Procedure:
A mixture of 3-amino-4-hydroxybenzonitrile (50 mg, 0.37 mmol) and potassium O-ethyl-xanthate (65 mg, 0.41 mmol) in pyridine (0.75 mL) was heated at reflux for 2 h. After cooling, the mixture was poured into ice-water. Then concentrated hydrochloric acid (0.2 mL) was added. The solid was collected, washed with water and dried to give 2-thioxo-2,3-dihydro-benzooxazole-5-carbonitrile 30 mg (46%).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]1[C:12]([CH3:17])=[N:13][CH:14]=[C:15]([CH3:16])[C:9]1=[C:8]2[CH2:18][CH2:19][N:20]([CH3:24])[CH:21]([CH3:23])C)C.[CH2:25](C1C2=C(CCN(C)C(C)C)C3C(N2C(C)=NC=1C1C=CC=CC=1)=CC=CC=3)CCC>>[CH2:24]([N:20]([CH2:21][CH3:23])[CH2:19][CH2:18][C:8]1[C:7]2[C:11](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:10]2[C:12]([CH3:17])=[N:13][CH:14]=[C:15]([CH3:16])[C:9]=12)[CH3:25]
Reactant: CCCCc1c(-c2ccccc2)nc(C)n2c1c(CCN(C)C(C)C)c1ccccc12
Reactant: CCc1cccc2c(CCN(C)C(C)C)c3c(C)cnc(C)n3c12
Product: CCN(CC)CCc1c2ccccc2n2c(C)ncc(C)c12

Procedure:
Similarly, by replacing 5-(2-chloroethyl)-1,4-dimethylpyrimido-[1,6-a]indole with an equivalent amount of another compound of formula 1 described in Example 12 and using N-methyl-N-(1-methylethyl)amine, the following compounds of formula 1 are obtained, respectively; 9-ethyl-1,4,N-trimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine, 8-methoxy-1,4,N-trimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine,7-phenylmethoxy-1,4,N-trimethyl-N-(1-methylethyl)pyrimido-[1,6-a]indole-5-ethanamine,1,N-dimethyl-N-(1-methylethyl)-4-propylpyrimido[1,6-a]indole-5-ethanamine,3,4-diethyl-1,N-dimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine,1,4-diethyl-N-methyl-N-(1-methylethyl)-3-phenylpyrimido[1,6-a]indole-5-ethanamine, and 4-butyl-1,N-dimethyl-N-(1-methylethyl)-3-phenylpyrimido[1,6-a]indole-5-ethanamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21].[OH-].[Na+].[C:24]([OH:27])(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([OH:27])(=[O:26])[CH3:25].[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In an autoclave were charged 2.44 g of (S)-1-(benzyloxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine (7.38 mmol), and 15.7 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80° C. whereby an internal pressure of 8 barr was observed. After allowing the reaction for 16 hrs, the reaction mixture was cooled to room temperature, followed by addition of a 30% by weight aqueous sodium hydroxide solution to adjust the pH to 13, and then ammonia was removed by distillation under reduced pressure. The residue was extracted with 15 mL of ethyl acetate three times, and the organic layers were combined. After washing with 3 mL of a saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a yellow oily material. When 10 mL of ethyl acetate, and 354 mg of acetic acid (0.8 equivalent) were added sequentially thereto, a crystal was precipitated. After stirring at 5° C. for 30 min, the crystal was filtrated under reduced pressure, which was washed with 10 mL of ethyl acetate, and thereafter vacuum drying was carried out to give a white crystal of 1.1684 g (yield: 56%, purity: 100% by weight, optical purity: 100% e.e.)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:27]=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:17]=[CH:18][N:19]=2)[CH:23]=[CH:24][C:25]=1[Cl:33])#[CH:29]
Reactant: ClCCl
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: N#N
Solvent: CC#N
Product: C#Cc1cc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)ccc1Cl
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1374 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring (or ethynyl group) of erlotinib (fragment at m/z 152.0259, calc: 152.0261 for C8H7ClN+). 1H-NMR spectra data indicate the chlorine substitution is at the 4-position of the 3-ethynylphenyl ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (s, 6H), 3.78 (m, 4H), 4.36 (m, 4H), 4.68 (s, 1H), 7.39 (s, 1H), 7.66 (d, J=8.8, 1H), 7.86 (dd, J=8.8, 2.4, 1H), 8.06 (d, J=2.4, 1H), 8.46, (s, 1H), 8.89 (s, 1H).