Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:26][C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12

Procedure:
20 cm3 of sulphinyl chloride and one drop of dimethylformamide are added at a temperature in the region of 20° C. under an argon atmosphere to 1.39 g (4.53 mmol) of 3-carboxy-6-fluoro-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 1.7 g of 3-chlorocarbonyl-6-fluoro-1-(quinol-4-yl)-1H-indole in the form of a cream solid which is used directly in the following step.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:12][N:11]1[C:3]2[C:2]([NH:14][CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:19][OH:20])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:13])=[N:10]1
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Reactant: CC(C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC(CO)C(C)C)c2c(n1)c(C)nn2C
Reaction time: 50 h
Yield: 45.6 %

Procedure:
A mixture of 8 g (0.04 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 3), 4.5 g (0.045 mol) of L-valinol (2-amino-3-methyl-1-butanol) and 8 ml of triethylamine in 50 ml of dimethylformamide is stirred at 50°-55° C. for 50 hours and evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with a saturated solution of sodium bicarbonate, dried over MgSO4, and evaporated in vacuo. The residue is stirred in pet ether to give 4.8 g (45%) of 2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]-pyrimidine-7-yl]amino-3-methyl-1-butanol, mp 166°-168° C. from acetonitrile.
Reaction SMILES: [N:1]1([C:7]2[O:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[N:1]1([C:7]2[O:11][C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(N2CCOCC2)o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nnc(N2CCOCC2)o1)OCC(Cl)(Cl)Cl
Yield: 13.2 %

Procedure:
To a solution of 5-morpholin-4-yl-1,3,4-oxadiazol-2-ylamine (1.00 g, 5.88 mmol) and pyridine (0.570 ml, 7.05 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.976 ml, 7.05 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to yield 269 mg (13.3%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.C([BH3-])#[N:14].[Na+].C([O-])(=O)C.[NH4+]>CO>[CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[NH2:14]
Reactant: CC(C)CC(=O)c1cccnn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(N)c1cccnn1
Temperature: 70 °C
Yield: 27.1 %

Procedure:
A suspension of 3-methyl-1-(pyridazin-3-yl)butan-1-one (0.85 g, 5.2 mmol; CAN 138835-88-8), sodium cyanoborohydride (1.2 g, 19.2 mmol) and ammonium acetate (1.28 g, 16.6 mmol) in methanol (11.1 mL) was heated at 70° C. for 12 h. The solvent was removed under reduced pressure and the residual oil was partitioned between EtOAc and 1 M aqueous HCl solution. The aqueous layer was basified with 10% aqueous NaOH solution and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. Filtration and evaporation provided the title compound (233 mg, 27%) as brown oil which was sufficiently pure to be used in the next reaction step. MS (EI): m/e=166.2 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:10]1([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([CH2:23][NH2:24])[CH2:20][C@H:19]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[N:10]1([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20][C@H:19]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](CNCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
Benzyl bromide (0.067 mL, 0.56 mmol) was added to a mixture of (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-aminomethyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride salt (0.247 g, 0.564 mmol), DMF (10 mL) and K2CO3 (0.312 g, 2.26 mmol), prepared as in Reference 12. The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with 1N hydrochloric acid (30 mL). The dilution was washed with ethyl acetate (30 mL). The aqueous layer was basified with 2N sodium hydroxide (40 mL) and extracted with methylene chloride (40 mL). The extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 262, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((benzylamino)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (23 mg, 0.044 mmol, 8%), as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.03 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.58 (d, J=7.6 Hz, 2H), 7.37-7.30 (m, 3H), 7.25-7.17 (m, 3H), 7.03-6.94 (m, 5H), 5.30, 5.19 (m, 2H), 4.49-4.46 (m, 2H), 3.89-3.84 (m, 1H), 3.74 (s, 2H), 2.69-2.52 (m, 2H), 2.16-1.87 (m, 2H). MS (EI) for C29H29FN6O3. found 529.3 (MH+).
Reaction SMILES: [CH:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH2:13]O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CO.CN(C=O)C>[C:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)#[N:13]
Reactant: CCOC(=O)c1coc(C=O)n1
Reactant: NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)c1coc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A solution of ethyl 2-formyloxazole-4-carboxylate (650 mg, 3.84 mmol) in methanol (25 mL) was cooled to 0° C. and 50% aqueous hydroxylamine (0.22 mL, 7.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. Solvent was removed under reduced pressure and the crude product (0.52 g) obtained was dissolved in DMF (20 mL). T3P (3.4 mL, 5.65 mmol; 50% in EtOAc) was added to the reaction mixture and heated to 100° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and the organic product was extracted with EtOAc. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford ethyl 2-cyanooxazole-4-carboxylate (0.34 g, yield 53%) as an off white solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 4.48-4.41 (q, J=7.0 Hz, 2H), 1.44-1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=C([Cl:95])C=3OC)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[C:26]([Cl:95])[C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-3-methoxybenzyl)phosphonate (Compound 54B, 200 mg, 0.306 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 81 mg, 0.321 mmol) to afford 203 mg of the title compound as a racemic mixture (75%). MS (ESI): m/z=887.65/889.64 [M+H]+. UPLC: tR=1.68 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][Br:10])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(Br)ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: Fc1ccc(Br)nc1CBr
Temperature: 55 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a solution of 6-bromo-3-fluoro-2-methylpyridine (0.5 gr, 2.63 mmol) in dichloromethane (5 ml) were added at room temperature N-bromosuccinimide (937 mg, 5.26 mmol) and azo-di-isobutyronitrile (86 mg, 0.526 mmol). After 17 h stirring at 55° C. the reaction mixture was quenched by the addition of water and the product was extracted into dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 6-bromo-2-(bromomethyl)-3-fluoropyridine (388 mg) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:17])[CH:10]=3.Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:17][CH2:30][CH2:31][CH2:32][OH:33])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
The compound (47 mg) obtained in Example 33 was suspended in DMF (2 mL) and to the suspension was added 3-bromopropanol (11 μL) and potassium carbonate(19 mg) The mixture was stirred at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride:methanol=100:0˜10:1) to obtain the title compound (27 mg; 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[F:10].CON(C)[C:14]([C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Fc1cc([Mg]Br)ccc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
0.5M (4-Chloro-3-fluorophenyl)magnesium bromide (22.5 mL, 11.2 mmol) as a solution in THF was added dropwise to a cold (0° C.) solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.45 g, 5.61 mmol) in THF (25 mL) under N2, and the reaction was allowed to warm up to room temperature overnight. The next morning, the mixture was placed in an ice bath and carefully quenched with ice. The reaction mixture was concentrated. The residue was treated for 1 hour with a solution of 30% sodium potassium and then extracted with ethyl acetate (2×). The organic layer was dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (5:1) to give (R)-tert-butyl 2-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (1.12 g, 61%). m/z (APCI-pos) (M+1)-Boc=228.1, 230.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:43])(=[O:42])[CH3:41]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:43])(=[O:42])[CH3:41]
Reactant: CC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: CC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of acetic acid (0.034 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib acetate form II.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[OH:22])[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1>C(C(C)=O)C(C)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:31][CH:32]1[CH2:34][CH2:33]1)[CH2:2]2
Reactant: CC(=O)Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Yield: 84.2 %

Procedure:
A suspension of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-hydroxy-4-acetamido-5-chlorobenzamide (6.75 g; 0.02 moles) (m.p. of hydrochloride 315°-317° C. (d)), potassium carbonate (2.76 g; 0.02 moles), 91.5% bromomethylcyclopropane (3.54 g; 0.024 moles) and methyl isobutyl ketone (40 ml) was boiled under reflux for 48 hours. After cooling, the reaction mixture was washed with water, 1N sodium hydroxide aqueous solution and again with water. The organic solution was dried (Na2SO4), decolorized with charcoal and the solvent removed in vacuo to give crude N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide (6.6 g) as an oil, which was crystallized from acetonitrile, m.p. 211°-213° C. (d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([OH:17])[C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Yield: 80.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-3-nitro-1-(4-thiomorpholinylsufonyl)benzene (330 mg, 0.97 mmol) was reduced with hydrogen and 10% Pd/C (150 mg) to form the desired product (240 mg, 80%). 1H NMR (MeOD-d4): δ 7.08 (d, 1H), 6.98(d, 1H), 3.59 (t, 4H), 2.68 (t, 4H).
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]([Br:30])=[CH:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][C:23]2([CH2:27][CH2:28][CH3:29])[CH2:26][O:25][CH2:24]2)=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Br:30][C:11]([Br:10])=[CH:12][CH:13]1[CH2:14][CH2:15][CH:16]([C:19]23[O:21][CH2:22][C:23]([CH2:27][CH2:28][CH3:29])([CH2:26][O:25]2)[CH2:24][O:20]3)[CH2:17][CH2:18]1
Reactant: CCCC1(COC(=O)C2CCC(C=C(Br)Br)CC2)COC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCC12COC(C3CCC(C=C(Br)Br)CC3)(OC1)OC2
Temperature: 25 °C

Procedure:
Boron trifluoride etherate (40 μl) was added to a stirred solution of 3-propyloxetan-3-ylmethyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (0.57 g) in dry dichloromethane (10 ml) at -70° C. The mixture was allowed to warm to room temperature over 16 hours. Triethylamine (0.6 ml) was then added. The organic phase was washed with brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on alumina eluting with 3:7 dichloromethane:hexane saturated with ammonia. 1-[4-(2,2-Dibromovinyl)cyclohexyl]-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless oil (0.34 g).
Reaction SMILES: N1([O:10][C:11](=[O:43])[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)C2C=CC=CC=2N=N1.[CH3:44][O-].[Na+]>CO.Cl>[CH3:44][O:10][C:11](=[O:43])[C:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH:36]3[S:40][C:39](=[O:41])[NH:38][C:37]3=[O:42])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[CH:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(C)cc(C)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 62 %

Procedure:
To a solution of 48 (240 mg, 0.4 mmol) in methanol (10 mL) was added sodium methoxide (0.5 N in methanol, 2 mL). After 10 min the mixture was diluted with 1N HCl (2 mL) and the product was extracted into ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography using hexanes:ethyl acetate (3:2) to yield 49(122 mg, 62%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.71 (s, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.68 (s, 2H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.73 (s, 3H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.12 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.COC(=O)CN(CC1C=CC=CC=1)CC(NC(OC(C)(C)C)=O)C>C1COCC1.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:8]
Reactant: NCCc1ccc(F)cc1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)CN(Cc1ccccc1)CC(C)NC(=O)OC(C)(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(F)cc1C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6. mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all of the HOBt had completely dissolved, EDCI (2.21 g, 11.6 mmol) was added and the resulting orange solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was chromatographed on silica eluting with 15% EtOAc in hexanes giving the desired benzamide (2) as white crystals (3.07 g, 10.4 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:17]=4[NH:16][C:15](=[O:18])[CH2:14]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc(Nc2cccc3c2NC(=O)C3)c1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 7-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (80 mg, 0.33 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (113 mg, 0.37 mmol), N,N-diisopropylethylamine (0.22 g, 1.67 mmol) and HATU (0.14 g, 0.37 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:24]([C:28]1[Se:32][C:31]([N+:33]([O-:35])=[O:34])=[C:30]([NH2:36])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CN(C=O)C.[OH-].[Na+]>>[C:24]([C:28]1[Se:32][C:31]([N+:33]([O-:35])=[O:34])=[C:30]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)c([N+](=O)[O-])[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3[N+](=O)[O-])c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 5-(tert-butyl)-2-nitroselenophene-3-ylamine in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 172-174° C. IR (KBr) vmax 3431, 2942, 2860, 1616, 1436, 1309, 1281, 1197, 1121, 1025, 863 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.67 (1H, s, exchangeable with D2O), 8.90 (1H, s), 8.83 (1H, s), 7.30 (1H, s), 7.25 (1H, s), 4.30 (2H, t, J=6.2 Hz), 4.03 (3H, s), 3.73 (4H, t, J=4.4 Hz), 2.61 (2H, t, J=7.2 Hz), 2.51 (4H, br s), 2.14 (2H, pentet, J=6.6 Hz), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 176.6, 156.0, 153.4, 152.8, 150.3, 148.4, 144.9, 130.1, 120.1, 109.9, 107.8, 99.8, 67.5, 67.0, 56.3, 55.4, 53.8, 37.9, 32.0, 26.1; LC-MS (positive ion mode): m/z 548, 550 (M+H)+.