Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[CH:14])=[CH:7][C:5]=2[N:6]=1.[CH2:15]([Br:18])[C:16]#[CH:17]>>[Br-:18].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[CH:14])=[CH:7][C:5]=2[N+:6]=1[CH2:17][C:16]#[CH:15]
Reactant: C#CCBr
Reactant: C#CCOc1ccc2sc(C)nc2c1
Product: C#CCOc1ccc2sc(C)[n+](CC#C)c2c1
Product: [Br-]
Yield: 54.1 %

Procedure:
20.4 g of 2-methyl-5-propargyloxybenzothiazole and 12.5 g of propargyl bromide were heated on a hot water bath at 80° to 100° C for 3 hours. The precipitated crystals were washed with acetone to give 17.5 g of 2-methyl-3-propargyl-5-propargyloxybenzothiazolium bromide, m.p. 244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[N:11]=2)[N:8]=1.CC(O)=O>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:13]=3)[NH2:19])[N:11]=2)[N:8]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.5 g, 1.75 mmol) in ethanol (20 mL) and water (5 mL) containing AcOH (10.5 mmol) is added iron (0.491 g, 8.79 mmol). The mixture is heated at 80° C. for 4 hours, cooled, concentrated under reduced pressure, and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL), the organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.328 g, 73%) as a light yellow solid: Rf 0.21 (EtOAc); LCMS (m/z)=255.5 [M+H]+, tR=4.89 min. (10 min run).
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]=[O:14].[C-:15]#[N:16].[K+]>O.C(O)C>[CH3:6][C@@H:7]1[CH:12]=[CH:11][CH2:10][CH2:9][C@H:8]1[CH:13]([OH:14])[C:15]#[N:16]
Reactant: C[C@@H]1C=CCC[C@H]1C=O
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1C=CCC[C@H]1C(O)C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Sodium bisulfite (10.4 g., 0.1 mole) was dissolved in 50 ml. H2O. Absolute ethanol (50 ml.) and trans-2-methyl-3-cyclohexene-1-carbaldehyde (85%, 8.6 g., 0.07 mole) were added and the mixture heated in an oil bath at 63°-65° C. for 1.5 hours, then cooled to 15° C. in an ice-water bath. KCN (13 g., 0.2 mole) in 50 ml. H2O was added at 15°-18° C. The reaction mixture was stirred at room temperature 0.5 hour and extracted with 150 ml. ether. The ether was back-washed with 75 ml. H2O and concentrated in vacuo to yield title product as an oil, 5.5 g. Based on pnmr, the product contained 85% trans isomer (doublet at 4.6 ppm, J=4) and 15% cis isomer (doublets at 4.2 and 4.35, J=2).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][O:30][CH:31]1[CH2:34][NH:33][CH2:32]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:29][O:30][CH:31]1[CH2:34][N:33]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32]1
Reactant: COC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4ccccc4)nc3c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxyazetidine hydrochloride (37.5 mg, 304 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel, and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-Methoxyazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (75 mg, 66.6%) as a very insoluble white solid. mp.: 269-270° C. MS: m/z=432.3 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: COCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 27 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-methoxyethyl)amino]ethoxy}quinazolin-4-amine (obtained as described in Example 24, preparation of starting materials) to give the title compound in 27% yield; NMR spectrum (DMSO-d6) 3.18 (s, 1H), 3.24 (s, 2H), 3.48 (s, 3H), 3.55-3.60 (m, 1H), 3.86-3.98 (m, 2H), 4.10-4.15 (m, 2H), 4.32 (t, 1H), 4.43 (t, 1H), 4.51-4.57 (m, 1H), 5.31 (s, 2H), 7.17 (d, 1H), 7.25 (d, 1H), 7.33-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.99-8.05 (m, M1H), 8.46 (s, 1H), 8.60 (d, 1H), 9.84 (s, 1H); Mass spectrum MH+ 538.
Reaction SMILES: [N:1](Cl)=[O:2].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.C(Cl)(Cl)(Cl)[Cl:16]>>[Cl:16][C:13]([C:12](=[O:14])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)=[N:1][OH:2]
Reactant: O=NCl
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccc(C(C)=O)cc1
Product: COc1ccc(C(=O)C(Cl)=NO)cc1
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a stirred solution of 60 g (0.92 mole) of nitrosyl chloride dissolved in 1300 ml of carbon tetrachloride at 5°-10° C. was added, over a period of 10 minutes, a solution of 60 g (0.4 mole) of p-methoxyacetophenone in 200 ml of carbon tetrachloride. The reaction mixture was then warmed to 35° C. and stirred at 35°-38° C. for 90 minutes during which the product precipitated (some cooling was necessary to maintain the temperature in the specified range). The reaction mixture was then warmed to 40° C. and after 15 minutes was cooled to 5° C. and filtered. The filter cake was washed with 400 ml of carbon tetrachloride and air-dried to provide 53.6 g (62.7% yield) of 1-chloro-1-p-methoxybenzoylformaldoxime as a white solid, m.p. 118°-125° C., which was sufficiently pure for further synthetic use.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][C:17]([F:20])([F:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.561 g; 19.70 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 1 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2,2,2-trifluoroethoxy)benzaldehyde as a colorless oil. LC-MS (conditions A): tR=0.75 min.; no ionisation.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46]I>CN(C=O)C.CS(C)=O>[CH3:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46][NH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: COC(=O)CCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (80 mg, 0.182 mmol) in 2:1 DMF/DMSO (0.6 mL) was added N,N-diisopropylethylamine (32 μL, 0.272 mmol) followed by methyl-4-iodobutyrate (19 μL, 0.136 mmol). The mixture was stirred at room temperature overnight then partitioned with EtOAc (15 mL) and water (10 mL). The layers were separated and the organics dried over Na2SO4. After concentration in vacuo, the residue was purified by column chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 100:0 to 90:10 DCM/MeOH) to afford 4-(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-butyric acid methyl ester (39 mg, 53%) as a white solid: m/z 541 [M+1]+.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:32][CH2:33][CH3:34])[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH2:21][CH3:22]>C(O)C>[ClH:1].[CH2:32]([N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH2:33][CH3:34]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CCC1CCCNC1
Solvent: CCO
Product: CCCN(CCC)CCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Product: Cl
Yield: 67 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(dipropylamino)ethyl]piperidine in a yield of 67% of theory. Colourless crystals, m.p. 202°-205° C. (ethanol).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17](O)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[CH3:15][N:14]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]1=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Solvent: O
Product: CN1C(=O)c2c(-c3ccccc3)noc2CC1c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To 550 ml. of polyphosphoric acid maintained at a temperature of 100° to 105° C. there is added 36.5 grams (0.114 moles) 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide in portions. The mixture is then stirred at 100° for 5 hours and then poured onto 2 liters of ice and water. The resulting solid is filtered and purified by recrystallization to give 5-methyl-6,7-dihydro-3,6-diphenyl isoxazolo [4,5-c]pyridin-4(5H)-one; m.p. 108° to 111° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][C:14]1=[O:22].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>C1COCC1.O>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][CH:15]1[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[O:13][C:14]1=[O:22]
Reactant: O=C1CC2CCCCC2O1
Reactant: BrCc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC2CCCCC2C1Cc1ccc2ccccc2c1
Temperature: -78 °C

Procedure:
Under argon, a solution of diisopropylamine (3.36 ml, 24 mmol) in 20 ml of dry THF was cooled to 0° C. and admixed with butyllithium (9.6 ml, 24 mmol, 2.5 M in hexane). The solution was stirred with ice-cooling for 15 min, cooled to −78° C. and admixed with a solution of hexahydro-benzofuran-2-one (2.8 g, 20 mmol) in 10 ml of THF. This mixture was stirred at −78° C. for 1 h, and a solution of 2-bromomethylnaphthalene (5.31 g, 24 mmol) in 20 ml of THF was then added. The mixture was stirred at −78° C. for another 2 h and then at room temperature overnight. Water was then added, the organic solvent was removed under reduced pressure and the aqueous phase was extracted with MTBE. The combined ether phases were dried over magnesium sulphate, filtered and concentrated. Purification was carried out by column chromatography. Yield: 2.5 g (44.6%). Rf (cyclohexane/ethyl acetate 3:1)=0.69, Rf (cyclohexane/ethyl acetate 1:1)=0.83 MS (CI): m/e=281 [M+H+]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].[C:58]1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.C[O-].[Na+]>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:55])=[O:56])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:58]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(C4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 150 °C
Yield: 47.2 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.4 mmol), 5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}aniline (Example 163, step D) (117 mg, 0.36 mmol), and p-toluenesulfonic acid (180 mg, 0.95 mmol) were weighed into a 20 mL microwave vial. 7 mL of trifluoroethanol was added and the mixture was heated in the microwave to 150° C. for 2 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2.5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (135 mg, 0.17 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.39 (d, J=6.60 Hz, 1H), 8.46 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.05 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.62, 2.02 Hz, 1H), 7.70 (d, J=9.17 Hz, 1H), 7.56 (s, 1H), 7.41-7.49 (m, 1H), 7.37 (d, J=8.07 Hz, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.96 (t, J=6.97 Hz, 1H), 6.89 (s, 1H), 6.58 (t, J=5.50 Hz, 1H), 4.26 (q, J=7.09 Hz, 2H), 3.79-3.82 (m, 3H), 3.26-3.36 (m, 2H), 3.06 (s, 3H), 3.02 (d, J=13.20 Hz, 4H), 2.68-2.76 (m, 2H), 2.59-2.68 (m, 1H), 2.20 (s, 3H), 2.02-2.14 (m, 2H), 1.65-1.76 (m, 2H), 1.43 (t, J=6.97 Hz, 3H). MS (ESI): 796 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Product: CCN(CC)c1nc(N2CCCC2)cc(N2CCNCC2)n1

Procedure:
A solution of 2-diethylamino-4-piperazino-6-chloro-pyrimidine (4.10 g) in pyrrolidine (4.10 g) is heated for 12 hr at 100°, then concentrated. The concentrate is partitioned between aqueous sodium bicarbonate and methylene chloride. The phases are separated, the organic phase is dried and concentrated to give 2-diethylamino4-piperazino-6-pyrrolidino-pyrimidine. A solution of this amine (4.01 g), 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (5.41 g), and potassium carbonate (1.75 g) are stirred in acetonitrile (200 ml) for 19 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (methylene chloride to 4% methanol/methylene chloride) to give the free base corresponding to the title compound. An ethyl acetate solution of this compound is converted to the hydrochloride salt with ether/hydrochloric acid to give the title compound.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[CH:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N(CC)CC)C.[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33].CN(C)C=O>O>[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:15][C:14]([CH:9]2[N:8]3[C:17](=[O:18])[CH:6]([N:5]4[C:4](=[O:19])[C:3]5=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]5[C:1]4=[O:24])[C@H:7]3[S:11][C:10]2([CH3:12])[CH3:13])=[O:16])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
6-Phthalimido-2,2-dimethyl-penam-3-carboxylic acid p-nitrobenzyl ester is prepared by placing a mixture of 1.0 g. of 6-phthalimido-2,2-dimethyl-penam-3-carboxylic acid, 0.4 ml. of triethylamine, 0.75 g. of p-nitrobenzyl bromide and 10 ml. of dimethyl formamide in a refrigerator for 3 hours. Thereafter, 10 ml. of water are added and the resulting precipitate formed is filtered, washed with acetone and recrystallized from methylethyl ketone to yield colorless crystals; mp 233°-34° C.; nmr (CDCl3) 89(S,3H); 111(S,3H); 287(S,1H); 322(S,2); 338.5(d,1H,J=4.5 Hz); 342(d,1H,J=4.5 Hz); 472 cps (m,8 ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:27]2[CH:31]=[CH:32][C:24]([Br:23])=[CH:25][CH:26]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) and commercially available 4-bromobenzoic acid (78 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (102 mg) was added, and the admixture was stirred at room temperature for 17 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 43 mg of the title compound (yield: 52%).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:27]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]([CH2:3][I:27])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])=[C:20]([F:26])[CH:21]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine (0.236 g, 0.564 mmol) (from Example 19, Step E, supra) in dichloromethane (30 mL) was added I2 (1.43 g, 5.64 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired 4-(4-bromo-2-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as an off white oil. (Yield 0.034 g, 11%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].O>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:16][CH2:15][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pt]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reaction time: 4 h
Yield: 106.6 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (15 g, 75.28 mmol) was dissolved in ethanol (150 ml) and treated with 70% ethylamine/H2O (6.06 ml, 75.29 mmol), followed by 5% Pt/C JM type 117 (2.25 g, 20 wt %). The reaction mixture was subjected to hydrogenation at 2 bar, 50° C. with stiring for 4 hours. The reaction mixture was purged with nitrogen and filtered through GF/F filter paper. The catalyst was washed with ethanol (2×15 ml). The liquors were combined and evaporated to dryness to give N-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamine as a colourless oil (18.33 g, 107%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:37]2[CH:36]=[C:16]([CH:15]=[CH:14][C:38]=2[CH3:39])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:33])([F:34])[F:35])[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC(C)C)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 141-143° C.; 1H NMR (300 MHz, CDCl3) δ: 9.82 (1H, s), 8.34 (1H, s), 8.20-8.23 (1H, d, J=7.8 Hz), 7.96 (1H, s), 7.84-7.86 (1H, d, J=8.1 Hz), 7.54 (1H, s), 7.29-7.31 (3H, m), 6.81 (1H, s), 6.63-6.66 (1H, d, J=8.4 Hz), 5.11 (1H, brs), 4.08 (1H, m), 2.46 (3H, s), 2.29 (3H, s), 1.28-1.31 (6H, d, J=6.3 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H26F3N6O: 519.2115. found: 519.2116.