Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16](O)=[O:17])[C:10]2=[O:34])[S:6][CH:7]=1)#[N:2].C(C1SC=C(CN2CC[C@H](N(CC(O)=O)S(C3C=CC4C(=CC(OC)=CC=4)C=3)(=O)=O)C2=O)C=1)#[N:36]>>[C:1]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16]([NH2:36])=[O:17])[C:10]2=[O:34])[S:6][CH:7]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4cc(C#N)cs4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(N)=O)[C@H]3CCN(Cc4cc(C#N)cs4)C3=O)cc2c1

Procedure:
The tiltle compound is prepared as described in EXAMPLE 127, Part C, substituting 2-[[1-(4-cyanothiophene-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid for 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid. The title compound is obtained as a white foam.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1)=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cn1c([N+](=O)[O-])cnc1C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c([N+](=O)[O-])cnc1C=O

Procedure:
210 parts of 2-dichloromethyl-1-methyl-5-nitroimidazole are stirred in 800 parts by volume of 10 percent strength by weight sulfuric acid for 2 hours at 100° C. The mixture is then neutralized with 550 parts of 6N sodium hydroxide solution, with intense cooling, and the resulting solution is extracted with 4 times 500 parts by volume of methylene chloride. The combined extracts are dried. 126 parts (82% of theory) of 2-formyl-1-methyl-5-nitroimidazole of melting point 93° C. (after recrystallization from toluene) are obtained.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CC(N(C)C)=O>[Br:8][C:9]1[C:17]2[C:16]([N:40]3[CH2:41][CH2:42][C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:39]3)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Triethylamine (3.55 mL, 25.45 mmol) was added to 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 61) (3.28 g, 8.48 mmol) and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (WO2008075109) (3.07 g, 11.88 mmol) in DMA (50 mL) at 20° C. The resulting suspension was stirred at 70° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with water (75 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (3.60 g, 69.7%) as a white solid.
Reaction SMILES: C(OC(N1CCC([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH3:24])[CH:13]=2)CC1)=O)C.[OH-].[K+]>C(O)(C)C>[CH3:24][O:23][CH2:22][CH2:21][N:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:15]2)=[CH:13]1
Reactant: CCOC(=O)N1CCC(c2cn(CCOC)c3ncccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COCCn1cc(N2CCCCC2)c2cccnc21

Procedure:
0.86 g (2.59 mmol) of 4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were added to a solution of 1.71 g (25.9 mmol) of potassium hydroxide in 25 ml of isopropanol. The mixture was refluxed for 20 hours. The solvent was distilled off and cold water was added. This solution was acidified with concentrated hydrochloric acid and then basified with 8 N aqueous sodium hydroxide solution. This aqueous solution was extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. 0.42 g (68% of yield) of the expected product were obtained as an oil.
Reaction SMILES: [CH2:1]1[C@@H:6]2[CH2:7][NH:8][C@H:9]([CH2:11][OH:12])[CH2:10][N:5]2[CH2:4][CH2:3][O:2]1.CCN(CC)CC.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][C@@H:9]1[CH2:10][N:5]2[C@H:6]([CH2:1][O:2][CH2:3][CH2:4]2)[CH2:7][NH:8]1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1CN2CCOC[C@@H]2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Temperature: 25 °C

Procedure:
(7S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol (D50, 680 mg, 3.95 mmol) was almost dissolved in dry DCM (12 mL) before adding Et3N (1.10 mL, 7.90 mmol), followed by TBDMS-Chloride (894 mg, 5.93 mmol). The resulting reaction mixture was stirred over the weekend at R.T., under argon. Left stirring for 2 more hours.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+]([C:12]1[CH:17]=CC=C[CH:13]=1)([O-])=O.OCC(CO)O.B(O)(O)O.OS(O)(=O)=O.[OH-].[Na+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:17][CH:12]=[CH:13]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: OCC(O)CO
Product: Brc1ccc2ncccc2c1
Yield: 22.1 %

Procedure:
To a mixture of 24 g (140.0 mmol) of 4-bromoaniline, 8.2 ml (80.0 mmol) of nitrobenzene, 38.7 ml (530.0 mmol) of glycerol, 4.7 g (17 mmol) of iron sulfate heptahydrate, and 8.65 g (140 mmol) of boric acid there were added, at −10° C., 22.5 ml of conc. H2SO4. The reaction mixture was then heated under reflux over a period of 10 h. Following adjustment of the pH to pH>12 with a 50% strength aq. NaOH solution there were obtained from the residue 3.69 g (17.7 mmol, 13%) of 6-bromoquinoline by steam distillation.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH:10]=[C:11](Br)[CH:12]=2)=[N:2]1.[C:16]([O:19][CH2:20][C:21]1[C:22]([N:30]2[CH2:41][CH2:40][N:39]3[C:32](=[CH:33][C:34]4[CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][C:38]=43)[C:31]2=[O:44])=[N:23][CH:24]=[CH:25][C:26]=1B(O)O)(=[O:18])[CH3:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:30]2[CH2:41][CH2:40][N:39]3[C:32](=[CH:33][C:34]4[CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][C:38]=43)[C:31]2=[O:44])=[N:23][CH:24]=[CH:25][C:26]=1[C:11]1[CH:12]=[C:7]([NH:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[C:8](=[O:15])[N:9]([CH3:14])[CH:10]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc[nH]n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 289b (200 mg, 0.74 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-{3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (360 mg, 0.90 mmol), PdCl2(dppf) (41 mg, 0.050 mmol), K3PO4 (320 mg, 1.5 mmol), sodium acetate (123 mg, 1.5 mmol), acetonitrile (10 mL), and water (0.2 mL). The system was evacuated and then refilled with N2. Then it was heated at 90° C. for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 289c as a pale yellow solid (150 mg, 38%). MS-ESI: [M+H]+ 542.3.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([OH:24])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCCl.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:4]([O:24][C:35](=[O:37])[CH3:36])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H](O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)Oc1cc(Cl)ccc1OC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
To a reaction vessel were added (R)-1-(4-chloro-2-hydroxyphenoxy)-3-phthalimido-2-propanol 348 mg (1.00 mmol), sodium carbonate 159 mg (1.50 mmol) and 1,2-dichloroethane 4 mL. After to the mixture was dropped acetic anhydride 122 mg (1.20 mmol), the mixture was stirred at room temperature for 15 hours. After terminating the reaction by adding water, the water layer was removed and the organic layer was washed with an aqueous 5% HCl solution and an aqueous 5% NaCl solution successively. The organic layer was taken and the solvent was evaporated to give crude (R)-1-(4-chloro-2-acetoxyphenoxy)-3-phthalimido-2-propanol 372 mg (yield 92%, chemical purity 97%) as a pale yellow solid.
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH2:5])=[O:7])=[CH:9][NH:10][C:11]4=[N:12][CH:13]=3)=[N:18][N:19]2[CH2:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Temperature: 80 °C
Yield: 23.9 %

Procedure:
N-tert-Butyl-2-(6-fluoro-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (42 mg, 68.9 μmol) was placed in a sealed tube and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (785 mg, 531 μL, 6.89 mmol) was added and the tube was sealed and the mixture heated at to 80° C. After 15 h the mixture was cooled and concentrated in vacuo. Recrystallization from dichloromethane/methanol and cyclohexane gave 2-(6-fluoro-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (7 mg, 16.5 μmol, 24.0%) as a white powder. MS (M−H)−=422; 1H NMR (DMSO-d6) δ: 8.42 (s, 1H), 7.72 (dd, J=8.9, 5.1 Hz, 1H), 7.65 (s, 1H), 6.73 (d, J=9.4 Hz, 1H), 6.37-6.47 (m, 1H), 4.82 (s, 2H), 2.89-3.09 (m, 6H), 2.82 (d, J=4.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1occc1C(=O)Cc1cccnc1
Reactant: COC(OC)N(C)C
Product: Cc1occc1C(=O)C(=CN(C)C)c1cccnc1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(3-pyridinyl)ethanone (1207 mg, 6 mmol) in N,N-dimethylformamide dimethyl acetal (797 μl, 6.00 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title compound as an orange oil (750 mg, 49%). LC/MS [M+H]+=257.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 98 %

Procedure:
4-Chlorobenzylamine (1.0556 g) was dissolved in pyridine (5 ml), and to the solution was added dropwise ethyl chloroformate.(0.855 ml) during 5 minutes under ice-cooling. After the mixture was stirred for 3 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.562 g, 98%).
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:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:29][CH:30]1[CH2:33][N:32]([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]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:31]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Reactant: FC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), 3-fluoroazetidine hydrochloride (74.7 mg, 669 μmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (228 μl, 1.34 mmol) in tetrahydrofurane (7 ml) is stirred for 18 hours room temperature. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (36 mg, 37.3%) as a light brown solid. mp.: 247-9° C. MS: m/z=421.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(Cl)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-chlorophenyl isocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=478.3/480.3.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:14])[C:12]#[CH:13]>>[CH2:11]([NH:14][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:12]#[CH:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C#CCN
Product: C#CCNS(=O)(=O)c1ccccc1

Procedure:
A benzenesulfonyl chloride derivative of the general formula (2) is reacted with propargylamine to obtain an N-propargylbenzenesulfonamide derivative of the general formula (4). A compound of the general formula (4) is reacted with 2-trifluoromethylbenzoyl halide to synthesize a compound of the general formula (1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=O)[C:5](=[O:12])[NH:6][C:7]=1[C:8]([Cl:11])([F:10])[F:9].[NH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:15])[C:5](=[O:12])[NH:6][C:7]=1[C:8]([Cl:11])([F:9])[F:10]
Reactant: COC(=O)c1cc(Br)c(C(F)(F)Cl)[nH]c1=O
Reactant: NCC1CC1
Agent: Cl
Solvent: CC#N
Product: O=C(NCC1CC1)c1cc(Br)c(C(F)(F)Cl)[nH]c1=O

Procedure:
At room temperature, 350 mg (1.11 mmol) of methyl 5-bromo-6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 5 ml of acetonitrile and stirred with 0.5 ml of aminomethylcyclopropane for 12 h. The reaction mixture was then added to 1N hydrochloric acid, and the resulting precipitate was filtered off with suction. The precipitate was dried, again triturated with 1N hydrochloric acid, filtered off with suction and washed with water. Drying gave 240 mg (62% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH3:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[O:13]
Reactant: O=CO
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of 24.2 g of 5,6-diamino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidinedione (XVI) in 60 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 17.8 g (XVII). The amide (XVII) was refluxed in 50 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from ethanol. Yield 11.6 g (46%), NMR. ##STR10##
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:7][N:8]=1.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I>CN(C=O)C>[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:12]3[CH2:13][CH2:14][N:10]([CH2:9][C:6]4[S:5][C:4]([Cl:3])=[N:8][CH:7]=4)[C:11]3=[N:15][N+:16]([O-:18])=[O:17])[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:7][N:8]=1
Reactant: ICCCCCCI
Reactant: O=[N+]([O-])N=C1NCCN1Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])N=C1N(CCCCCCN2CCN(Cc3cnc(Cl)s3)C2=N[N+](=O)[O-])CCN1Cc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (60%, 0.48 g, 12 mmol) in 20 ml of DMF was prepared. 1-(2-Chloro-5-thiazolylmethyl)-2-nitroiminoimidazolidine (2.61 g, 10 mmol) was added to this suspension. The resulting mixture was then stirred for 1 hour at room temperature. 1,6-Diiodohexane (1.64 g, 5 mmol) was added dropwise to this reaction mixture over the course of 30 minutes while cooling the reaction mixture with ice. Following completion of dropping, the mixture was stirred for 4 hours at room temperature. The DMF was distilled off from the reaction mixture under reduced pressure. The residue was then shaken with a mixture of water and chloroform. After separating the chloroform layer and drying, the solvent was distilled off under reduced pressure. The semi-solid residue was subjected to silica gel column chromatography with a mixture (15:1 (v/v)) of ethyl acetate and ethanol as the eluate. The crude product was recrystallized from methanol. The yield of crystalline product was 0.22 g (70%), and the melting point was 204 to 206° C. The results of elementary analysis and NMR analysis are shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[N:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[N:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2nnccc2n1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2nnccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a cooled (0° C.) solution 7-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid ethyl ester (242 mg, 0.626 mmol) in DCM (6 mL) was added iodine monochloride (1.25 mL 1M in DCM 17.0 mL) dropwise over 1 minute. The mixture was allowed to warm to ambient temperature, stirred for 1 hour, then partitioned between ethyl acetate and a saturated solution of sodium thiosulfate. The organic layer was separated, washed with water, dried (Na2SO4), filtered and evaporated to give a residue. The residue was subjected to flash chromatography (Si-PPC, 1:1 DCM:ethyl acetate eluent) to provide the title compound as an orange solid (242 g, 88%). LCMS (method B): RT=3.03 min, M+H+=441.
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>O1CCCC1>[F:37][C:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][CH:4]([C:1](=[S:47])[NH2:2])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC(CC(CCC(C)(C)F)C(N)=S)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalent of acetic acid 3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester in tetrahydrofuran cooled to 0° C. is added 0.5 equivalents of Lawesson's reagent dropwise. The yellow suspension is allowed to warm to room temperature and stirred for about 5 h. The reaction mixture is concentrated to dryness, then purified by silica gel chromatography to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g; 2.81 mmol) and sodium azide (0.547 g; 8.43 mmol) in DMF (8 mL) was stirred for 18 hours at 80° C. and was concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. After separation, the dichloromethane solution was dried over magnesium sulphate and was evaporated to give 0.943 g (100%) of 3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a solid.