Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=1>CS(C)=O.[OH-].[Na+]>[OH:25][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:2][C:3]2[NH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14][CH:15]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: ClCc1cc2ccccc2[nH]1
Reactant: CCCCCC(O)c1ccc(O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCC(O)c1ccc(OCc2cc3ccccc3[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
2-Chloromethyl indole (8 g, 0,048 mol) and 2-hydroxy-5-(1-hydroxyhexyl)pyridine (9.36 g, 0.048 mol) were dissolved in DMSO (250 ml) and to this mixture, 2N sodium hydroxide solution was added (25 ml, 0.05 mol). The clear, homogeneous reaction mixture became warm, and this mixture was stirred at room temperature overnight. The solution was poured into warer (500 ml), and was extracted thoroughly with ethyl acetate (4×50 ml). The combined extract was washed with 1N sodium hydroxide sclution, water and brine. After drying the organic extract over MgSO4, all volatiles were removed to leave a brown oil (9 g). This crude product was purified by HPLC (silica gel, 20% ethyl acetate in hexane) to yield the pure product (8.6 g, 55%) as a yellowish semi-solid.
Reaction SMILES: [C:1]([O:17][CH3:18])(=[O:16])[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:19]([N:26]1[CH2:30]C[CH:28](O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCCC.[H-].[Na+]>[CH2:19]([N:26]1[CH2:27][CH2:28][CH:18]([O:17][C:1](=[O:16])[C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[OH:3])[CH2:30]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Product: O=C(OC1CCN(Cc2ccccc2)C1)C(O)(c1ccccc1)c1ccccc1
Yield: 101.5 %

Procedure:
To a solution of 12 g methyl benzilate and 8.2 g 1-benzyl-3-pyrrolidinol in 200 ml n-heptane is added 100 mg sodium hydride and the mixture refluxed for 4 hours, separating the methanol formed in a Dean-Stark separator. The cooled organic phase is washed with water and then extracted with 2N HCl. The aqueous phase is made alkaline with solid K2CO3 and extracted with ether to give 1-benzyl-3-(2,2-diphenyl-2-hydroxyacetoxy)pyrrolidine as an oil (18.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1C=CC=C(C)N=1.CS(OS(C)(=O)=O)(=O)=O.[Br-:31].[Li+]>C1COCC1.C(OCC)(=O)C.O>[Br:31][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: [Br-]
Reactant: O=[N+]([O-])c1ccc(CCCO)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCCBr)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
3-(4-nitrophenyl)propanol (5.0 g) was dissolved in THF (100 ml), 2,6-dimethylpyridine (5.1 ml) and methanesulfonic acid anhydride (6.7 g) were added to the mixture, and the mixture was stirred for 12 hours at 50° C. Lithium bromide (3.6 g) was added to the mixture, and the mixture was stirred for 8 hours at 60° C. After cooling to room temperature, the reaction solution was added to water, and dissolved in ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-(3-bromopropyl)-4-nitrobenzene (3.1 g).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O>[Cl:23][C:4]1[CH:3]=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of the 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.500 g, 1.28 mmol), dichlorobis(tro-o-tolylphosphine)palladium(II) (0.101 g, 0.128 mmol), and potassium carbonate (0.531 g, 3.84 mmol) in dioxane (20 mL) and water (1 mL) heated to 90° C. was added phenylboronic acid (0.390 g, 3.20 mmol) and the reaction allowed to stir for 1 h. The reaction was cooled to room temperature, filtered (celite), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) gave 0.422 g (85%) of 2-[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 163-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].OO.C(O)(=[O:20])C>C1(C)C=CC=CC=1.C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:20]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c(SCCC(C)C)c(=O)o1
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(S(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C

Procedure:
4-Hydroxy-3-isopentylthio-6-methyl-2-pyrone (4.5 g., 0.020 mol), 30% hydrogen peroxide (2.44 g., 0.0220 mol), and 35 ml. glacial acetic acid were combined and stirred over night at room temperature. The clear solution was diluted with a mixture of toluene and ethanol and the acetic acid was removed by codistillation in vacuo. A yellow liquid was recovered which solidified upon cooling. The compound was recrystallized from n-hexane to recover 2.5 g. (51 percent) of shiny yellow platelets. One additional recrystallization from n-hexane gave the pure compound as tiny white crystalline needles: m.p. 80°-81°C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH3:20][O:21][C:22]1([O:42][CH3:43])[CH:41]=[CH:40][C:25]([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH2:23]1>N1C=CC=CC=1>[CH3:43][O:42][C:22]1([O:21][CH3:20])[CH:23]=[CH:24][C:25]([C:26]([CH:17]([OH:18])[CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:40][CH2:41]1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: COC1(OC)C=CC(C(Cl)(c2ccccc2)c2ccccc2)=CC1
Solvent: c1ccncc1
Product: COC1(OC)C=CC(C(c2ccccc2)(c2ccccc2)C(O)COCCOCCOCCOCCOCCO)=CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a solution of hexaethylene glycol (8.46 grams, 30 mmoles) in 250 ml dry pyridine, a solution of 4,4-dimethoxytrityl chloride (3.38 grams, 10 mmoles) in 50 ml dry pyridine was added dropwise at room temperature. The resulting solution was stirred at room temperature for additional 5 hours. The solvent was then evaporated to dryness, and the residue was extracted with 200 ml ethylacetate/200 ml 5% sodium bicarbonate solution, washed twice with water and twice with brine solution. The obtained organic layer was dried over anhydrous sodium sulfate, evaporated and purified by silica gel column chromatography using 5% methanol in dichloromethane, 0.5% pyridine. The resulting 4,4-dimethoxytrityl-hexaethylene glycol compound (5.23 grams, 89% yield) migrated with Rf=0.29.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12](C(OC(C)(C)C)=O)[C@@:11]([CH2:21][OH:22])([CH3:20])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@@:11]([CH2:21][OH:22])([CH3:20])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cncc(F)c2)CC[C@@]1(C)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (200 mg, 0.644 mmol) in DCM (5 mL) was added 4M HCl in dioxane (1.61 mL, 6.44 mmol). The reaction was stirred at ambient temperature for 16 hours and then concentrated to afford ((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanol hydrochloride (130 mg, 96% yield). MS (apci) m/z=211.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([OH:18])[CH:6]=1)=[O:4]>CO.ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([OH:18])[C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1=C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 14 h

Procedure:
[(1,2-Bis(2R,5R)-2,5-dimethylphospholano)benzene](cyclooctadiene)rhodium(I) tetrafluoroborate (23 mg, 1 mol %) was added to a degassed solution of (3S,4R)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid methyl ester (1 g, 3.9 mmol) in methanol (5 ml). The reaction mixture was transferred to a bomb and, after purging with nitrogen and then hydrogen, a hydrogen pressure of 5 bar was applied and the reaction stirred for 14 h. The pressure was released and the bomb purged with nitrogen. Concentration of the reaction mixture gave a residue which was redissolved in dichloromethane (5 ml) Addition of silica (0.5 g) was stirring removed the catalyst from the reaction, and filtration and concentration of the organic solution gave the title compound as an off-white solid of 98% d.e. in quantitative yield.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:2].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:3][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: ClCc1cccnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1cccnc1
Temperature: 80 °C
Yield: 23 %

Procedure:
3-(Chloromethyl)pyridine hydrochloride (328 mg, 2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), potassium carbonate (442 mg, 3.2 mmol) and potassium iodide (33 mg, 0.2 mmol) in DMF (25 ml) at ambient temperature and the reaction mixture then heated at 80° C. for 2.5 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was dissolved in a mixture of ethyl acetate (19 ml) and methanol (1 ml) and the insolubles removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (50/45/5). The purified product was dissolved in hot methylene chloride and saturated ethereal hydrogen chloride was added. The mixture was concentrated to half volume by evaporation, the resulting precipitate was collected by filtration and dried under vacuum at 70° C. to give 4(4-chloro-2-fluoroanilino)-6-methoxy-7-((3-pyridyl)methoxy)quinazoline hydrochloride(103 mg, 25%).
Reaction SMILES: CC(C)([O-])C.[K+].BrC1C=C(F)C=CC=1CC(=O)C.C(C(C1C=CC(F)=CC=1Br)C#N)(=O)C.ClC1C=CC=C(F)C=1N=C=S.IC.[C:46]([CH:49]([C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:62]=1[Br:68])[C:50](=S)[NH:51][C:52]1[C:57]([F:58])=[CH:56][CH:55]=[CH:54][C:53]=1[Cl:59])(=O)[CH3:47].O.C(O)(=O)C.[CH3:74][NH:75][NH2:76]>C1COCC1>[Br:68][C:62]1[CH:63]=[C:64]([F:67])[CH:65]=[CH:66][C:61]=1[C:49]1[C:46]([CH3:47])=[N:76][N:75]([CH3:74])[C:50]=1[NH:51][C:52]1[C:57]([F:58])=[CH:56][CH:55]=[CH:54][C:53]=1[Cl:59]
Reactant: CC(=O)C(C(=S)Nc1c(F)cccc1Cl)c1ccc(F)cc1Br
Reactant: CNN
Agent: CC(=O)C(C#N)c1ccc(F)cc1Br
Agent: CC(=O)Cc1ccc(F)cc1Br
Agent: CC(C)(C)[O-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nn(C)c(Nc2c(F)cccc2Cl)c1-c1ccc(F)cc1Br
Reaction time: 1 h

Procedure:
To a solution of potassium tert-butoxide (0.41 g, 3.3 mmol) in THF (20 mL) at 0° C. was added a solution of 1-(2-bromo-4-fluorophenyl)-2-propanone (i.e. the product of Step A) (0.70 g, 3.0 mmol) in THF (10 mL) over 5 minutes. Stirring was continued for 1 h and then the temperature was reduced to −10° C. A solution of 1-chloro-3-fluoro-2-isothiocyanatobenzene (i.e. the product of Step B) (0.57 g, 3.0 mmol) in THF (10 mL) was added over 6 minutes, and stirring was continued for 15 minutes. Iodomethane (0.54 g, 3.8 mmol) was added, and the cooling bath was removed to provide a reaction mixture containing the intermediate compound α-acetyl-2-bromo-N-(2-chloro-6-fluorophenyl)-4-fluorobenzene-ethanethioamide. After 5 min, water (0.2 mL, 11 mmol), glacial acetic acid (0.53 mL, 9.1 mmol) and methylhydrazine (0.81 mL, 15 mmol) were added in rapid succession, and the reaction mixture was heated to reflux for 6 h. The crude reaction mixture was then concentrated under reduced pressure and purified by MPLC (0 to 100% ethyl acetate in hexanes as eluent) to provide the title product, a compound of the present invention, as an off-white solid (0.55 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=O)C.Cl[C:37]1[CH:38]=[C:39]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:62][O:61][CH2:60]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:26][C:9]1[CH:8]=[C:7]([C:37]2[CH:38]=[C:39]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([N:53]4[CH2:58][CH2:57][N:56]([CH:59]5[CH2:62][O:61][CH2:60]5)[CH2:55][CH2:54]4)=[CH:49][N:48]=3)[C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[N:42]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[C:13](=[O:25])[C:14]3[S:20][C:19]4[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=4[C:15]=3[CH2:16][CH2:17]2)[CH:10]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1c2sc3c(c2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4n2)c1CO)CCCC3
Temperature: 110 °C
Yield: 19.7 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 103g (200 mg, 0.44 mmol), 6-chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 108a (155 mg, 0.44 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol), Pd2(dba)3 (28 mg, 0.024 mmol), Cs2CO3 (261 mg, 0.8 mmol), and dioxane (25 mL). After three cycles of vacuum/argon flash, the reaction mixture was heated at 110° C. for 16 h. The mixture was then evaporated in vacuo and the residue was extracted with Ethyl acetate (10 mL×2). The combined Ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 111 (59 mg, 22%). MS: [M+H]+ 681. 1H NMR (500 MHz, DMSO) δ 9.94 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.44-7.46 (m, 3H), 7.34-7.36 (m, 1H), 4.64-4.66 (m, 1H), 4.54-4.57 (m, 2H), 4.42-4.48 (m, 3H), 4.35-4.38 (m, 1H), 3.96-4.10 (m, 1H), 3.79-3.89 (m, 1H), 3.42-3.45 (m, 1H), 3.14-3.16 (m, 4H), 2.54-2.96 (m, 4H), 2.47-2.50 (m, 2H), 2.37-2.41 (m, 4H), 1.79 (t, J=4.0, 4H)
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]=[C:33]1[CH2:38][O:37][C:36]2[CH:39]=[CH:40][C:41]([CH:43]=O)=[N:42][C:35]=2[NH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][C:13](=[O:24])[N:12]2[CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][CH:4]([NH:3][CH2:43][C:41]3[CH:40]=[CH:39][C:36]4[O:37][CH2:38][C:33](=[O:32])[NH:34][C:35]=4[N:42]=3)[CH2:9][CH2:8]2)=[N:17][CH:18]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 71 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (164 mg, 0.440 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was treated with triethylamine (194 μl, 1.40 mmol) and stirred for 0.25 h before addition of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (71 mg, 0.40 mmol). The reaction was stirred for 0.5 h before addition of NaBH(OAc)3 (254 mg, 1.20 mmol). The reaction was stirred for a further 0.5 h before addition of sat. aq NaHCO3 (20 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (144 mg, 71%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23](=[O:26])[NH:24][CH3:25])[CH:20]=[C:19]([Cl:27])[C:18]=1[C:28](Cl)=[O:29]>>[Cl:16][C:17]1[CH:22]=[C:21]([CH:20]=[C:19]([Cl:27])[C:18]=1[C:28]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:29])[C:23]([NH:24][CH3:25])=[O:26]
Reactant: CNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Product: CNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3cnc(NC(=O)C4CC4)cc23)c(Cl)c1

Procedure:
3,5-Dichloro-4-({5-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)-N-methylbenzamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,6-dichloro-4-(methylcarbamoyl)benzene carbonyl chloride (Compound No. 20).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[N:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[N:3][N:4]=1
Reactant: Cc1nnc(Cl)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nnc(CBr)c2ccccc12
Temperature: 90 °C
Yield: 51.3 %

Procedure:
To a solution of 1-chloro-4-methyl-phthalazine (179 mg, 1.00 mmol) and N-bromosuccinimide (187 mg, 1.05 mmol) in CCl4 (4 mL) under argon is added 2,2′-azobisisobutyronitrile (25 mg, 0.15 mmol). The mixture is heated at 90° C. for 2 h. After solvent removal at reduced pressure, the residue is purified on silica gel (25% to 50% ethyl acetate/hexane) to recover 49 mg of 1-chloro-4-methylphthalazine and give 132 mg (51%) of 2 as a light-brown solid, mp 96-98° C. (dec). IR 2861, 1530, 1392, 1285 cm−1; 1H NMR (CDCl3) 5.10 (s, 2H, CH2), 8.01-8.14 (m, 2H, 6,7-PhthH), 8.29 (m, 1H, 5-PhthH), 8.41 (m, 1H, 8-PhthH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].I[CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1>>[O:23]=[C:21]1[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19][C@@H:18]([CH2:17][NH:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:15])[O:22]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CI)OC3=O)cc2N1
Reactant: NCCn1c(=O)[nH]c2ccccc2c1=O
Product: O=C1CSc2ccc(N3C[C@@H](CNCCn4c(=O)[nH]c5ccccc5c4=O)OC3=O)cc2N1
Yield: 19 %

Procedure:
Starting from 3-(2-aminoethyl)-2,4(1H,3H)-quinazolinedione (prepared according to J. Med. Chem. (1992), 35(26), 4903-10) and 6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one (prepared according to WO 2008/126034) and using Procedure F, the title compound was obtained as a yellow solid (23 mg; 19% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:50][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:11]=[C:10]([CH:9]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:50])[CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1cccc(C=Cc2ccnc(Br)c2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Yield: 83 %

Procedure:
2-Bromo-4-[2-(3-trifluoromethyl-phenyl)-vinyl]-pyridine (289 mg, 0.88 mmol), tris(dibenzylideneacetone)dipalladium(0) (160 mg, 0.18 mmol) and 2-(dicyclohexylphosphino)biphenyl (160 mg, 0.46 mmol) are mixed in dry THF (6 mL). Then Argon is bubbled through the solution for 5 min and 1.0 M LiHMDS (3.1 mL, 3.1 mmol) is added. Then the reaction mixture is heated at 65° C. for 16 hrs before the saturated NH4Cl aqueous solution (20 mL) is added along with water (30 mL). The mixture is extracted with EtOAc (3×35 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 193 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:15]=[C:14]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[CH:19]=[N:18][N:17]=3)[S:13][CH:12]=2)=[O:9])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:21]1([N:20]2[CH:19]=[N:18][N:17]=[C:16]2[C:14]2[S:13][CH:12]=[C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH:15]=2)[CH2:23][CH2:22]1
Reactant: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A suspension of 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide (55 mg, 0.14 mmol), 3-pyridine boronic acid (17 mg, 0.14 mmol), dppf(Pd)Cl2 (5.2 mg, 0.0071 mmol), potassium carbonate (49 mg, 0.35 mmol) in degassed toluene (0.70 mL), degassed water (0.35 mL) and degassed ethanol (0.35 mL) was heated at 90° C. for 3 hours. The aqueous layer was separated, the organic layer was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide as a white powder (11 mg, 20% yield). N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)-3,4′-bipyridine-2′-carboxamide; C20H16N6OS. 389.2 (M+1). 1H NMR (DMSO) δ 11.45 (s, 1H), 9.11 (d, J=2 Hz, 1H), 8.85 (d, J=5 Hz, 1H), 8.70-8.74 (m, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.31-8.36 (m, 2H), 8.10 (dd, J=2, 5 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J=5, 8 Hz, 1H), 3.56-3.59 (m, 1H), 1.11-1.27 (m, 4H).