Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:29]([C:39](=O)[CH:40]([CH3:42])[CH3:41])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:23][CH:22]=1.O1CCCC1.[Cl-].[NH4+]>CCCCCCC.C1(C)C=CC=CC=1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:12][C:13](=[O:14])[O:15]3)[C:39]([CH:40]([CH3:42])[CH3:41])=[C:29]([C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[C:28]=2[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:25][CH:26]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
A solution of 0.79 g (2.89 mmol) of (±)-cis-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate and 1.00 g (2.41 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of ~R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 15 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled and poured into 100 mL of tetrahydrofuran and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with brine. To the organic layer is added 5 mL of 10% hydrochloric acid solution and the solution is stirred for 15 hours. To this solution is added 1.2 g of sodium hydroxide and the mixture is stirred for 30 hours. The reaction is stopped by adding 50 mL of water, 30 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 50 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 10 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][O:18][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CO)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: O=C(COC(=O)c1ccccc1)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
150 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide was dissolved in 0.5 ml of pyridine, and 150 mg of benzoyl chloride was added dropwise to the solution under ice cooling. After the addition, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off and water was added. The mixture was alkalized with aqueous ammonia, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by TLC (developing solvent: chloroform/methanol=19/l) to afford 165 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]benzoyloxyacetamide.
Reaction SMILES: [OH:1][C:2]([CH3:50])([CH3:49])[C:3]#[C:4][C:5]1[N:6]=[C:7]([N:20](C(OC(C)(C)C)=O)[CH2:21][C@@H:22]([NH:34]C(=O)OC(C)(C)C)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N:15][CH:14]=[CH:13]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1)[CH2:21][NH:20][C:7]1[S:8][C:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)=[C:5]([C:4]#[C:3][C:2]([CH3:49])([OH:1])[CH3:50])[N:6]=1
Reactant: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C#Cc1nc(NC[C@@H](N)Cc2ccc(C(F)(F)F)cc2)sc1-c1ccc2cnccc2c1
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
(S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)-5-(isoquinolin-6-yl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.010 g, 0.01 mmol) was taken up in 1 mL of DCM and TFA (0.2 mL) was added. After 1.5 hours, the solvent was removed under reduced pressure. The residue was loaded onto a Varian Mega Bond ELUT SCX column in MeOH, and eluted with 1M NH3 in MeOH to provide the free base. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (pipette column, 2.5% to 10% MeOH/DCM) to afford 4-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(isoquinolin-6-yl)thiazol-4-yl)-2-methylbut-3-yn-2-ol (0.002 g, 28% yield) as a yellow oil: LCMS (M+H) 511 calc. for C27H26F3N4OS 510.6. 1H NMR (400 MHz, CD3OD) δ ppm 9.17 (s, 1H) 8.41 (d, J=5.87 Hz, 1H) 8.28 (s, 1H) 8.07-8.13 (m, 2H) 7.79 (d, J=5.87 Hz, 1H) 7.62 (d, J=8.02 Hz, 2H) 7.47 (d, J=8.02 Hz, 2H), 3.47-3.25 (m, 3H) 2.95 (d, J=4.89 Hz, 1H) 2.73 (dd, J=13.40, 7.34 Hz, 1H) 1.60 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][CH2:30][C:27]4[CH:28]=[CH:29][N:24]5[CH:23]=[CH:22][N:21]=[C:25]5[CH:26]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: NCc1ccn2ccnc2c1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3ccn4ccnc4c3)c2C1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (250 mg, 0.82 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (270 mg, 1.83 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was subjected to microwave irradiation at 185° C. for 4 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:12])[CH:6]2[CH3:13].[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:14][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]1=[S:12]
Reactant: COc1ccc2c(c1)C(C)C(=S)N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-methoxy-3-methylthiooxindole (420 mg, 2 mmol) and N-chlorosuccinimide (270 mg, 2 mmol) in carbon tetrachloride (74 ml) was stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was evaporated to dryness, yielding crude 3-chloro-5-methoxy-3-methylthiooxindole. The residue was dissolved in tetrahydrofuran (10 ml) and added to a vigorously stirred slurry of red mercuric oxide (435 mg, 2 mmol) and boron trifluoride etherate (290 mg, 2 mmol) in aqueous 20 percent tetrahydrofuran (40 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and the filtrate was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give 5-methoxyisatin (287 mg, 81%), mp 202°-204° (recrystallized from benzene).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH:22]([CH3:24])[CH3:23])[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH3:27])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29]>>[OH:1][CH:3]([CH2:4][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH:22]([CH3:23])[CH3:24])[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:26][CH3:27])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C(C)C)c(=O)c2c1
Reactant: CC(C)(C)N
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)(C)C)cc3)n(C(C)C)c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-isopropyl-6-methoxy-3,4-dihydro-quinazolin-4-one and tert. butylamine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5](=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)=[CH2:7].[H][H]>CO.[C].[Pd]>[F:1][C:2]([F:19])([F:20])[CH2:3][O:4][C:5](=[O:18])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=1)[CH3:7]
Reactant: C=C(C(=O)OCC(F)(F)F)c1ccc(CC(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)OCC(F)(F)F)cc1
Yield: 86.1 %

Procedure:
To a mixture of 2.86 g of 2-(p-isobutylphenyl)acrylic acid-2,2,2-trifluoroethyl ester in 50 ml of methanol was added 0.25 g of palladium-carbon(10%). Hydrogenation was carried out at ordinary temperature and pressure and stopped when a theoretical amount of hydrogen was absorbed. The palladium-carbon was filtered off to give a filtrate. The filtrate was then concentrated in vacuo to yield 2.48 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester. Mass spectrum: parent ion 288 m/e.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:21]CC(C)(C)N=1.[BH4-].[Na+]>>[F:1][C:2]([F:27])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[O:21]
Reactant: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1
Agent: [BH4-]
Agent: [Na+]
Product: O=Cc1ccccc1CCCCCCCCCCCC(F)(F)F

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:34])[N:14]([CH3:33])[C:15]([CH:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Li+].[CH3:36]C([N-]C(C)C)C.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C[Si](C=[N+]=[N-])(C)C>O1CCCC1.CO.C(OCC)C>[C:29]([O:28][CH:24]([C:15]1[N:14]([CH3:33])[C:13](=[O:34])[C:12]2[NH:8][CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[C:25]([O:27][CH3:36])=[O:26])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccccc2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
An ice cold mixture of 2-(1-benzyl-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (64.0 mg, 0.140 mmol) in Tetrahydrofuran (THF) (2.0 mL) was treated with dropwise addition of LDA, 2M solution in heptane/THF/ethylbenzene (0.140 mL, 0.279 mmol) and then allowed to stir at 0° C. for 45 minutes. Additional LDA (70 uL) was added and then stirred an additional 10 minutes. The mixture was quenched by adding 1N HCl and acidified to pH 2. The mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude debenzylation product as an orange residue. An ice cold mixture of the crude debenzylation product in methanol (1.0 mL) and diethyl ether (1.0 mL) was treated with trimethylsilyl diazomethane, 2M solution in hexanes (0.140 mL, 0.279 mmol) and then stirred at ambient temperature for 10 minutes. Additional trimethylsilyl diazomethane, 2M solution in hexanes (0.140 mL, 0.279 mmol) was added, the mixture was stirred for 5 minutes, cooled to 0° C. and then quenched with AcOH. The mixture was concentrated and then purified on silica gel (0-10% DCM/MeOH) to give the slightly impure desired product as a yellow residue (39 mg, 73% yield) which was used in the subsequent step without further purification. LC/MS (m/z) ES+=383 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:1][CH2:2][CH2:3][CH:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CC(C)=CC(O)CCN
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCC(O)C=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
(±)-1-Amino-5-methyl-hex-4-en-3-ol (28.5 g, 219 mmol) and diisopropyl ethylamine (45.9 mL, 263 mmol) were dissolved in dichloromethane (400 mL) and cooled on an ice bath. Methyl chloroformate (17 mL, 219 mmol) in dichloromethane (20 mL) was added slowly. The mixture was stirred for 2 h. at 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added and the phases separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were dried, filtered and evaporated to give (±)-(3-hydroxy-5-methyl-hex-4-enyl)carbamic acid methyl ester (38.9 g, 100%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A solution of 4-(4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g, 0.510 mmol) in 1,2-dichloroethane (5.00 mL) was treated with sodium triacetoxyborohydride (0.424 g, 2.00 mmol) and HOAC (0.0300 mL, 0.500 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution (10 mL) and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo and purified by preparative TLC plates using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (53.0 mg, 23.0%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.19 (m, 7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:9][C:8]2[CH:7]=[N:6][N:5](C(=O)C)[C:4]=2[CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:1][C:2]1[S:9][C:8]2[CH:7]=[N:6][NH:5][C:4]=2[CH:3]=1
Reactant: CC(=O)n1ncc2sc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1cc2[nH]ncc2s1
Temperature: 95 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
A mixture of 1-(5-bromo-thieno[3,2-c]pyrazol-1-yl)-ethanone [12.0 g, 49.0 mmol Intermediate (51)], 1,4-dioxane (120 mL), and 2 M aqueous potassium carbonate (80.0 mL) was stirred at 95° C. under nitrogen. After 20 hours, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (200 mL). The mixture was washed twice with water (100 mL) and brine (100 mL) successively, dried over magnesium sulfate, and concentrated in vacuo. The product was dried under vacuum to give 5-bromo-1H-thieno[3,2-c]pyrazole [9.48 g, 95%, Intermediate (52)] as an off-white solid. TLC Rf 0.26 (silica, 1:1 ethyl acetate/heptane); LC/MS: 202.93 (M+H), RT=2.79 minutes; 1H NMR (300 Mhz, CDCl3) δ 10.8 (br s, 1H), 7.70 (s, 1H), 7.12 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-methoxypyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.125 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.17 min (Method A); M+H=401 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.39-8.26 (m, 2H), 8.21-8.07 (m, 2H), 8.04-7.96 (m, 1H), 7.66-7.56 (m, 1H), 7.45-7.36 (m, 1H), 3.91 (s, 6H), 3.60 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([NH:32][NH:33][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:20])=[O:31]
Reactant: NNC(=O)CCl
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Reaction time: 3.5 h
Yield: 30.2 %

Procedure:
To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (1.0 g, 3.48 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.6 ml, 6.96 mmol) and the reaction stirred for 3.5 h. The solvent was evaporated under reduced pressure and the resulting residue redissolved in dichloromethane (20 ml). To the solution was added chloroacetic acid hydrazide (1.3 g, 8.97 mmol) and triethylamine (2.9 ml, 20.9 mmol) and the reaction mixture stirred for 4 h and then left to stand overnight. The solvent was evaporated under reduced pressure and the resulting residue purified by flash column chromatography eluting with 50-100% (v/v) ethyl acetate in heptane to give 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (397 mg, 1.05 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[CH3:15]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:15])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 6-chloro-4-phenyl-pyridazin-3-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (52%). MS (ESI+): m/z=220.064 ([M+H]+).
Reaction SMILES: N12CCCN=C1CCCCC2.[NH:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([C:23]([CH2:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)=[CH:24][N:25]=3)[N:22]=2)[CH:14]=[N:13]1.[C:37]([CH:39]=[C:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)#[N:38]>C(#N)C>[C:37]([CH2:39][C:40]1([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([C:23]([CH2:26][C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)=[CH:24][N:25]=4)[N:22]=3)[CH:14]=[N:13]2)[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]1)#[N:38]
Reactant: c1cnc2ccc(Cc3cnc4ncc(-c5cn[nH]c5)nn34)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (68 μL, 0.46 mmol) was added to a mixture of 6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline (50.0 mg, 0.153 mmol) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (0.068 g, 0.30 mmol) in acetonitrile (1 mL). The reaction was stirred at 60° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-70%) to give the desired product (30 mg, 35.7%). LCMS: (M+H)=550.5.
Reaction SMILES: [CH3:1][C:2]1([C:13]([NH:15][C@H:16]([C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([C:13]([NH:15][C@H:16]([C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)C1(C)CC(c2ccccc2)=NO1)C(=O)COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)N[C@@H](CC(=O)O)C(=O)COc2ccccc2)CC(c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
The compound prepared in Example 3 (530 mg, 1.136 mmol) was dissolved in dichloromethane (6 ml), and trifluoroacetic acid (3 ml) was added at 0□. The mixture was stirred for two hours while it was slowly warmed to room temperature, and concentrated under reduced pressure to give the title compound (Ibb) (465 mg) with a stoichiometric yield.