Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].N.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(=CC)C=C.[CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([CH:35]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20].[Cl-].[NH4+]>O1CCCC1>[C:30]([O:29][C:28]([NH:27][CH2:26][C:25]1[CH:35]=[C:21]([CH:19]([OH:20])[C:4]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:6][CH2:7][O:3]2)[CH:22]=[CH:23][C:24]=1[O:36][CH3:37])=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1ccco1
Reactant: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Agent: C=CC(C)=CC
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)C=CCO1
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
0.057 g of lithium was added to 120 ml of liquid ammonia and 30 ml of tetrahydrofuran at −78° C. under an atmosphere of nitrogen gas. After stirring for 15 minutes, a solution of 0.462 g of ethyl furan-2-carboxylate in 20 ml tetrahydrofuran was added dropwise. After stirring for 30 minutes, 3-methyl-1,3-pentadiene was added drop by drop until the deep blue color faded. A solution of 0.397 g of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate in 15 ml of tetrahydrofuran was added dropwise to the yellow reaction mixture. After stirring at −78° C. for 2 hours, 30 ml of saturated aqueous ammonium chloride was added, and ammonia was evaporated under a flow of nitrogen gas. 200 ml of ethyl acetate and 100 ml of water were added, and the organic layer washed with 100 ml of brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 0.407 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.F[B-](F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C.O>[CH3:30][O:29][N:20]([CH3:24])[C:12](=[O:14])[CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(/C=C/CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/CC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
To the mixture of carboxylic acid (557) (5.7 g, 29.5 mmol) in DMF (150 mL) was added O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (9.5 g, 29.5 mol). After stifling for 5 minutes, N,O-dimethylhydroxylamine. HCl (2.9 g, 29.5 mmol) was added, followed by Et3N (8.2 mL, 58.9 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40% EtOAc in hexanes) to provide (E)-N-methoxy-4-(4-methoxyphenyl)-N-methylbut-3-enamide (558) (2.1 g, 29.6%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:22]([OH:37])[CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:20][C@@H:21]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:22]([OH:37])[CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:19])[C:13]([CH3:14])([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Yield: 25.9 %

Procedure:
In a manner analogous to that described in Example 6, 68 mg (0.26 mmol) of N-benzyloxycarbonyl-3-methyl-L-valine were coupled with 90 mg (0.26 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide to give 40 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-3-methyl-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 90° C. (decomposition); MS m/e 594 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.Cl.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=1)[C:22]([NH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]2)=[CH:27][CH:26]=1)=[O:23].C(N(CC)CC)C>CN(C=O)C.O.FC(F)(F)C(O)=O>[CH3:35][N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([NH:24][C:22]([C:21]3[CH:20]=[C:19]([CH:38]=[CH:37][CH:36]=3)[CH2:18][NH:17][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[CH:14][CH:13]=3)=[O:23])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-n5cncn5)cc4)c3)cc2C1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Dissolve 4-[1,2,4]triazol-1-yl-benzoic acid (29 mg, 0.15 mmol) and CDI (N,N′-carbonyldiimidazole) (25 mg, 0.15 mmol) in DMF (2 mL) and stir the mixture for 1 h. To this add 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (50 mg, 0.14 mmol) and triethylamine (0.095 mL, 0.68 mmol) and stir the mixture overnight. Dilute the mixture with water (1 mL) and trifluoroacetic acid (0.2 mL) and purify by prep-HPLC (5%-70%, CH3CN/H2O) to give the desired product 4-[1,2,4]triazol-1-yl-benzoic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (51 mg, 0.086 mmol). MS, electrospray 467.4 (M+H), rt 1.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 1-(2-amino-5-bromophenyl)ethanone (200 mg, 0.93 mmol) in CH2Cl2 (5 mL) was added N-chlorosuccinimide (125 mg, 0.93 mmol). The mixture was stirred at room temperature overnight. Analysis indicated that the reaction was incomplete; therefore, additional N-chlorosuccinimide (125 mg, 0.93 mmol) was added and the mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by CombiFlash (40 g column, 0-10% EtOAc/heptane) to afford 1-(2-amino-5-bromo-3-chlorophenyl)ethanone (206 mg, 89%).
Reaction SMILES: C[O:2]/[CH:3]=[C:4]1\[CH2:5][CH2:6][O:7][C:8]2[C:13]\1=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2.BrB(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH:3]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[O:2]
Reactant: CO/C=C1\CCOc2cc(C#N)ccc21
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)OCCC2C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(4E)-4-(methoxymethylidene)-3,4-dihydro-2H-chromene-7-carbonitrile (230 mg, 1.1 mmol) was dissolved in dichloromethane (6 mL). The solution was cooled to −78° C. To above solution was added tribromoborane (1.7 mL, 1 M, 1.7 mmol) dropwise over a course of 5 min and subsequently stirred for 30 min at −78° C. To the reaction mixture was added saturated sodium bicarbonate, extracted with dichloromethane (2×20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated. The crude product was used without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.0-7.4 (3H, aromatic), 6.58 (1H, s), 4.55 (2H, m), 2.98 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][OH:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:21])([CH2:22][CH2:23][O:24][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCOc1ccc([N+](=O)[O-])cc1)O2

Procedure:
2-(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-yl)ethanol (prepared as described in Preparation 39) was reacted with p-chloronitrobenzene and the reaction mixture was treated and purified as described in Preparation 2, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)sc2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 33b, 1.3 g, 3.08 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.61 g, 15.4 mmol) in water (3 ml) was added to it at 25° C. The reaction mixture was then heated at about 75° C. under stirring for 3 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10% HCl to bring pH to between 5 and 6. The mixture so obtained was extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.10 g, 90.9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)CCl>[Cl:9][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccccn1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCCl
Product: CC(Cl)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of 107.16 g (1 mole) of 2-ethyl-pyridine in 400 ml of ethylene chloride was heated at reflux while adding in portions 150 g (0.65 mole) of trichloroisocyanuric acid (min. 90% available chlorine) over 5 hours and the mixture was stirred for another 2 hours and then cooled and vacuum filtered. The filtrate was washed with 50 ml of 5% of potassium hydroxide, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].[I-:16].[K+]>Cl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[I:16]
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1I

Procedure:
2-chloro-6-nitroaniline (143-1; 1.0 g, 0.0058 mol) was dissolved in hydrochloric acid (10 mL) and cooled in an ice bath. Then a solution of sodium nitrite (0.68 g, 0.0098 mol) in water (10 mL) was added very slowly with stirring. After 15 min the reaction mixture was filtered through glass wool in to a solution of potassium iodide (4.1 g, 0.024 mol) in water (10 mL). The resulting orange mixture was stirred at room temperature overnight. Then it was extracted with ethyl acetate and washed with 10% aqueous sodium hydroxide solution (50 mL) solution. Organic layer was washed with saturated aqueous sodium chloride solution and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.854-7.835 (d, J=7.6 Hz, 1H), 7.788-7.768 (d, J=8 Hz, 1H), 7.624-7.584 (t, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:7]([CH3:19])=[CH:6][C:5]=1[O:20][CH3:21].FC(F)(F)S(O[C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:34]([C:44](=[O:47])[NH:45][CH3:46])[C:33]=2[CH:48]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([C:8]4[C:7]([CH3:19])=[CH:6][C:5]([O:20][CH3:21])=[C:4]([CH:9]=4)[C:3]([O:2][CH3:1])=[O:22])=[CH:48][C:33]=3[C:34]=2[C:44](=[O:47])[NH:45][CH3:46])=[CH:42][CH:41]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Methyl-2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.2 g, 3.92 mmol, 1 eq), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.6 g, 3.92 mmol, 1 eq), Cesium carbonate (3.8 g, 11.7 mmol, 3 eq) and Tetrakis triphenylphosphinepalladium (0.13 g, 0.11 mmol, 0.03 eq) were dissolved in 1,4-dioxane/water and the above solution was stirred at 90° C. for 10 h. Then the reaction mixture was diluted with water and product was extracted with ethyl acetate and purified by combiflash chromatography using 40% ethyl acetate/hexane as eluent. Yield: 0.95 g (55%). 1HNMR (400 MHz, DMSO-d6): δ 2.3 (s, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 7.15 (s, 1H), 7.51 (s, 1H), 7.64 (m, 2H), 7.65 (m, 2H), 7.74 (d, 1H, J=8.48 Hz), 8.00-8.01 (m, 2H), 8.48 (d, 1H). LCMS: (ES+) m/z=448 (M+H).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].Cl[CH2:19][CH2:20][C:21]12[CH2:28][CH2:27][CH2:26][N:25]1[CH2:24][CH2:23][CH2:22]2.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[N:25]12[CH2:26][CH2:27][CH2:28][C:21]1([CH2:20][CH2:19][NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[Cl:10])[CH2:22][CH2:23][CH2:24]2
Reactant: ClCCC12CCCN1CCC2
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Clc1ccccc1NCCC12CCCN1CCC2
Yield: 40.1 %

Procedure:
To nitrobenzene (30.0 ml), 2-chloroaniline (600 mg, 4.70 mmol), 5-(2-chloroethyl)-1-azabicyclo[3.3.0]octane (hydrochloride, 1.98 g, 9.42 mmol) and anhydrous potassium carbonate (3.90 g, 28.2 mmol) were added to react same for 10 hours at 120° C. subsequent to addition of 10% aqueous sodium hydroxide solution, the reaction mixture was extracted by ethyl acetate, washed by sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to afford the desired compound (499 mg, 40.1%), as a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21](CC2C=CC(OC)=CC=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>C(O)(C(F)(F)F)=O>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(C)c4)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnc3c(Nc4ccccc4)cc(N[C@H]4CC[C@H](N)CC4)nn23)ccn1
Temperature: 70 °C

Procedure:
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.201 mmol) and (trans)-cyclohexane-1,4-diamine (9459 mg, 4.016 mmol) were heated at 160° C. for 1 hour. The reaction mixture was dissolved in TFA (5 mL) and heated at 70° C. for 2 hours. The reaction mixture was concentrated, dissolved in methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-aminocyclohexyl)amino)-8-anilino-N-(2-methyl-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (39 mg, 48.5% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.320 minutes, [M+H]=457.28. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35-11.58 (1H, m), 9.33 (1H, s), 8.48-8.74 (1H, m), 8.14 (1H, s), 7.93-8.04 (1H, m), 7.87 (3H, d, J=4.28 Hz), 7.59-7.81 (1H, m), 7.31-7.52 (3H, m), 7.07-7.26 (1H, m), 6.87-7.06 (1H, m), 6.29 (1H, s), 3.53-3.77 (1H, m), 2.93-3.22 (1H, m), 2.65 (3H, s), 2.05-2.25 (2H, m), 1.87-2.09 (2H, m), 1.09-1.52 (4H, m).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.CCCCCC.C(OCC)(=O)C.[C:33]([NH:40][C@H:41]([C@H:49]1[O:53][C:52](=[O:54])[CH2:51][CH2:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[C:33]([NH:40][C@H:41]([C@H:49]1[O:53][C:52](=[O:54])[C@H:51]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1

Procedure:
In analogy with Example 1b), 1.5 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one, dissolved in 32 ml of THF, are deprotonated with 9.8 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated with 1.0 g of 4-bromomethylbenzonitrile (Fluka; Buchs/Switzerland) dissolved in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 1:1) affords the pure title compound: TLC Rf (D)=0.33.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OOC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH3:21])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: Clc1ccccc1
Product: CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 51.5 %

Procedure:
A solution of 20.0 grams (72 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 10.5 grams (72 mmol) of di-tert-butyl peroxide, and 30 ml of chlorobenzene is heated for six hours in a Fischer-Porter pressure bottle (nitrogen atmosphere, bath temperature 145-150° C.). The crude reaction product is purified by flash chromatography (silica gel; 50:1 heptane:ethyl acetate) and then recrystallized from methanol to afford 10.8 grams (51% yield) of the title compound as a white solid melting at 67-68° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3].[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([N:5]([CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)NC1CCCOc2ccccc21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C1CCCOc2ccccc21)S(C)(=O)=O

Procedure:
1.0 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine (Example 8a) were reacted with sodium hydride and iodobutane in DMF analogously to Example 11. After recrystallization of the crude product (1.0 g) from isopropanol, 0.4 g of 5-(N-butyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 78-79° C.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:31]C1C2C(=CC(B3OC(C)(C)C(C)(C)C3)=CC=2)N=C(C2C=CC=CC=2)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([C:19]([CH3:31])=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(-c2ccccc2)nc2cc(B3CC(C)(C)C(C)(C)O3)ccc12
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ncnc(N)c34)ccc12

Procedure:
7-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described for 7-cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline and 2 equivalents of cesium carbonate was used in place of 3 equivalents of sodium carbonate; 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 1H), 2.17 (m, 1H); 2.47-2.52 (m, 2H); 2.67-2.72 (m, 2H); 2.82 (d, J=0.8 Hz, 3H); 4.14-4.25 (m, 1H); 5.78 (brs, 2H); 7.46-7.56 (m, 3H); 7.77 (d, J=0.8 Hz, 1H); 7.92 (s, 1H); 7.98 (dd, J=8.6, 1.8 Hz, 1H); 8.15-8.18 (m, 3H); 8.39 (d, J=1.6 Hz, 1H); MS (ES+): m/z 407.03 (100) [MH+], HPLC: tR=3.54 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C1(C)C=CC=CC=1.CCOCC>[C:2]([O:6][C:7](=[O:11])[C@@H:8]([N:9]1[C:24](=[O:25])[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:26])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A suspension of (2S) alanine tert-butyl ester hydrochloride (2.05 g, 11.2 mmol), diisopropylethylamine (1.83 mL, 10.6 mmol) and phthalic anhydride (1.48 g, 10 mmol) in toluene (10 mL) was refluxed for 3 hours under Dean-Stark conditions. The reaction was cooled to room temperature, diluted with Et2O, washed with 1N HCl and then with aq. sat. NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to afford the sub-title compound as a white powder (2.465 g, 90%): 1H NMR (400 MHz CDCl3) δ 1.45 (9H, s), 1.68 (3H, d), 4.90 (1H, q), 7.75 (2H, d), 7.88 (2H, d).