Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([O:27][CH3:28])[C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C:38](=[NH:51])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[C:38](=[N:51][C:13]1[C:12]([O:27][CH3:28])=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([CH:29]([CH3:30])[CH3:31])[O:10]2)=[CH:15][CH:14]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1c(OS(=O)(=O)C(F)(F)F)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1c(N=C(c2ccccc2)c2ccccc2)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Temperature: 130 °C

Procedure:
A stirred mixture of trifluoromethanesulfonic acid 3-(4-chlorophenyl)-2-isopropyl-8-methoxy-4-oxo-4H-chromen-7-yl ester (2.41 g, 5.05 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (5.6 g, 10.1 mmol, 2 eq.), tris(dibenzylideneacetone)dipalladium (0) (3.08 g, 3.36 mmol, 0.665 eq.), sodium t-butoxide (0.58 g, 6.06 mmol, 1.2 eq.) and benzophenone-imine (1.1 g, 1.02 ml, 6.06 mmol, 1.2 eq.) in toluene (160 ml) is heated under reflux at 130° C. for 45 min. The reaction mixture is allowed to cool to room temperature and filtered through a pad of Celite filter aid. The Celite is washed with methylene chloride, and the filtrate is evaporated to dryness in vacuo to afford 7-(benzhydrylideneamino)-3-(4-chlorophenyl)-2-isopropyl-8-methoxy-chromen-4-one as a red oil. A stirred solution of the red oil in tetrahydrofuran (80 ml) is treated with 2M HCl solution (80 ml). After 30 min, the reaction mixture is basified with 17% ammonia solution and washed with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo to afford a dark residue. This is purified by flash chromatography (cyclohexane/ethyl acetate=9:1) to afford the title compound.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.[CH3:21]/C(/C(C)=O)=N\O.C1(C)C=CC=C(C=O)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[O:6][C:7]=1[CH3:8]
Reactant: CC(=O)/C(C)=N/O
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: Cc1cccc(C=O)c1
Product: Cc1cccc(-c2nc(CI)c(C)o2)c1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and m-tolualdehyde gave 4-iodomethyl-5-methyl-2-m-tolyloxazole.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH2:31]([Si:38](Cl)([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:46]([Si:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Reactant: Cl[Si](Cc1ccccc1)(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CC[C@H](O[Si](Cc3ccccc3)(Cc3ccccc3)Cc3ccccc3)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 15.7 g of 3β,7β-dihydroxy-15β,16β-methylene-5-androsten-17-one in 750 ml of methylene chloride is combined with 9 ml of triethylamine and 200 mg of dimethylaminopyridine and cooled to -20° C. Within 30 minutes, 19.4 g of tribenzylsilyl chloride in 10 ml of methylene chloride is added dropwise thereto. The reaction mixture is stirred for one hour at -20° C. and one hour at 0° C., diluted with methylene chloride, and washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution, and water. After drying over sodium sulfate, the mixture is concentrated under vacuum. Chromatography on silica gel with hexane-acetone yields 27.5 g of 3β-tribenzylsilyloxy-7β-hydroxy-15β,16β-methylene-5-androsten-17-one.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20]I.[H-].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:20][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Yield: 97.1 %

Procedure:
To a solution of N-Cbz-leucine (1.38 g, 5.2 mmol) in THF (15 mL) at 0° C. was added methyl iodide (2.5 mL, 40.1 mmol). Sodium hydride (60% dispersion in oil, 0.6 g, 15 mmol) was added cautiously, and the resultant mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (25 mL) and water (2 mL) was added dropwise. The mixture was concentrated to dryness, and the residue was partitioned between ether (15 mL) and water (50 mL). The organic layer was extracted with saturated aqueous NaHCO3 (25 mL), and the combined aqueous extracts were acidified to pH 2 with 3N HCl. The product was extracted with EtOAc (3×25 mL), dried over MgSO4, filtered, and concentrated to afford the title compound (1.41 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>O.CN(C=O)C>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNCCNc1ccc([N+](=O)[O-])cn1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a suspension of resin-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and DMF (30 mL) at 23° C. was added H2O (2 drops), K2CO3 (2.9 g, 21 mmol) and PhSH (2.2 mL, 21 mmol). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound dimethyl [2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)ethyl]amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][N:12]=2)[CH:7]=[CH:8][C:9]=1Br)([O-:3])=[O:2].BrC1C=CC([C:29]#[N:30])=CC=1.[N+](C1C=C(C=CC=1Br)C#N)([O-])=O>CN1CCCN(C)C1=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[C:29]#[N:30])([O-:3])=[O:2]
Reactant: CCCCCCCc1cnc(-c2ccc(Br)c([N+](=O)[O-])c2)nc1
Reactant: N#Cc1ccc(Br)cc1
Agent: N#Cc1ccc(Br)c([N+](=O)[O-])c1
Solvent: CN1CCCN(C)C1=O
Product: CCCCCCCc1cnc(-c2ccc(C#N)c([N+](=O)[O-])c2)nc1

Procedure:
A mixture of 37.8 g of 2-(3-nitro-4-bromophenyl)-5-n-heptylpyrimidine (obtainable by nitration of 4-bromobenzonitrile, converting the 3-nitro-4-bromobenzonitrile into the corresponding amidine hydrochloride and heating the latter together with n-heptylmalondialdehydtetramethylacetale), 18 g of Cu-(I)-cyanide and 100 ml of 1,3-dimethyltetrahydro-2(1H)pyrimidinon (DMPU) is heated at 150° for 3 hours. After cooling the mixture is filtered, the filtrate and the residue are extracted with methylene chloride and the organic phase is evaporated. 2-(3-Nitro-4-cyanophenyl)-5-n-heptylpyrimidine (F. 73°) is obtained by purification by chromatography. The obtained material is heated together with 33.4 g of CsF in 120 ml of DMPU at 110° for 4 hours. After cooling the mixture is poured onto 600 ml of ice water. After extraction with methylene chloride and purification by chromatography 2-(3-fluoro-4-cyanophenyl)-5-n-heptylpyrimidine (m.p. 43°, clp. 0°, Δε=-37) is obtained
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)O1.Br[C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O.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].C(Cl)Cl>[CH3:18][CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:10][C:11]=1[C:19]([F:20])([F:21])[F:22])[CH3:17]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nccs2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 52.4 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane (D42) (160 mg), 2-bromo-1,3-thiazole (119 mg) and cesium carbonate (237 mg) in acetonitrile (15 mL) and water (3.75 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (39.6 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 1 h. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (150 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D66) (73 mg). MS (ES): C13H12F3NOS requires 287. found 288.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br>ClCCl>[Br:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: ClCCl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 9-phenylanthracene (10 grams) and ferric chloride (0.065 gram) in 100 milliliters of dichloromethane were added 6.70 grams of bromine in 30 milliliters of dichloromethane through an addition funnel at room temperature. The reaction mixture was stirred for 3 hours, and then washed with aqueous sodium thiosulfate and water. After removal of the solvents, the crude residue was recrystallized from ethanol to yield 12.5 grams of 10-bromo-9-phenylanthracene. The structure of this compound was confirmed by proton NMR analysis.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(O)c(F)c5)nn34)ccnc2c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(OCCN6CCOCC6)c(F)c5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-hydroxyethyl)morpholine (0.0964 ml, 0.788 mmol), triphenylphosphine (0.238 g, 0.909 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenol (0.253 g, 0.606 mmol)(prepared according to General Method A) in THF (10 mL) was added DEAD (0.144 ml, 0.909 mmol). Stirred at room temperature for 1 h. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=531.2 [M+1]+. Calc'd for C28H27FN6O4: 530.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[CH3:34][NH:35][CH3:36].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:35]([CH3:36])[CH3:34])=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 50, a tetrahydrofuran solution (2.0M, 0.21 ml, 0.42 mmol) of dimethylamine, 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) at room temperature, followed by stirring at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (35 mg, 0.066 mmol, 90%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc3ncccc3c2)c(S(C)(=O)=O)c1

Procedure:
2 mmol of methyl 4-chloro-3-methylsulfonylbenzoate, 2 mmol of 6-hydroxyquinoline and 6 mmol of K2CO3 were stirred at 130° C. for 2 h in 20 ml of DMF (anhydrous). The mixture was then poured into 100 ml of saturated aqueous NaHCO3 solution and extracted 3 times with 100 ml of EA. The extract was dried over Na2SO4, the solvent was removed in vacuo and the product was reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][N:21]2[CH:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:15]([CH2:33][CH3:34])=[N:14]1.[H-].[Na+].[CH3:37]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][N:21]2[CH:30]([CH2:31][O:32][CH3:37])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:15]([CH2:33][CH3:34])=[N:14]1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CN1Cc2ccccc2CC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CN1Cc2ccccc2CC1COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 200 mg (0.39 mmol) of the compound of step A in 5 mL of THF was treated with 10 mg (0.42 mmol) of sodium hydride and stirred for 30 minutes at room temperature. Then 0.1 mL (1.6 mmol) of methyl iodide was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water and the product was extracted into ethyl acetate which was dried and evaporated. The crude product was flash chromatographed on silica gel to give the desired product in 26% yield as a colorless oil. 1H-NMR (CDCl3) δ 0.90 (3H, t, J=7), 1.20 (3H, t, J=7), 2.39 (2H, q, J=7), 2.65 (2H, q, J=7), 2.88-2.96 (1H, m), 3.16-3.20 (1H, m), 3.32 (3H, s), 3.55-3.78 7H, m), 6.90-7.24 (4H, m), 7.65 (2H,s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:39][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 110 °C

Procedure:
A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol), benzylamine (0.214 g, 2.0 mmol), Pd2(dba)3 (60 mg), Davephos (80 mg), NaOtBu (140 mg, 1.46 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 110° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to give {4-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]+ 514.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:3]=1.[Cl-].[CH:19]1([Zn+])[CH2:21][CH2:20]1.C1COCC1.C1([Mg]Br)CC1.C1COCC1.[NH4+].[Cl-]>C1COCC1.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.[Cl-].[Zn+2].[Cl-].C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:3]=[C:2]([CH:19]3[CH2:21][CH2:20]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[CH:12][CH:13]=1
Reactant: [Zn+]C1CC1
Reactant: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br[Mg]C1CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1ccc(-c2cc(C3CC3)n3nccc3n2)cc1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (2.1 g, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.92 g, 0.8 mmol) in THF (14 mL) was added at 20° C. 0.25 M cyclopropylzinc chloride/THF suspension (ca. 128 mL, 32 mmol; freshly prepared by stirring a mixture of 64 mL of 0.5 M cyclopropylmagnesium bromide/THF and 64 mL of 0.5 M zinc chloride/THF for 1 h at 0° C., followed by 1 h at 20° C.) and the mixture was refluxed in an atmosphere of argon for 1.5 h. After the slow addition at 0° C. of saturated aqueous NH4Cl solution (20 mL), the mixture was partitioned between EtOAc and 10% sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using EtOAc/hexane (1:5 v/v) as eluent to give 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo-[1,5-a]pyrimidine (1.50 g, 69%) as an off-white solid. MS (ISP) 270.4 [(M+H)+]; mp 137-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:26][CH:27]=4)[O:19][N:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:34](=O)([O-])[O-].[K+].[K+].IC.C(=O)([O-])[O-].[Cs+].[Cs+].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:34])[C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:26][CH:27]=4)[O:19][N:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc(Nc2ccc(F)c(Cl)c2)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(F)c(Cl)c1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 56 h
Yield: 28.8 %

Procedure:
To a solution of 2-N-(3-Chloro-4-fluorophenyl)-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1,3,5-triazine-2,4-diamine (Example 413, 0.049 g, 0.101 mmol) in DMF (1 mL) was added potassium carbonate (0.028 g, 0.028 mmol) and iodomethane (0.021 g, 0.152 mmol). The reaction mixture was stirred at room temperature for 14 h after which time further iodomethane (0.042 g, 0.304 mmol) was added and the mixture was stirred at room temperature for 56 h. LCMS indicated incomplete conversion so further iodomethane (0.014 g, 0.105 mmol) was added and the mixture was heated to 50 C for 12 h. After this time cesium carbonate (0.032 g, 0.105 mmol) was added and the mixture was heated to 50 C for 1 h. Further iodomethane (0.021 g, 0.152 mmol) and cesium carbonate (0.064 g, 0.201 mmol) were added and the mixture was heated to 50 C for 14 h. Sodium hydride (60% dispersion in mineral oil, 0.004 g, 0.105 mmol) and further iodomethane (0.042 g, 0.304 mmol) were added and the mixture stirred for 1 h at 50 C. The mixture was quenched with water/ammonia/MeOH (1 mL) and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The solid was dissolved in DMF (0.5 mL) and Sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.152 mmol) and iodomethane (0.042 g, 0.304 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water/ammonia/MeOH (1 mL) and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue was purified by HPLC Method B to afford the title compound (0.004 g, 8%).