Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=1.C(N(CC)CC)C>CN(C)C=O.O>[F:23][C:24]([F:41])([F:42])[C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:35])[F:34])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([Br:9])=[CH:11][CH:12]=3)[CH2:32]2)[CH:28]=[C:27]([C:37]([F:38])([F:39])[F:40])[CH:26]=1
Reactant: ON=Cc1ccc(Br)c2ccccc12
Reactant: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CC(c3ccc(Br)c4ccccc34)=NO2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Chlorosuccinimide (2.05 g, 15.5 mmol) was added to a solution of 4-bromo-1-naphthalenecarboxaldehyde oxime (i.e. the product of Example 4, Step A, 3.20 g, 12.8 mmol) in N,N-dimethylformamide (20.0 mL). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-bis(trifluoromethyl)-5-[1-(trifluoromethyl)ethenyl]benzene (5.13 g, 16.6 mmol, prepared according to the method described in J. Org. Chem. 1959, 24, 238-239) and triethylamine (5.4 mL, 38.4 mmol) in N,N-dimethylformamide (10.0 mL) was added. After stirring for an additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate/hexanes to afford the title compound as a white solid (3.2 g). 1H NMR (CDCl3): δ 8.89 (m, 1H), 8.35 (m, 1H), 8.13 (s, 2H), 7.99 (s, 1H), 7.81 (d, 1H), 7.69 (m, 2H), 7.37 (d, 1H), 4.38 (d, 1H), 3.94 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])=[O:4].[Cl-].[NH4+].O.[C:17](OCC)(=O)C>>[C:7]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:17]
Reactant: COC(=O)c1ncccc1C(=O)Cl
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ncccc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium methylsulfonylmethyl(methyl)cuprate(I) is chilled to -78°, and 2-methoxycarbonylnicotinoyl chloride (3.2 g, 16.0 mmol) is slowly added, keeping the temperature at -65 to -70. The mixture is stirred at -78° for 1 hour, after which aq. ammonium chloride is added. The mixture is warmed to RT, poured into water and ethyl acetate and extracted with ethyl acetate. The combined organic phases are dried and reduced and the product is purified by prep. TLC to give methyl 3-acetyl-2-pyridinecarboxylate.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([CH3:18])([CH3:19])[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1c(CC(C)(C)C(=O)OC)ccc2c1OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1c(CC(C)(C)C(=O)O)ccc2c1OCO2
Yield: 44.4 %

Procedure:
A solution of the product from Stage (iii) (10 g) and 2N sodium hydroxide (50 ml) in ethanol (50 ml) was heated under reflux for 30 min. The solution was cooled, poured into water, acidified with 2N hydrochloric acid and extracted with ether. The extracts were dried and evaporated and the residue purified by FCC using hexane/ether (7:3) as eluent. The product was crystallised from hexane to give the title compound (4.2 g) as a white solid, m.p. 73°-74°.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:16])=[O:15]
Reactant: OCC1CCC2CCCCN2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylanine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:14]2)[CH2:10][CH2:9]1)=O)(C)C.Cl.[CH3:29][C:30]([CH3:49])([O:32][C:33]([NH:35][C@H:36]([CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]([OH:39])=O)=[O:34])[CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:49][C:30]([O:32][C:33](=[O:34])[NH:35][CH:36]([C:37]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:14]2)[CH2:12][CH2:13]1)=[O:39])[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(c3ccccn3)c3ccccc32)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(CCCc1ccccc1)C(=O)N1CCC2(C=C(c3ccccn3)c3ccccc32)CC1
Yield: 69.7 %

Procedure:
The intermediate from Step A (120 mg, 0.33 1 mmol) was treated with 4N HCl as in Example 85, Step A. The residue was reacted with the compound prepared in Example 73, Step B (97 mg, 0.33 mmol), EDC (94.7 mg. 0.496 mmol), HOBT (67 mg, 0.49 mmol) and NMM (0.076 ml, 0.66 mmol) according to the procedure described for Example 1, Step A. The title compound (123 mg, 0.23 mmol) was obtained as a white solid after flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:14].Cl[CH2:16][CH2:17][CH:18]1[O:22][C:21](=[O:23])[N:20]([CH3:24])[CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(O)CCC.[I-].[K+]>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][CH:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[CH2:19]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc(N2CCNCC2)ccc1F
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: Cc1cc(N2CCN(CCC3CN(C)C(=O)O3)CC2)ccc1F
Yield: 81 %

Procedure:
A mixture of 5.5 g (0.029 mol) of 1-(4-fluoro-3-methylphenyl)piperazine, 5.6 g (0.034 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 12.1 g (0.114 mol) of anhydrous sodium carbonate, and 0.3 g (0.002 mol) of potassium iodide in 250 mL of 1-butanol was heated at reflux for 16 h. The mixture was concentrated under reduced pressure and the residue partitioned between 300 mL of benzene and 300 mL of water. The benzene layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a light-pink oil. The oil was converted to the oxalic acid salt and the solid was recrystallized from methanol to yield 10.0 g (81%) of white solid, mp 200°-203° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:53]1([CH:59]([NH2:69])[C:60]2([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:63][O:62][CH2:61]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:18])[F:19])[C:4]=1[C:5]([NH:69][CH:59]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:60]1([N:64]2[CH2:65][CH2:66][CH2:67][CH2:68]2)[CH2:63][O:62][CH2:61]1)=[O:6]
Reactant: NC(c1ccccc1)C1(N2CCCC2)COC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C1(N2CCCC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2,4-Bis(trifluoromethyl)-6-methoxybenzoic acid (155 mg, 0.538 mmol) was dissolved in 2 mL dimethylformamide. N,N-Diisopropyl ethyl amine (78 mg, 0.605 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (205 mg, 0.539 mmol) were added. After 5 minutes of stirring at room temperature C-phenyl-C-(3-pyrrolidin-1-yl-oxetan-3-yl)-methylamine (intermediate B) (125 mg, 0.539 mmol) in 2 mL dimethylformamide was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0-1:1) yielded 2-methoxy-N-[phenyl-(3-pyrrolidin-1-yl-oxetan-3-yl)-methyl]-4,6-bis-trifluoromethyl-benzamide as an off-white solid (173 mg, 64%), MS: m/e=503.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CN[C@@H]1CCCC[C@H]1NC.[N-:36]=[N+:37]=[N-:38].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.O.CC(OC)(C)C.[Cu]I>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([N:36]=[N+:37]=[N-:38])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(Br)ccc2F)(C(F)F)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N=[N+]=[N-])ccc2F)(C(F)F)COC1
Temperature: 70 °C

Procedure:
To a solution of 7.27 g (17.18 mmol) [5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester and 2.443 g (17.18 mmol) trans-N,N′-dimethylcyclohexane-1,2-diamine in 237 ml EtOH was added a solution of 8.93 g (137 mmol) sodium azide and 1.361 g (6.87 mmol) sodium-ascorbate in 102 ml water. The mixture was degassed and brought under nitrogen atmosphere. CuI (1.309 g, 6.87 mmol) was added and the mixture was heated at 70° C. The initially formed suspension turned into a homogeneous blue solution. The mixture was cooled to it, diluted with water and TBME. The organic phase was washed with brine and dried with MgSO4.H2O. The crude product was purified by chromatography on silica gel (hexane/5-8% TBME) to give the desired product as a colorless solid.
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl-].[Na+]>O.C(=O)(O)[O-].[Na+]>[NH2:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)C(N)C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-cyano-2-(hydroxyimino)acetate (1 eq) in 70 mL of water and 56 mL of aq. sat. sodium bicarbonate was added portionwise throughout 10 minutes Na2S2O4 (2.8 eq) The reaction mixture was stirred at room temperature for 1 hour. The solution was saturated with sodium chloride, extracted with methylene chloride (300 mL×3) and then the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the titled compound, which was used to next step without further (55%). LC/MS (m/z): 129.0 (MH+), Rt:0.25 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH:10]([C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:10]([C:12]1[N:13]([CH3:17])[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[N:16]=1)=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cn1cc([N+](=O)[O-])nc1C=O
Reaction time: 8 h

Procedure:
Fuming nitric acid (3 ml) was cooled to -10° C., to which 3 ml of concentrated sulfuric acid were added dropwise. The resulting mixture was added dropwise at an internal temperature of -10° C. or lower to 0.5 g (4.54 mmol) of 2-formyl-1-methylimidazole. The temperature of the thus-obtained was naturally allowed to rise to room temperature, at which the mixture was allowed to stand overnight. The reaction mixture was poured into ice, followed by neutralization with sodium carbonate. The resultant mixture was extracted twice with methylene chloride. The organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate and then concentrated. The residue was crystallized from ethyl ether/ethanol, whereby 0.21 g (1.35 mmol) of the title compound was obtained as cream-colored crystals (yield: 29.8%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)cc1Br
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Product: COC(=O)c1ccc(Cl)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C

Procedure:
This compound was prepared using the procedure described in Example 234 and Intermediate C and methyl 2-bromo-4-chlorobenzoate as starting materials. 1H NMR (300 MHz, CD2Cl2) δ 9.33 (s, 1H), 7.84 (d, 1H), 7.20-7.30 (m, 4H), 7.15 (s, 1H), 6.68 (d, 1H), 6.13 (s, 1H), 3.72 (s, 3H), 2.06 (s, 3H), 1.31 (s, 9H). ES-MS m/z 398.3 (MH)+; HPLC RT (min) 4.27.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:23]>C(O)C.[Pd]=O>[ClH:23].[S:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=[C:16]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c(s1)CCN(Cc1ccccc1)CC2
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2c(s1)CCNCC2
Reaction time: 3 h

Procedure:
15.4 gm (0.049 mol) of ethyl 6-benzyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]-azepine-2-carboxylate were dissolved in 200 of ethyl alcohol by the addition of 50 ml of 1 N hydrochloric acid. After the addition of 5 gm of palladium oxide, the mixture was hydrogenated in an autoclave for 3 hours at 80° C. and under a hydrogen pressure of 5 bars. After the reaction mixture had been cooled, the catalyst was filtered off, the filtrate was evaporated, and the residue was triturated with acetone. The product was suction-filtered and washed several times with acetone.
Reaction SMILES: Br[C:2]1[C:3]([NH2:29])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][N:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1.[C:30]1([CH3:36])C=CC=C[CH:31]=1.O.C1([B-](F)(F)F)CC1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:36]1([C:2]2[C:3]([NH2:29])=[N:4][CH:5]=[N:6][C:7]=2[N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][N:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH2:30][CH2:31]1
Reactant: Cc1ccccc1
Reactant: CN(C)CC(c1ccc(C(F)(F)F)cc1)N1CCN(c2ncnc(N)c2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Product: CN(C)CC(c1ccc(C(F)(F)F)cc1)N1CCN(c2ncnc(N)c2C2CC2)CC1

Procedure:
In a microwave vial containing 5-bromo-6-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (84.00 mg; 0.18 mmol; 1.00 eq.) in toluene (3.00 ml; 28.23 mmol; 159.07 eq.) and water (0.30 ml; 16.65 mmol; 93.84 eq.) was added palladium(ii) acetate (3.98 mg; 0.02 mmol; 0.10 eq.), potassium cyclopropyltrifluoroborate (52.52 mg; 0.35 mmol; 2.00 eq.), cesium carbonate (127.21 mg; 0.39 mmol; 2.20 eq.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.54 mg; 0.04 mmol; 0.20 eq.). The mixture was microwaved at 125° C. for 30 min before it was filtered the desired product was purified with Waters prep-HPLC. LC-MS: (M+1=435, obsd.=435)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47](B4OC(C)(C)C(C)(C)O4)=[CH:46][CH:45]=3)=[O:42])=[CH:36][CH:35]=2)=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:3]=[C:2]([C:47]1[CH:48]=[CH:49][C:44]([NH:43][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[O:42])=[CH:45][CH:46]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)c5cc(F)c(-c6cccnc6)cc5n4)cc3)cc2)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline (90 mg, 0.000259 mol), 1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (144.7 mg, 0.0003114 mol), cesium carbonate (212.3 mg, 0.000647 mol), DMF (5 mL) and water (2.5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (9.07 mg, 0.0000131 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (15 mg, 6%) 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 9.0 (s, 1H), 8.93 (brs, 1H), 8.68-8.72 (m, 1H), 7.92-8.73 (m, 5H), 7.52-7.64 (m, 5H), 7.35 (d, J=8.1 Hz, 2H), 3.85 (s, 8H), 3.46-3.57 (m, 4H), 2.24-2.37 (m, 4H), 2.19 (s, 3H); LC-MS (ESI): Calculated mass: 646.2; Observed mass: 647.2 (RT: 0.11 min).
Reaction SMILES: C(O)(=O)C.OO.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>O>[Cl:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]2[C:9]([CH:10]=1)=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[O:17][N:7]=2
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1N
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc2c(-c3ccc(Cl)cc3)onc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of 300 ml of glacial acetic acid and 150 ml of 30% hydrogen peroxide was heated on a steam bath for 1 hr, cooled, and treated with 28.0 g (0.1 mole) of (2-amino-5-chloro-3-methylphenyl)(4-chlorophenyl)methanone. The mixture was heated to 95° C. and 450 ml of acetic acid was added to dissolve all solids. The stirred mixture was heated at 60°-70° C. for 5 hr, poured into 2.5 liters of water and let stand at ambient temperature overnight. The solid was collected by filtration, washed with water and recrystallized from 2-propanol to yield 12.3 g (44%) of fluffy, off-white solid, m.p. 151°-152° C.
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:20]([C:2]2[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][C:8]3([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[CH3:18])=[C:21]2[C:25]=1[C@H:24]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:23][CH2:22]2
Reactant: Cc1cc(OCC2(O)CCOCC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(O)CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-((4-bromo-3,5-dimethylphenoxy)methyl)tetrahydro-2H-pyran-4-ol following a procedure analogous to that described in Step 5 of Intermediate 1. The product is purified by HPLC on reversed phase. LC (method 7): tR=1.17 min; Mass spectrum (ESI+): m/z=577 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[C:9]1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:32][CH3:33])[C:11]=2[N:10]=[C:9]1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (390 mg, 0.93 mmol) in DMF (3 mL) was added iodoethane (150 mg, 0.962 mmol), followed by potassium carbonate (350 mg, 2.54 mmol). The reaction was stirred at 40° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (271 mg, 65.2% yield) as yellow solid. LCMS retention time 1.765 min; LCMS MH+ 447.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]C1C=CC=CC=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:31]>CO.O1CCOCC1>[ClH:31].[ClH:31].[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccccc1C(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the compound prepared in Example 303 (1.00 g) in methanol (10 mL) was treated with hydrogen chloride solution in 1,4-dioxane (4 mol/L; 7.52 mL) and stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure and azeotropped from methanol several times to furnish the title compound (0.76 g), which was used without further purification, possessing the following physical data.