Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:38])[CH:30]=2)=[O:37])=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.63 mmol) in 3.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.047 mL, 0.377 mmol) and the reaction stirred at rt for 2 hours. The reaction was quenched with 1.0 mL MeOH, stirred for 15 min and then evaporated. The sample was partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4, and evaporated to a tan solid. The solid was chromatographed eluting with CH2Cl2, EtOAc, then 3% MeOH/EtOAc to give the title compound as a white solid (79 mg, 88%). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.35 (m, 2H), 7.28 (s, 1H), 7.16-7.23 (m, 2H), 7.10-7.16 (m, 1H), 6.96-7.02 (m, 2H), 6.76 (d, J=7.0 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 60 °C

Procedure:
A mixture of rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.6 mmol) (from Example 12b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 8 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, 3% then 10% ethyl acetate in dichloromethane as solvent). Combined fractions were recrystallized from dichloromethane-hexanes to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as white crystals. (Yield 0.14 g, 49.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Br)[CH3:33].Cl>C1COCC1.C(OCC)(=O)C>[CH2:32]([C:11]1[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])=[C:13]([CH3:27])[N:12]=1)[CH3:33]
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.314 ml (13% THF solution, 1 mol/l) of ethylmagnesium bromide was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]=[C:9]([C@@H:11]2[O:16][CH2:15][N:14](S(C(C)(C)C)=O)[CH:13]([CH:23]([CH3:25])[CH3:24])[CH2:12]2)[S:8][CH:7]=1)=[O:5].Cl>CC#N.CCO>[CH2:2]([O:3][C:4]([C:6]1[N:10]=[C:9]([C@H:11]([OH:16])[CH2:12][C@@H:13]([NH:14][CH3:15])[CH:23]([CH3:25])[CH3:24])[S:8][CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1csc([C@H]2CC(C(C)C)N(S(=O)C(C)(C)C)CO2)n1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1csc([C@H](O)C[C@@H](NC)C(C)C)n1
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a 0.18 M solution of tetrahydrooxazine 33 (0.200 g, 0.514 mmol) in 9:1 MeCN/EtOH (2.9 mL) with MP-BH3CN (2.52 mmol/g, 0.204 g, 0.514 mmol) was added dropwise HCl (4.0 M in 1,4-dioxane, 0.515 mL, 2.06 mmol) with stirring. Stirring was continued for 3 h at rt, and then the solution was concentrated and purified by HPFC (95:5:1 to 90:10:1 CH2Cl2:EtOH:NH4OH). The product fractions were concentrated, diluted with EtOAc, and washed once with sat. NaHCO3 (aq) to remove excess ammonia salts. The aqueous fraction was back-extracted once with EtOAc. The combined organic fractions were dried with Na2SO4 and concentrated to afford 0.143 g of N-methyl tubuvaline ethyl ester 35 (97%) as a foamy solid. [α]25D=+70.5 (c=0.8, CHCl3). IR (film): 1087, 1232, 1315, 1492, 1713, 2947, 3119 cm−1. 1H NMR (500 MHz, d4-MeOD): δ 0.89 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.8 Hz), 1.39 (t, 3H, J=7.0 Hz), 1.88-2.04 (m, 3H), 2.38 (s, 3H), 2.43-2.48 (m, 1H), 4.38 (q, 2H, J=7.0 Hz), 5.14-5.18 (m, 1H), 8.32 (s, 1H). 13C NMR (125 MHz, d3-MeCN): δ 14.6, 17.3, 20.1, 28.8, 33.1, 33.9, 61.9, 63.5, 72.1, 128.6, 148.2, 162.4, 180.8. HRMS (FAB) calcd. for C13H23N2O3S (M+H): 287.1429. Found 287.1427.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1>>[CH:11]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: O=C(Cl)C1CC=CCC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(NC(=O)C2CC=CCC2)cc1

Procedure:
4-(3-Cyclohexene-1-carbonylamino)-benzoic acid was prepared as described in Example 3 from 12 g (0.0875 mol) of p-aminobenzoic acid and 13.9 g (0.0963 mol) of 3-cyclohexene-1-carboxylic acid chloride.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[H][H]>CO.[Pd]>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[OH:1]
Reactant: O=Cc1ccc2c(c1O)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1O)CCC2
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 4-Hydroxy-indan-5-carbaldehyde (5 gm) in Methanol (80 ml), 10% wt/wt Palladium-charcoal (500 mg) was added. The hydrogenation was carried out for 8 hours at 55-60° C. in an autoclave at 240-250 psi using Hydrogen gas. The reaction mixture was filtered through hyflow bed and distilled under vacuum to give 4.0 gm of title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][CH3:22]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][CH3:22])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (1000 mg, 4.32 mmol) and methyl L-norvalinate hydrochloride (1090 mg, 6.49 mmol) are reacted by general procedure 6. The crude product is purified by workup method 1. The product is obtained in quantitative yield.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:24])[C:14](=[O:25])[C:13]=2[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:24])[C:14]([OH:25])([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cccc21
Solvent: C1CCOC1
Product: O=C1c2c(O)cccc2C(O)(c2ccccc2)c2cccc(O)c21

Procedure:
The process of the present invention comprises reacting phenyl lithium with 1,8-dihydroxy anthraquinone in the presence of an anhydrous organic solvent, such as tetrahydrofuran, to form 1,8,10-trihydroxy-10-phenyl-9-anthrone which is then reduced with a reducing agent so as to produce 1,8-dihydroxy-10-phenyl-9-anthrone.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)C.[Cl-].[Na+]>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]2)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O[C@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc(N2CCC[C@H](O)C2)ccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
A solution of (3S)-3-piperidinol hydrochloride (3.00 g, 21.7 mmol), 5-fluoro-2-nitrophenyl methyl ether (Example 22, step A) (3.38 g, 19.76 mmol) and K2CO3 (9.00 g, 65.22 mmol) in DMSO (75 mL) was stirred overnight. The next morning, the reaction was diluted with diethyl ether and saturated aqueous sodium chloride. The ether layer was washed thrice with H2O, and the combined aqueous layers were subsequently washed twice with diethyl ether. The combined organic layers were dried over Na2SO4, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to give the title compound as a pale yellow solid (3.90 g, 15.47 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.59-1.71 (m, 2H), 1.79 (s, 1H), 1.86-1.96 (m, J=12.96, 6.41, 6.27, 3.48 Hz, 1H), 1.96-2.04 (m, 1H), 3.13-3.24 (m, 2H), 3.47 (ddd, J=12.59, 6.36, 3.20 Hz, 1H), 3.66 (dd, J=12.82, 3.48 Hz, 1H), 3.86-3.92 (m, J=7.44, 3.94, 3.74, 3.74 Hz, 1H), 3.93 (s, 3H), 6.34 (d, J=2.56 Hz, 1H), 6.43 (dd, J=9.34, 2.38 Hz, 1H), 7.98 (d, J=9.34 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]=1[CH3:31]>ClC1C=CC=CC=1>[Br:21][C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]=1[CH2:31][Br:1]
Reactant: Cc1oc2ccccc2c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: BrCc1oc2ccccc2c1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
2.7 g (15.3 mmoles) of N-bromosuccinimide and 0.4 g (2.7 mmoles) of azobisisobutyronitrile were added to a solution of 2.8 g (13.3 mmoles) of 3-bromo-2-mehtylbenzofuran dissolved in 30 ml of monochlorobenzene. The mixture was stirred at 80° C. for 30 minutes to give rise to a reaction. After confirmation of the disappearance of the raw materials, the reaction mixture was cooled to room temperature. The insolubles were removed by filtration. The filtrate was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.0 g (yield: 79.0%) of 3-bromo-2-bromomethylbenzofuran.
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.[CH:24]([O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=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: CC(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccnc(OC(C)C)c4)cc3c21

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) and 2-Isopropoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 92.1.1) to give the title compound as a white solid. (HPLC: tR 2.56 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.23-8.19 (m, 2H), 8.14-8.09 (m, 1H), 8.00-7.96 (m, 1H), 7.64-7.62 (m, 1H), 7.05-7.02 (m, 1H), 6.80-6.78 (m, 1H), 5.28 (hp, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 1.94 (s, 311, 1.34-1.29 (m, 6H))
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>>[C:1]1([C:7]2[CH:16]=[C:15]([C:17]([Cl:22])=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Product: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
2-phenyl-4-quinolinecarbonyl chloride was synthesized from commercially available 2-phenyl-4-quinolinecarboxylic acid and thionyl chloride according to a routine method.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:14]1[C:5]2[CH:6]=[C:7]([C:8]([OH:20])=[O:13])[S:11][C:1](=[O:3])[C:4]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C(=O)O)c1C=C1SC(=S)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cccc2c(=O)sc(C(=O)O)cc12

Procedure:
A solution of 0.6 g. (2 mM) of the benzylidenerhodanine of Example 16 in 10 ml. of 15% NaOH is refluxed under nitrogen for 0.5 hour, cooled, and poured into cold dilute HCl to form a tan precipitate. The solid is collected, washed with water and recrystallized from methanol to give 5-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as yellow needles, m.p. 283°-284°.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]12[N:38]=[CH:37][N:36]=[C:35]1[CH:34]=[N:33][CH:32]=[N:31]2>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]56[N:38]=[CH:37][N:36]=[C:35]5[CH:34]=[N:33][CH:32]=[N:31]6)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC12N=CN=CC1=NC=N2
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(C45N=CN=CC4=NC=N5)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-chloropurine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[Na])(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: Ic1ccccc1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1C
Product: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
1.00 g (4.46 mmols) of N,N-di(4-methoxyphenyl)amine (31a), 1.00 g (4.90 mmols) of iodobenzene (32a), 0.502 g (5.23 mmols) of t-BuONa and 0.010 g (0.044 mmols) of Pd(CH3COO)2 were dissolved in anhydrous xylene, and while refluxing the solution in an atmosphere of nitrogen, 1.0 ml of 0.237 M of P(But)3 was further dropped, followed by refluxing for 4 hours.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1>CS(C)=O.CCOCC>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][CH:9]=2)=[N:16][CH:17]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (60% dispersion in oil; 1.2 g, 30 mmol) in 30 mL of DMSO was added a solution of 4-(trifluoromethyl)phenol (1.86 g, 30 mmol) in 20 mL of DMSO and the mixture was stirred for 30 min. To this was added methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution was heated overnight at 70° C. The reaction was cooled to room temperature and then diluted with Et2O. The solution was washed with H2O, brine, dried with Na2SO4, suction filtered, and the solvent removed in vacuo. The residue was purified via normal phase column chromatography over SiO2 using 15% Et2O/pentane to yield 6-(4-trifluoromethylphenoxy)-nicotinic acid methyl ester (4.5 g) as a colorless solid: 1H-NMR (300 MHz, CDCl3) δ 8.81 (dd, J=2.5, 0.6 Hz, 1H), 8.33 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.31-7.24 (m, 2H), 7.02 (dd, J=8.5, 0.6 Hz, 1H), 3.93 (s, 3H); EIMS m/z 297 ([M]+).
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[F:11][CH:12]([F:33])[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:27]=[O:28])=[C:15]([C:29]([F:32])([F:31])[F:30])[N:14]=1.Cl>CCCCCC.CCOCC.O>[F:33][CH:12]([F:11])[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:27]([C:7]2[O:6][CH:10]=[CH:9][CH:8]=2)[OH:28])=[C:15]([C:29]([F:32])([F:30])[F:31])[N:14]=1
Reactant: c1ccoc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccco2)c1CC(C)C
Temperature: -6 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To 2.5N n-BuLi in hexane (30 mL) cooled to 0° C. was added in a slow stream furan (7 g, 0.1 mol) in anhydrous ether (60 mL). The mixture was heated at reflux for 3 h under a nitrogen atmosphere and then cooled to -6° C. A solution of methyl 2- (difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6 g, 17.6 mmol) in anhydrous ether (20 mL) was added dropwise and stirring was continued for 2 h. The mixture was then poured into iced water, acidified with conc. HCl and extracted with methylene chloride. The extract was washed with water and brine, dried (MgSO4), and conc. The oily residue was purified by chromatography with 10% ethyl acetate/cyclohexane to yield 4.4 g of methyl 2-(difluoromethyl)-5-(2-furanylhydroxymethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate as an orange oil, a 61% yield. nD25 1.4863.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O>[F:22][C:21]([F:24])([F:23])[C:20]1[C:12]([C:8]2[N:7]=[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([NH:1][C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:11]3=[N:10][CH:9]=2)=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1cnc(-c2cnc3c(N)ccnc3n2)c(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cnc(-c2cnc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a de-gassed mixture of 6-(8-amino-pyrido[2,3-b]pyrazin-3-yl)-5-trifluoromethyl-nicotinamide (51 mg, 0.15 mmol), cesium carbonate (98 mg, 0.3 mmol), 2-chloro-5-trifluoromethyl pyridine (27 mg, 0.15 mmol) in dioxane (5 mL) under nitrogen, add Pd2 dba3 (9 mg) and xantphos (7 mg). Stir the mixture at 100° C. for 3 hours, cool, add water (10 mL) and extract with EtOAc. Dry the combined extracts over Na2SO4, concentrate under vacuum. Purify by chromatography eluting with DCM/MeOH/ammonium hydroxide mixture to give the title compound. MS 480.15 (M+1). 1H NMR δ (CDCl3) 9.82 (1H, s), 9.30-9.32 (2H, m), 8.98 (1H, d), 8.71 (1H, d), 8.62 (1H, s), 8.49 (1H, d), 7.98 (1H, dd), 7.50 (1H, d). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[N:35]=[C:36]=[O:37].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[NH:35][C:36](=[O:37])[N:2]([CH3:1])[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: CNc1ncnc(Nc2ccc(N3CCN(C)CC3)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2ncnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)c1Cl
Reaction time: 3 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for 70 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is added portion-wise to a boiling solution of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added and stirring is continued for totally 5 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM/MeOH/NH3aq, 97:3:0.2) gives the title compound: ESI-MS: 547/549 [MH]+; tR=3.5 min (purity: 100%, gradient J); TLC: Rf=0.40 (DCM/MeOH+1% NH3aq, 95:5).