Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.C[O:24][CH2:25][CH2:26][NH:27][CH3:28]>CC(O)=O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]([CH2:26][CH2:25][OH:24])[CH3:28])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CNCCOC
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN(CCO)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (65 mg, 0.22 mmol) and (2-methoxyethyl)methylamine (300 mg, 3.99 mmol) and AcOH (12 drops) are heated 100° C. for 2 h. Additional (2-methoxyethyl)methylamine is added and heating is continued for 1 hr. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated and the residue is triturated with EtOAc-hexane. The solid which formed is collected by filtration and dried under vacuum to provide the title compound (53 mg, 65%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:45])[CH2:14][CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[CH2:14][C:13]([OH:45])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred ice cold solution of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid tert-butyl ester (130 mg, 0.24 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as a white powder (77 mg, 66%): IR (solid) 1670, 1716, 1782 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.96-0.99 (1H, m), 1.23-1.26 (2H, m), 1.42-1.44 (1H, m), 1.60 (1H, m), 1.91-1.98 (1H, m), 2.51-2.89 (2H, m), 3.11-3.22 (1H, m), 3.57-3.60 (1H, m), 4.30-4.72 and 5.05-5.29 (4H, 2 m), 7.11-7.17 (2H, m), 7.24-7.30 (2H, m), 7.34-7.38 (2H, m), 7.57-7.63 (2H, m), 8.07-8.61 (1H, m); 13C NMR (100 MHz, DMSO) δ (DMSO+TFA) 18.8/18.9 (CH2), 22.2/22.3 (CH2), 25.8/26.1 (CH2), 31.5/33.2 (CH2) 43.2 (CH2), 50.6/51.1 (CH), 54.4/54.5 (CH), 82.8/82.9 (2d, J 178.6/178.1, CH2F), 119.9/120.0 (CH), 120.4/120.5 (CH), 124.0/124.1 m (CH), 125.9/126.0 (C), 126.4/126.5 (CH), 139.6/139.7 (C), 156.0/156.4 (CO), 170.3 (CO), 170.7/170.8 (CO), 202.2/202.3 (2d, J 14.6/15.1, CO).; 19F (376 MHz, DMSO) δ chemical shift (multiplicity, relative intensity) −226.7 (t, 3), −226.9 (t, 3), −230.4 (t, 1), −231.2 (t, 1), −232.7 (t, 10), −233.0 (t, 10).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([F:21])=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccccc2)c1
Yield: 26.1 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (750 mg, 1.95 mmol), phenyl boronic acid (418 mg, 4.87 mmol) and palladium (II) acetate gave the title compound as a white solid (195 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 2H), 7.46-7.38 (m, 3H), 7.35 (dd, J=4.3, 11.7 Hz, 2H), 7.08 (dd, J=8.6, 10.1 Hz, 1H), 5.10 (s, 1H), 4.60 (s, 1H), 3.33-2.10 (m, 6H), 1.67 (d, J=7.9 Hz, 6H), 1.67 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.9, 157.4, 136.2, 129.3, 129.0, 128.7, 127.9, 127.6, 125.7, 125.6, 71.0, 66.1, 55.7, 55.1, 47.5, 46.6, 29.9, 29.6, 25.5, 24.5, 19.5, 15.5 ppm. Purity: 98% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C23H27FN2O2.0.29 (CHCl3): C, 67.08; H, 6.60; N, 6.72. Found: C, 67.09; H, 6.95; N, 6.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[Cl:11][CH2:12][C:13](Cl)=[O:14]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[CH2:12][Cl:11]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccn1
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 9.42 g. (0.1 mole) of 2-aminopyridine in 50 ml. of methylene chloride was added dropwise 4.0 ml. (0.05 mole) of chloroacetyl chloride in 20 ml. of the same solvent, keeping the reaction temperature at -20° to -10° C. for one hour. After stirring at room temperature for 10 hours, 50 ml. of water was added and the organic layer separated. The organic solution was washed with water and a brine solution and was dried over magnesium sulfate. Removal of the solvent in vacuo gave 6.64 g. (78%), m.p. 114°-117° C., of the desired product.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])=[O:4])[CH3:2].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCS(=O)(=O)CCCO
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of 3-(ethylsulfonyl)-1-propanol (from step (i) above; 13.4 g, 88 mmol) and p-toluenesulfonyl chloride (16.8 g, 88 mmol) in DCM (150 mL) was treated with TEA (13.4 g, 132 mmol), added dropwise. The resulting mixture was stirred at rt for 3 h before being washed with aqueous ammonium chloride solution. The organic layer was then separated, dried and concentrated in vacuo. The product was crystallised from ether containing a small amount of DCM to yield 17.9 g (66%) of the title compound.
Reaction SMILES: [Br:1]Br.P(Br)(Br)Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH:16](O)[CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(Cl)Cl>[Br:1][CH:16]([CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:17]
Reactant: CC(O)CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To phosphorous pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(C)c(S)c1
Reactant: O=C(O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(SCCC(=O)O)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
43.4 g (1.086 mol) of sodium hydroxide was added to 230 mL of water, 75.0 g (0.543 mol) of 2,5-dimethylthiophenol (purchased from Aldrich Chemical Company) was then added and the mixture was cooled to about 10° C. 91.30 g (0.597 mol) of 3-bromopropionic acid (purchased from Aldrich Chemical Company) was added in portions keeping the temperature below 25° C. The mixture was warmed to room temperature, stirred for 2 hr under nitrogen, and was then washed with diethyl ether (3×500 mL). The aqueous layer was acidified with 1N HCl and filtered to yield 112.79 g of the title compound of Step A as a solid melting at 97-98° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.34 (s,3H), 2.68 (t,2H), 3.1 (t,2H), 6.9 (d,1H), 7.06-7.14 (m,2H).
Reaction SMILES: [Na].[S:2](Cl)(Cl)=O.[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=O)[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1>C1(C)C=CC=CC=1>[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=[S:2])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1
Reactant: O=S(Cl)Cl
Reactant: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
The entire portion of the above sodium salt was added ~400 ml of thionyl chloride slowly (reaction was slightly exothermic) and stirred at room temperature for 10 minutes. The thionyl chloride was removed by rotary evaporation at 70° C. and the residue azeotroped once with toluene. The residue was suspended in 600 ml of methylene chloride and to the suspension was added diisopropylethylamine cautiously until the solution was basic. The reaction solution was washed with 3×200 ml of 1N hydrochloric acid and 3×200 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, concentrated by rotary evaporation, taken up in toluene, charcoaled twice and concentrated by rotary evaporation. The residue (60 g) was taken up in ethyl acetate and passed through a short bed of silica gel using 25% hexane-75% ethyl acetate as the eluant. Similar fractions were combined to give ~25 g of crude (but 95% (min)) purity oil which is 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-phenylpyrido[3,2-f]-1,4 -oxazepin-5(4H)-one. To 12.5 g (0.04 mole) of the above amide was added 125 ml of toluene and 16 g (0.04 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphotane-2,4-disulfide. The reaction mixture was heated to reflux for 4 hr. After standing overnight, the toluene was decanted off, washed with 3×100 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was further purified by column chromatography using silica gel as the stationary phase and eluting with ethyl acetate: hexane 1:1, (v/v). Like fractions were combined and concentrated giving 8.5 g (64%) of desired product, m.p. 156°-58° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36](O)=[O:37]>CN(C)C=O>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([CH:39]=1)[C:36]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:37]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1F
Reactant: Nc1cccnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.21 g, 2.19 mmol), EDC (0.34 g, 1.75 mmol), HOBT (0.36 g, 2.33 mmol) and N-ethylmorpholine (0.37 ml, 2.91 mmol) were added to a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 103; 0.5 g, 1.46 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hours. The N,N-dimethylformamide was removed on a buchi and the residue was diluted with ethyl acetate (50 ml) washed with saturated aqueous sodium hydrogencarbonate (1×25 ml) and water (1×25 ml) and dried (MgSO4), filtered and evaporated to yield the title compound as a white solid. 0.6 g.
Reaction SMILES: [OH:1][C@:2]([CH3:12])([CH2:7][C:8]([O:10]C)=[O:9])[C:3]([O:5]C)=O.ClC(Cl)(Cl)[C:15]([N:17]=C=O)=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:12][C@:2]1([CH2:7][C:8]([OH:10])=[O:9])[O:1][C:15](=[O:16])[NH:17][C:3]1=[O:5]
Reactant: COC(=O)C[C@@](C)(O)C(=O)OC
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@]1(CC(=O)O)OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of (R)-dimethyl 2-hydroxy-2-methylsuccinate (530 mg, 3.0 mmol) in DCM (10 mL) at 0° C. was added dropwise trichloroacetyl isocyanate (530 mL, 4.5 mmol). The ice bath was removed and the reaction mixture stirred for 2 h then quenched by the addition of MeOH (2 mL) and evaporated under reduced pressure to dryness. To the residue was added 1 M K2CO3 (15 mL, 15 mmol) and the reaction mixture heated at reflux for 0.5 h. The reaction mixture was allowed to cool to rt, extracted with Et2O (2×), then acidified to pH 2 by the addition of 1 N HCl and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was triturated with Et2O, and the triturate evaporated under reduced pressure. The residue was chromatographed by silica gel chromatography eluting with 1 to 10% MeOH/DCM (bromocresol green stain) to give Compound 42a (130 mg, 24% yield) as a clear colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.95 (br. s., 1H), 3.14 (d, J=17.3 Hz, 1H), 2.97 (d, J=17.3 Hz, 1H), 1.62 (s, 3H). The structure was confirmed by single crystal X-ray diffraction analysis with material crystallized from Et2O/hexanes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=1)([CH3:6])[CH3:5])[CH3:2].[NH2:23][C@@H:24]([CH3:41])[CH2:25][N:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:38]=[C:37]([F:39])[C:34]([C:35]#[N:36])=[C:33]([Cl:40])[CH:32]=2)=[N:27]1>>[Cl:40][C:33]1[CH:32]=[C:31]([C:28]2[CH:29]=[CH:30][N:26]([CH2:25][C@@H:24]([NH:23][C:12]([C:10]3[N:11]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=3)=[O:14])[CH3:41])[N:27]=2)[CH:38]=[C:37]([F:39])[C:34]=1[C:35]#[N:36]
Reactant: CCOC(C)(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CCOC(C)(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-ethoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.15 mmol, 380 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.15 mmol, 320 mg). The product was purified by flash-chromatography. Yield 260 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.01 (s, 9H), 0.80-0.91 (m, 5H), 0.94 (t, 3H), 1.23 (s, 6H), 3.21 (q, 2H), 3.58 (t, 2H), 4.33-4.42 (m, 2H), 4.53-4.59 (m, 1H), 5.53 (s, 2H), 6.61 (d, 1H), 7.41 (d, 1H), 7.52 (d, 1H), 7.59 (d, 1H), 7.64 (s, 1H), 7.74 (s, 1H). LC-MS: [M+1]=589.23.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][N:21]([CH:23]=O)[CH3:22].C(OC(OCC)N(C)C)C.C(Cl)Cl.CO>CO>[Br:1][C:2]1[N:18]=[C:17]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CN(C)C=O
Agent: CCOC(OCC)N(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)C=Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
The compound was produced analogously to example 8 except that the following amounts were used: 2-bromo-2′-deoxyadenosine (330 mg, 1.0 mmol), DMF (3 ml), dimethylformamide-diethylacetal (0.85 ml, 5 mmol). Colourless amorphous solid (306 mg, 80%). TLC (CH2Cl2/MeOH, 9:1): Rf 0.33. UV (MeOH): 318 (28600), 238 (13000). 1H-NMR ((D6(DMSO): 2.32, 2.67 (2m, H—C(2′)); 3.14, 3.23 (2s, CH3—N); 3.56 (m, H—C(5′)); 3.86 (m, H—C(4′)); 4.39 (m, H—C(3′)); 4.95 (t, J=5.5 Hz, HO—C(5′)); 5.33 (d, J=4.3 Hz, HO—C(3′)); 6.31 (“t”, J=6.3 Hz, H—C(1′)); 8.44 (s, H—C(8)); 8.85 (s, H—C(N═)). Anal. calc. for C13H17BrN6O3 (385.22): C, 40.53; H, 4.45; N, 21.82; found: C, 40.66; H, 4.50; N, 21.79.
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=1.ClC1N=C(Cl)C2N=[C:26]([C:28]3[CH:33]=CC(F)=CC=3)C=CC=2N=1>>[Cl:16][C:14]1[CH:13]=[CH:12][C:4]2[N:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=[C:2]([CH:33]3[CH2:28][CH2:26]3)[C:3]=2[N:15]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Product: CC(=O)Nc1nc(C2CC2)c2nc(Cl)ccc2n1

Procedure:
The experimental procedure of example 12 was repeated, except for the use of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (a compound described in WO 2006/135993) instead of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The resulting compound was characterized as follows: MS (m/z) 263.0 [M+H]+; HPLC Rt=2.24 minutes (Method B).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[C:25]([CH2:29][C:30](O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)CC(=O)O
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNC(=O)CC(C)(C)C)ccc1-c1cnco1
Reaction time: 16 h

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 52 mg (0.45 mmol) of tert-butylacetic acid, 86 mg (0.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69 mg of HOAt were dissolved and stirred in 2 ml of dimethylformamide. After stirring for 16 hours the mixture was diluted with 10 ml of dichloromethane and washed with 10% citric acid solution in water, saturated sodium hydrogen carbonate solution and brine. The organic solution was then dried with solid magnesium sulphate, filtered and evaporated to give N-(3-methoxy-4-(5-oxazolyl)phenyl]-N′-[2-(3,3-dimethylbutyramido)-1,1-dimethylethyl]oxalamide as a pale yellow solid, MS: m/e 431.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[CH:5]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1ccc(-c2cn3ccnc3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3ccnc23)nc1
Temperature: 120 °C

Procedure:
108 mg (0.3625 mmol) of the 8-chloro-6-(2,4-dichlorophenyl)imidazo[1,2-a]pyrazine (Example 5A) were initially charged in 3 ml of DMSO, and 150 mg (0.543 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile (Example 2A) and 0.63 ml (3.62 mmol) of N,N-diisopropylethylamine were added. The mixture was heated at 120° C. for 12 h. Purification by chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 100:1) gave 12 mg (7% of theory) of the product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16]#[N:17].[SH2:21]>N1C=CC=CC=1>[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16](=[S:21])[NH2:17]
Reactant: S
Reactant: Cn1c(Br)c(Br)c(C#N)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cn1c(Br)c(Br)c(C(N)=S)c1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Diisopropylethylamine (1.1 mL, 6 mmol), 2,4,5-Tribromo-1-methylpyrrole-3-carbonitrile (2.16 g, 6 mmol) and pyridine (10 mL) are added to condensed hydrogen sulfide in a pressure tube at -78° C. The tube is sealed and the reaction mixture is stirred for 5 days at room temperature. The reaction mixture is then concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.47 g, mp 100.5°-102° C. dec.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].OS(O)(=O)=O.O>C(O)(C(F)(F)F)=O>[C:12]([C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.3 %

Procedure:
2-Trifluoromethyl-phenol (2.98 g, 18.3 mmol) was dissolved in 12 mL TFA and t-butanol (1.43 g, 19.3 mmol) and H2SO4 (0.24 mL) were added. The reaction was stirred at rt for 48 hrs, after which water was added and the compound was extracted into DCM. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2/1 Hex/EtOAc) to yield 2.01 g of the target compound.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][C:10]=1[Cl:31])C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[Cl:31][C:10]1[CH:11]=[C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Clc1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)cc1Cl
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To the mixture of 4 and benzyl-[2-chloro-4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-phenyl]-amine (60 mg, 1:1.4, 0.128 mmol, 1 eq) in dry EtOH (3 mL) was added Pd(OH)2 (30 mg, 50% w/w) and 1,4-cyclohexanediene (240 μL, 2.56 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight. Additional quantities of Pd(OH)2 (30 mg, 50% w/w) and 1,4-cyclohexanediene (240 μL, 2.56 mmol, 20 eq) were then added, and the mixture was again heated at 80° C. overnight. Once cooled down, the reaction mixture was filtered through a short celite pad, and eluted with MeOH (10 mL). The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography using hexane/EtOAc (1:9-0:1) as eluant to furnish E as a pale yellow solid (11.2 mg, 26%).