Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>ClCCl>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][N:6]=1
Reactant: Nc1ccc(OCc2ccccn2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
5-Amino-2-(pyridin-2-ylmethyloxy)pyridine (D2, 1.36 g, 0.0068 mole) in dichloromethane (50 ml) was cooled to 0° C. under argon. Triethylamine (1.04 ml, 0.0075 mole) was added, followed dropwise by phenyl chloroformate (0.94 ml, 0.0075 mole) and the mixture was stirred at room temperature for 4 hours, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate to leave the title compound (1.9 g, 87%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:29]2[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]2)[CH:17]=[C:18]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:30][CH:29]([C:16]2[CH:17]=[C:18]([N:21]([CH3:28])[CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:19]([CH3:20])=[C:14]([CH:15]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[CH2:32]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CN(C(=O)OC(C)(C)C)C3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CNC3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 2.7 %

Procedure:
To a stirred solution of tert-butyl 3-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl)azetidine-1-carboxylate (29 mg, 1.29 mmol) in DCM (4 ml) was added TFA (1 ml) and the solution was stirred at room temperature for 90 min after which the solvent was evaporated and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with a 1:1 mixture IPA:CHCl3 (2×50 ml), and the combined organic phases washed with brine (30 ml, dried with Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC to afford the title compound as a white solid (15 mg, 42%). LC-MS 100%, m/z=439.3, 1H NMR (500 MHz, MeOD) δ 7.19 (d, J=1.4 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 6.12 (s, 1H), 4.46 (s, 2H), 4.41-4.27 (m, 2H), 4.26-4.13 (m, 3H), 3.93 (d, J=11.4 Hz, 2H), 3.36 (td, J=11.3, 3.3 Hz, 2H), 3.06 (dq, J=14.6, 5.0 Hz, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.75-1.60 (m, 4H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1.O>O1CCCC1>[Cl:4][C:5]1[C:10]([CH:11]([OH:12])[CH3:1])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Methylmagnesium bromide solution (1.4 M in toluene/tetrahydrofuran (75:25); 2.4 mL, 3.4 mmol) was added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 500 mg, 2.8 mmol) in tetrahydrofuran at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layers were washed with water and brine, dried (sodium sulfate), filtered, and evaporated to give 1-(4,6-dichloro-pyrimidin-5-yl)-ethanol (540 mg, 100%) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 3H, J=6.3 Hz), 2.62 (br s, 1H), 5.48-5.54 (m, 1H), 8.68 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][C:26]1[CH:35]=[CH:34][C:29]2C(=O)[CH2:31][O:32][C:28]=2[CH:27]=1>C1(C)C=CC=CC=1>[Cl:24][C:20]1[C:29]2[CH:34]=[CH:35][C:26]([CH3:25])=[CH:27][C:28]=2[O:32][CH:31]=1
Reactant: Cc1ccc2c(c1)OCC2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(Cl)coc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of triphenylphosphine (8.8 g, 0.033 mol) and carbon tetrachloride (19.5 cm3) was stirred at 60° C. for 2 hr. A solution of 6-methylbenzofuran-3(2H)-one (5.0 g, 0.034 mol) in toluene (50 cm3) was added dropwise and the mixture was stirred at 115° C. for 18 hr. The cooled mixture was filtered and the solvent was removed from the filtrate. The residue was extracted with hot petroleum ether (b.p. 60°-80° C.). The extract was chromatographed on silica using petroleum ether (b.p. 60°-80° C.) as the eluant to give 3-chloro-6-methylbenzofuran (2.3 g, 0.014 mol, 40.0%) RF 0.51.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.Cl.N([O-])=O.[Na+].[Na+].[I-:23]>O>[F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([I:23])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2cc(F)ccc2F)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(F)c(Oc2ccc(I)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
Into a 250 mL 4-necked round-bottom flask, was placed 4-(2,5-difluorophenoxy)-aniline (9 g, 40.69 mmol, 1.00 equiv), hydrogen chloride (37%) (10.2 g, 100 mmol, 2.5 equiv) and water (20 mL). A solution of NaNO2 (3.1 g, 44.93 mmol, 1.10 equiv) in water (10 mL) was added dropwise with stirring at 0° C. over 5 min. After stirring at 0° C. for 30 min., the mixture was added into a solution of NaI (18 g, 120.00 mmol, 3.0 equiv) in water (20 mL) dropwise with stirring at 25° C. The resulting solution was stirred for 12 h at 25° C. and then extracted with ethyl acetate and the organic layers combined. The combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 10.5 g (78%) of 1,4-difluoro-2-(4-iodophenoxy)benzene as brown oil.
Reaction SMILES: [Br: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=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[Br: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=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccccc1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 79 %

Procedure:
Into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 621 mg of the title compound (79%) as a yellow powder in 99.3% purity by HPLC (Rt: 4.33, gradient of 8 mm, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:9])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of oxane-4-carboxylic acid (45 mg, 0.34 mmol), HATU (162 mg, 0.43 mmol) and DIPEA (43 μl, 0.25 mmol) in DMF (1 ml) is stirred at RT for 30 minutes. Tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (60 mg, 0.19 mmol) is added and stirring continued for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 40 mg (49%). HPLC-MS: M+H=422; tR=1.73 min (*Method—5).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].CO.[N+](=[CH2:22])=[N-]>CCOCC>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([O:10][CH3:22])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of BOC-L-Gln (20 g, 81 mmol) in 50 mL of EtOAC and MeOH at 0° C. was added diazomethane in 250 mL of Et2O with stirring. The resulting yellow solution was stirred at 0° C. for 5 minutes and then warmed up to room temperature and stirred for 20 minutes. Argon gas was then bubbled through the yellow reaction mixture to remove excess diazomethane. The crude product was concentrated and purified by crystallization from methyl-tert-butyl ether. Yield 100%. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.96 (m, 1H), 2.21 (m, 1H), 2.36 (m, 2H), 3.76 (s, 3H), 4.34 (m, 1H), 5.32 (m, 1H), 5.44 (bs, 1H), 6.16 (bs, 1H). Anal. (C11H20N2O5) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of 2,6-dichloroquinoline (1.5 g, 7.6 mmol) in DMF (50 ml) was added tert-butyl piperazine-1-carboxylate (7.1 g, 38.1 mmol, 5 eq), and potassium carbonate (2.1 g, 15.1 mmol, 2 eq). The mixture was stirred for 4 hours at 140° C. and then quenched by the addition of water (300 ml) and then extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (3×300 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-10% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford tert-butyl 4-(6-chloroquinolin-2-yl)piperazine-1-carboxylate as a light yellow solid (1.6 g, 61%). (ES, m/z): [M+H]+ 348; 1H NMR (300 MHz, DMSO): δ 8.03 (d, J=9.3 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.50-7.58 (m, 2H), 7.29 (d, J=9.3 Hz, 1H), 3.68-3.71 (t, J=5.1 Hz, 4H), 3.43-3.47 (t, J=4.5 Hz, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[NH2:8][C:9]1[C:18](I)=[CH:17][C:16]([Cl:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]2[C:9](=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[NH:8][C:3]([Si:2]([CH3:7])([CH3:6])[CH3:1])=[C:4]2[CH3:5]
Reactant: CC#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Cl)cc(I)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)cc2c(C)c([Si](C)(C)C)[nH]c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 58.2 %

Procedure:
Tetrabutylammonium chloride (100 mg, 0.4 mmol), trimethyl(prop-1-ynyl)silane (1.1 ml, 7.2 mmol), methyl 2-amino-5-chloro-3-iodobenzoate (1.0 g, 3.6 mmol), triphenylphosphine (47.2 mg, 0.1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and sodium carbonate (1.9 g, 18 mmol) in DMF were added to a sealed tube and the reaction was stirred at 100° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with ether and washed with saturated aqueous ammonium chloride and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was then purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-3-methyl-2-(trimethylsilyl)-1H-indole-7-carboxylate (620 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.72 (d, J=1.0 Hz, 1H), 3.98 (s, 3H), 2.37 (s, 3H), 0.40 (t, 9H); MS (ESI+) m/z 296 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F

Procedure:
3-Bromoaniline is coupled with 4-chloro-7-fluoro-6-nitroquinazoline, to produce 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, which is reacted thereafter with the sodium salt of 3-(4-morpholinyl)-1-propanol, as described hereinabove, to produce 4-[(3-bromophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline. The morpholino-substituted 6-nitroquinazoline is then reduced to the corresponding 6-aminoquinazoline, which is further reacted with bistributyltin, bromine-76 or bromine-77 and acryloyl chloride, as described hereinabove, to yield the final bromine-76 labeled or bromine-77 labeled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11](=[O:16])N(OC)C)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([CH:11]=[O:16])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1(C=O)CC1
Reaction time: 0.33 h

Procedure:
To a 0.05 M solution of [1-(methoxy-methyl-carbamoyl)cyclopropyl]carbamic acid tert-butyl ester in Et2O (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aluminum hydride (1.0 M in Et2O, 5 mL, 5.0 mmol). The reaction mixture was stirred for another 20 min and then quenched with 6 mL of a solution of KHSO4 in water. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with 1 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), and concentrated to yield (1-formylcyclopropyl)carbamic acid tert-butyl ester as a colorless oil (393 mg) which was used immediately in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8]([Cl:19])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1c(F)c(F)cc(C(=O)Cl)c1F
Reaction time: 4 h

Procedure:
In 200 ml of benzene was dissolved 6.10 g (0.026 mole) of 3-acetoxy-2,4,5-trifluorobenzoic acid (V), and to the solution was added 15 ml of thionyl chloride and stirred for 4 hours under reflux. After completion of the reaction, benzene and excess thionyl chloride were completely distilled off under reduced pressure to give 3-acetoxy-2,4,5-trifluorobenzoyl chloride (VI).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc2nccc(O)n2n1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nccc(Cl)n2n1

Procedure:
To a suspension of the product obtained in Step 1 (35 g) in 400 ml phosphorus oxychloride, 24 g of N,N-dimethylaniline was dropwise added at room temperature. The mixture was refluxed for two hours, excess phosphorus oxychloride was removed by distillation under normal pressure, and the reddish brown oil left was dissolved in 1.5 liters of chloroform. This solution was slowly poured into 800 ml of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after thorough mixing, and the aqueous layer was again extracted with one liter of fresh chloroform. The organic layers were joined together, washed with 500 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to about 100 ml, and 200 ml of n-hexane was added to this concentrate, giving 20 g of the objective compound as faint yellow crystals.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=[C:4]1[CH2:3][CH2:2][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: ICCC1=COc2ccccc2O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1=COc2ccccc2O1
Temperature: 60 °C

Procedure:
1 g (3.47 mmol) of the iodinated compound obtained in Step D and 0.964 g (5.2 mmol) of potassium phthalimide are dissolved in 20 ml of anhydrous N,N-dimethylformamide; the reaction mixture is then heated at 60° C. for 22 hours under argon. After cooling of the mixture, the solvent is evaporated in vacuo; the residue is then taken up in ethyl acetate. After washing with water and extraction of the aqueous phase with ethyl acetate, the organic phases are dried over magnesium sulphate. The solvent is then evaporated in vacuo; the title phthalimide is then obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 30/70).
Reaction SMILES: Cl.[N:2]1([C:7]2[N:12]=[C:11]([C:13]3[S:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]=3[CH3:22])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1>C(O)C>[N:2]1([C:7]2[N:12]=[C:11]([C:13]3[S:17][C:16]([NH2:18])=[N:15][C:14]=3[CH3:22])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CC(=O)Nc1nc(C)c(-c2cccc(-n3ccnc3)n2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cccc(-n2ccnc2)n1

Procedure:
Conc. HCl (0.3 ml) is added to a suspension of N-[5-(6-imidazol-1-yl-pyridin-2-yl)-4-methyl-thiazol-2-yl]-acetamide (30 mg) in ethanol (2 ml) at room temperature. The mixture is heated at reflux for 7 hours. Following cooing the mixture is partitioned between saturated aqueous NaHCO3 and CH2Cl2 containing 10% methanol and extracted a further 4×CH2Cl2 containing 10% methanol. Evaporation of the organic layers gives the title compound as a beige solid. 1H nmr (d4-methanol, 400 MHz) 8.50 (s, 1H), 7.94-7.86 (m, 2H), 7.45-7.37 (m, 2H), 7.16 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:11]=[CH2:12])[C:9]=1[Cl:10])[C:5]#[N:6].Cl[C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1.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>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.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:10][C:9]1[C:8]([CH:11]=[CH2:12])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: C=Cc1cc(C#N)cc(N)c1Cl
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C=Cc1cc(C#N)cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 100 °C
Yield: 50.8 %

Procedure:
A mixture of 3-amino-4-chloro-5-vinylbenzonitrile (75 mg, 0.42 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (149 mg, 0.420 mmol), Cs2CO3 (274 mg, 0.840 mmol), DPPF (23 mg, 0.042 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (24 mg, 0.042 mmol), and Pd(OAc)2 (28 mg, 0.13 mmol) in a microwave vial was flushed with nitrogen. Dioxane (3.5 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (106 mg, 51% yield) as an oil. This was dissolved in DCM (3 mL) and anisole (0.582 mL, 5.33 mmol) and TFA (3 mL) were added. After stirring at RT overnight, the solvent was removed and the yellow solid was dissolved in DCM. This was washed with a saturated aq. NaHCO3 solution and the organic phase was separated. The aqueous phase contained some suspended yellow solid and was exacted 2× with DCM. The combined organic phases were dried with sodium sulfate and the solvent was removed. The residue was suspended in a mixture of EtOAc:hexane=1:1 and filtration gave the title compound (59 mg) as a light yellow solid.