Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:23](C)C=O.N.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:14][OH:15])=[NH:23])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C(Cl)=NO)c(I)cc1OCc1ccccc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzimidoylchloride and N,N-dimethylformamide (110 mL) was added a 28% ammonia in water (12 mL) under ice-bath cooling. After stirring for 3 hours under ice-bath cooling, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:diethyl ether=1:4 to give the title compound (9.3 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:17][S-:18].[Na+]>CN1CCCC1=O>[CH3:17][S:18][C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: C[S-]
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)n1c(O)nc2ncc(SC)nc21

Procedure:
The title compound was prepared by reacting 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), sodium thiomethoxide (1.4 equiv), and N-methylpyrrolidone (5.9 volume equivalents) in a manner analagous to Example 1(c). LCMS m/z (APCI)=253.0 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:21]([OH:28])[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](=[O:28])[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2cc(C(O)CC3CCCC3)n(S(=O)(=O)c3ccccc3)c2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)CC3CCCC3)n(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 1-(-benzenesulfonyl-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanol (1.39 g, 3.47 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (5.15 g, 12.15 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 18% ethyl acetate/hexanes) afforded 1-(-benzenesulfonyl-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanone (0.59 g, 42%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccc(O)cc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 45 °C
Yield: 33.4 %

Procedure:
To a dry flask containing (R,R)—N-[3-(4-hydroxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide (100 mg, 0.347 mmol) is added dry acetone (2 mL), K2CO3 (50 mg, 0.347 mmol), and methyl iodide (19 μL, 0.313 mmol). The reaction mixture is heated 16 h at 45° C. and treated with additional methyl iodide (19 μL, 0.313 mmol). After heating for another 6 h, the solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The ethyl acetate solution is washed (satd aqueous K2CO3 (twice) and brine), dried (MgSO4), and the solvent evaporated. Chromatography over silica gel, eluting with EtOAc/hexanes, affords (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropane-carboxamide (35 mg, 33%) as a white solid. 1H NMR; ES-MS: m/e 303 (m+1).
Reaction SMILES: [C:1]1([C:7](=[N:9][OH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]([C:15]1([CH3:26])[O:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24]Cl)[CH2:17][O:16]1)=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:11][O:12][C:13]([C:15]1([CH3:26])[O:16][CH2:17][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:10][N:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:19][O:20]1)=[O:14]
Reactant: COC(=O)C1(C)OCC(CCCCCl)CO1
Reactant: CC(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccccc2)CO1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A mixture of 1-Phenyl-ethanone oxime (1.13 g), Methyl-5-(4-chloro-butyl)-2-methyl-[1,3]dioxane-2-carboxylate (prepared by processes known) (2.5 g) and cesium carbonate (4.0 g) in anhydrous dimethyl formamide was stirred at 60° C. for 18 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl-acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel using 7% ethyl acetate in petroleum ether as eluent to obtain 2.5 g of pure product.
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OP(OCCCC)(OCCCC)=O)CCC.OS(O)(=O)=O>[C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Agent: CCCCOP(=O)(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Product: O=Cc1cccc2ccccc12
Reaction time: 27 h
Yield: 65.3 %

Procedure:
1-naphthylmethanol (500 mg, 3.2 mmol) in 2 g tributylphosphate was allowed to react with electrochemically produced Co(III) sulphate at 24° C. in the cell of FIG. 1 but having a U-tube format, i.e. lacking the crank 23. (This cell was also used in the following reactions, unless otherwise stated.) The electrolyte solution was composed of 0.12M Co(II) sulphate in 2M H2SO4. After 27 hours at 200 mA, no starting material remained as shown by thin-layer chromatography. The organic material isolated from this run was placed on a silica gel column, which was eluted with a 20% ether in petroleum ether (bp=60°-80° C.) solution. The initial band gave 326 mg (2.09 mmol, 66%) of 1-naphthaldehyde. A second band gave 14 mg (0.08 mmol, 2%) of a yellow solid which was identified as 1-naphthoic acid by its infrared spectrum and mass spectrum. After recrystallization from ether-petroleum ether, colourless needles were obtained that had a melting point of 158°-162° C. (authentic sample mp=158°-162° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: CN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: C1CCOC1
Product: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]

Procedure:
3-Methylamino-4-nitro-benzoic acid (1.1 g) was prepared by following General Procedure A starting from 3-chloro-4-nitro-benzoic acid (1.0 g) and methylamine (2 M in THF, 8.1 mL) in THF. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C([C:23]([CH3:25])=[O:24])=C.O1CC[CH2:28][CH2:27]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:27][CH3:28])([CH2:13][CH2:14][C:23](=[O:24])[CH3:25])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: C=CC(C)=O
Reactant: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Reactant: C1CCOC1
Product: CCC1(CCC(C)=O)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
Methyl [(6,7-dichloro-2-ethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate (15.8 gm., 0.05 mole) is suspended in dry tetrahydrofuran (100 ml.) containing trition-B (1 ml.). The suspension is stirred at ambient temperature and methyl vinyl ketone (5.02 gm., 0.072 mole) is added. The solution which becomes warm initially, is stirred at ambient temperature for 4 hours. Then, the stirring solution is treated with methyl vinyl ketone (0.3 ml.) and triton-B (0.6 ml.) every 4 hours for the next twenty hours.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.Cl>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
2,3,4-Trifluoronitrobenzene (1.01 g) and ethyl pyruvate (1.15 g) were dissolved in ethanol (8 ml). After adding 5% Pd—C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.38 g) was obtained as slightly yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:9][NH:8][C@H:7]([C:10]2[NH:11][C:12]([C:15]3[CH:28]=[C:27]4[O:29][CH2:30][C:24]5[C:25]6[C:26]4=[C:17]([CH2:18][O:19][C:20]=6[CH:21]=[C:22]([C:31]4[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][C@H:38]([CH3:41])[N:37]6[C:42](=[O:52])[C@@H:43]([NH:47][C:48](=[O:51])[O:49][CH3:50])[CH:44]([CH3:46])[CH3:45])=[N:33][CH:32]=4)[CH:23]=5)[CH:16]=3)=[CH:13][N:14]=2)[CH2:6]1.[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:50][O:49][C:48]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:37]1[C@@H:38]([CH3:41])[CH2:39][CH2:40][C@H:36]1[C:34]1[NH:35][C:31]([C:22]2[CH:21]=[C:20]3[O:19][CH2:18][C:17]4[C:26]5[C:25]3=[C:24]([CH2:30][O:29][C:27]=5[CH:28]=[C:15]([C:12]3[NH:11][C:10]([C@@H:7]5[CH2:6][C@H:5]([CH2:4][O:3][CH3:2])[CH2:9][N:8]5[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[CH:62]([CH3:64])[CH3:63])=[N:14][CH:13]=3)[CH:16]=4)[CH:23]=2)=[CH:32][N:33]=1)=[O:52])=[O:51]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To the HCl salt of methyl (S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (40 mg) in DMF (1 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (13 mg, 0.075 mmol), HATU (21 mg, 0.055 mmol) and N-methylmorpholine (0.016 mL, 0.15 mmol). After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (43 mg). LCMS-ESI+: calculated for C45H56N8O9: 852.4; observed [M+1]+: 853.1.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14](=[O:31])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)[CH:9]=1)=[O:7])(C)(C)C>ClCCl.C(OCC)C>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14](=[O:31])[CH2:13][N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[CH:18][CH:19]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
0.049 g (0.115 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 0.988 g (8.67 mmol) tifluoroacetic acid. Having stirred at room temperature for 3½ hours, the batch is concentrated to dryness on the rotary evaporator. Two dissolution steps in toluene and respective concentrations on the rotary evaporator leave as a crude product a greenish solid which is solved in diethyl ether and precipitated with petroleum ether. Twenty minutes of centrifugation at 3000 rpm, decantation of the supernatant, displacement of the solvent residues in the nitrogen flow and drying in a vacuum desiccator yield the product as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[N:13]=[C:14]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:15]=[C:16]([NH2:17])[C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:38]([N:41]=[C:42]=[O:43])([CH3:40])[CH3:39].C(OCC)(=O)C>O1CCCC1>[NH2:17][C:16]1[C:11]2[S:10][CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][CH:38]([CH3:40])[CH3:39])=[O:43])[CH:7]=[CH:6][CH:5]=3)[C:12]=2[N:13]=[C:14]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[N:15]=1
Reactant: CC(C)N=C=O
Reactant: COc1cc(Nc2nc(N)c3scc(-c4cccc(N)c4)c3n2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(N)c3scc(-c4cccc(NC(=O)NC(C)C)c4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
The 7-(3-aminophenyl)-N2-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,4-diamine (20 mg, 0.047 mmol) synthesized in Example 11 was dissolved in anhydrous tetrahydrofuran (1 mL) and then triethylamine (20 μL, 0.14 mmol) and isopropyl isocyanate (5 mg, 0.057 mmol) were added. After stirring at room temperature for 4 hours, ethyl acetate (2 mL) was added and the mixture was washed with brine. After drying with MgSO4, the product was filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexane, 1/1) yielded the target compound of Example 12 (18 mg, 75% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[CH:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 50 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (101 mg, 0.17 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methanesulfonamide (147 mg, 0.44 mmol), sodium carbonate (45 mg, 0.43 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.2 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 89 mg (50% yield, 69% purity) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[PH:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[K]>>[CH2:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7]
Reactant: CCO[PH](=O)OCC
Reactant: CCOP(=O)(CCCl)OCC
Agent: [K]
Product: CCOP(=O)(CCP(=O)(OCC)OCC)OCC

Procedure:
For example, K. Moedritzer, R. R. Irani, J. Inorg. Nucl. Chem. 22 (1961) 297-304 describes by way of example a process which begins by reacting diethyl β-chloroethylphosphonate with potassium diethyl phosphonate to give tetraethyl ethylenediphosponate, which is then converted into the desired ethylenediphosphonic acid by hydrolysis with concentrated hydrochloric acid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH:8](Cl)[NH:7][CH:6]=[CH:5]2.C([NH2:21])(=O)C.C([O-])([O-])=O.[K+].[K+]>C(OC(=O)C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[C:8]([NH2:21])=[N:7][CH:6]=[CH:5]2
Reactant: FC(F)(F)Oc1cc2c(cc1Br)C=CNC2Cl
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nccc2cc(Br)c(OC(F)(F)F)cc12
Temperature: 180 °C
Yield: 24.2 %

Procedure:
4 g (12 mmol) of 6-Bromo-1-chloro-7-trifluoromethoxy-2H-isoquinoline are intermixed with 14 g acetamide (14 eq.) and 5 g (3 eq.) K2CO3. This mixture is heated for 1 h at 180° C. under stirring. The reaction mixture is stirred in ethylacetate (100 ml) and water (100 ml). The organic phase is separated, dried with Na2SO4 and the solvent removed under reduced pressure after filtration of the drying agent. For purification, a chromatography on silical gel (40-63μ, Merck) is performed with ethylacetate as mobile phase. 890 mg of a solid are obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(O)(=O)C>CN1CCCC1=O.CN(C)C1C=CN=CC=1>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:2]2[N:11]=[C:10]([NH:12][C@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of 4.00 g of tert-butyl (1R,2S)-2-[(2-chloro-6-methylquinazolin-4-yl)amino]cyclohexylcarbamate and 5.91 g of 4-methoxybenzylamine in 30 ml of N-methyl-2-pyrrolidone, 100 mg of 4-dimethylaminopyridine was added, and then the mixture was stirred at 110° C. for 24 hours. The reaction solvent was mixed with an aqueous 5% acetic acid solution and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 5.10 g of the desirable compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[F:25])[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
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: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1F
Yield: 65.5 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol), 1-(2,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (97.4 mg, 0.367 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol) and in the same manner as in Example 65, the title compound (115 mg, 66%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([O:19][CH3:20])[C:8](=[O:18])[CH:9]=[C:10]2[C:14](=[O:15])[O:13][C:12](C)(C)[O:11]2)=[CH:4][CH:3]=1>CO>[CH3:12][O:13][C:14](=[O:15])[C:10]([OH:11])=[CH:9][C:8](=[O:18])[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=1)[O:19][CH3:20]
Reactant: CON(Cc1ccc(Cl)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)cc1)OC
Yield: 52 %

Procedure:
N-(4-Chlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (52% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.80 (2H, s, NCH2), 6.45 (1H, s, CH), 7.25–7.33 (4H, m, aromatics). Anal. calcd for C13H14ClNO5: C, 52.10; H, 4.71; N, 4.67. Found: C, 51.86; H, 4.68; N, 4.45.