Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:25]1[S:26][C:27]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:32]([C@H:41]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:31]([CH3:52])=[CH:30][C:28]=2[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:48]([O:47][C@@H:41]([C:32]1[C:31]([CH3:52])=[CH:30][C:28]2[N:29]=[C:25]([N:15]3[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[CH2:16]3)[S:26][C:27]=2[C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])([CH3:49])([CH3:50])[CH3:51]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(C3CNCCN3C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
The mixture of tert-butyl 2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate (10 mg, 0.03 mmol), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (15 mg, 0.03 mmol), and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.5 mL) was heated at 140° C. for 4 hours. The mixture was cooled, and was quenched with water. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by reverse phase HPLC gave tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate. LCMS-ESI+: calc'd for C39H47ClN5O5S2: 732.3 (M+H+); Found: 732.2 (M+H+).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.O>CS(C)=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: O=CCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 672 mg of o-iodoxybenzoic acid in methyl sulfoxide (5 mL) was added 250 μL of 2-(4-fluorophenyl)ethanol and stirring was continued for 3 h. Water (20 mL) was added and the reaction mixture filtered, the filtrate was extracted with ether (3×20 mL), washed with brine (10 mL), dried over magnesium sulfate, and concentrated to give 2-(4-fluorophenyl) ethanal as an unstable oil. The material was immediately dissolved in acetonitrile (3.5 mL) at 0° C. and 264 μL of bromotrimethylsilane and 142 μL of methyl sulfoxide were added. After stirring for 1 h, water (10 mL) was added and the reaction mixture was extracted with ether (3×20 mL), washed with brine (10 mL), dried over magnesium sulfate, and concentrated to give the title compound (220 mg) as an unstable oil which was used immediately without further purification.
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.Cl[CH2:48][O:49][C:50](=[O:57])[C:51]([CH3:56])([CH3:55])[CH2:52][O:53][CH3:54].C(=O)([O-])[O-].[Rb+].[Rb+].CN(C)C(=O)C>O.C(OCC)(=O)C>[C:18]([O:17][CH2:16][CH2:15][O:14][C:13]1[C:12]([F:26])=[C:11]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])=[CH:8][CH:7]=2)[C:27]2[N:31]=[C:30]([O:32][CH2:48][O:49][C:50](=[O:57])[C:51]([CH3:56])([CH3:55])[CH2:52][O:53][CH3:54])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)(=[O:20])[CH3:19]
Reactant: COCC(C)(C)C(=O)OCCl
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [Rb+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)C(C)(C)COC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester (1.0 g, 1.57 mmol), 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (598 mg, 3.31 mmol), rubidium carbonate (255 mg, 1.10 mmol), and N,N-dimethylacetamide (20 mL) was stirred at 85° C. for 75 minutes. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture. The organic layer was collected, sequentially washed with water (100 mL) and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (560 mg) as a solid.
Reaction SMILES: [O:1]([C:8]1[C:13]2=[C:14]([CH3:18])[C:15]([OH:17])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([CH2:23][CH2:24][CH2:25]O)(=[O:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:19][S:20]([CH2:23][CH2:24][CH2:25][O:17][C:15]1[C:14]([CH3:18])=[C:13]2[N:12]([CH:16]=1)[N:11]=[CH:10][N:9]=[C:8]2[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: Cc1c(O)cn2ncnc(Oc3ccccc3)c12
Reactant: CS(=O)(=O)CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 4-phenoxy-5-methyl-6-hydroxypyrrolo-[2,1-f][1,2,4]triazine (1.0 g, 4.15 mmol, as prepared in WO 00/71129, which is hereby incorporated by reference), 3-methanesulfonylpropan-1-ol (1.15 g, 8.3 mmol) and PPh3 (2.17 g, 8.3 mmol) in THF (12 mL) at 0° C., was added DEAD (1.42 g, 8.3 mmol). The mixture was stirred at RT for 1 h. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with brine and dried (Na2SO4). The volatiles were removed and the solid obtained was triturated with dichloromethane to afford 6-(3-methanesulfonylpropoxy)-5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazine as a white solid (1.1 g, 73% yield). MS: (M+H)+=362.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[S:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C@@H:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>>[CH3:19][C@@H:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[S:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: C[C@@H]1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=S)[nH]1
Agent: [Na+]
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=S)[nH]1

Procedure:
The product is prepared by following the procedure described in example 1e (step 4e) using 200 mg of sodium (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate obtained in example 1e (step 2e) and 106 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)). After purification by silica column chromatography (eluent: 98/02 dichloromethane/ethyl dichloromethane), 71 mg of 1-((R)-2-methyl-2,3-dihydroindol-1-yl)-2-(4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)ethanone are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][C:14]1[CH:15]=[C:16]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])[S:20][C:17]2=[N:18][CH:19]=1.O>CC#N>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[S:20][C:17]2[C:16]([N:22]=1)=[CH:15][C:14]([CH2:13][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:19][N:18]=2)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
Pyrrolidine (2.8 mol, 203 g) and K2CO3 (2.8 mol, 395 g) were added to a suspension of 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (0.52 mol, 175 g) in CH3CN (1.7 L). The reaction mixture was stirred at room temperature for 16 h. H2O (1 L) was added and the mixture stirred for 30 min. The CH3CN was removed under vacuum and the resulting mixture was extracted with CH2Cl2 (3×1.5 L). The combined organics were washed with brine, dried (Na2SO4) and concentrated under vacuum to give 2-(2-nitrophenyl)-6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridine as a dark oil (150 g, 76% yield).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[CH3:43][N:44]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48](Br)[N:47]=1)[CH3:45]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:43][N:44]([CH3:45])[C:46]1[N:47]=[C:48]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@@H:23]([CH3:34])[C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CN(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C)n2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 15g) from toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, Example 15f)), ethanol (1 ml), 6-bromo-2-N,N-dimethylaminopyridine (0.201 g, Example 18a)) and tetrakis(triphenylphosphine)palladium(0) (0.020 g) with heating at 120° C. for 4 hours. The product was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.091 g).
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C1C=CC=CC=1.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1
Reactant: OB(O)c1ccccc1F
Reactant: OCCC1CCC=C1Br
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: OCCC1CCC=C1c1ccccc1F
Temperature: 80 °C

Procedure:
2-(2-Bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1 (1.21 g, 6.33 mmol) in benzene (40 mL), and Na2CO3 (7 mL, 2M) was treated with a solution of 2-fluorophenylboronic acid (1.08 g, 7.72 mmol) in EtOH (28 mL). Tetrakis(triphenylphosphine) palladium(0), Pd(PPh3)4 (0.38 g, 5 mol %) was added and the mixture was heated to 80° C. for 1.5 h. The mixture was diluted with water and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The oil was purified by column chromatography on silica gel with 30% EtOAc:hexane to give 2-[2-(2-fluoro-phenyl) -cyclopent-2-enyl]-ethanol Intermediate FIVE2 (1.21 g).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[S:3].[CH3:14][N:15]([CH3:17])[NH2:16]>C(O)C>[CH3:14][N:15]([CH3:17])[NH:16][C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: CN(C)N
Solvent: CCO
Product: COC(=O)c1ccccc1NC(=S)NN(C)C

Procedure:
A solution of methyl 2-isothiocyanatobenzoate (6.0 g, prepared as described in J. Org. Chem., 1962, 27, 3701) and N,N-dimethylhydrazine (6 ml) in ethanol (60 ml) was stirred at room temperature for 1 hour. The precipitate was filtered off and dried to give methyl 2(3'-dimethylaminothioureido)benzoate (6.73 g, m.p. 149°-152°).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3c(OCc4ccccc4)cccc23)C1(C)C
Yield: 40 %

Procedure:
A mixture of 7-benzyloxyindole (Matrix Scientific, 2.0 g, 9.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (13.4 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.3 g, 3.6 mmol, 40% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[N:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:23])[C:14]2[C:9](=[CH:10][C:11]([C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)=[C:12]([F:24])[CH:13]=2)[NH:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH2:39]Cl>O>[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH2:39][N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:24])=[C:11]([C:25]3[NH:29][CH:28]=[CH:27][N:26]=3)[CH:10]=2)[C:15](=[O:23])[N:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1=[O:6]
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(-c3ncc[nH]3)c(F)cc2c1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c2cc(F)c(-c3ncc[nH]3)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
Into 50 ml of dimethylformamide were dissolved 2.33 g of ethyl 1,4-dihydro-2,4-dioxo-6-fluoro-7-imidazolyl-3(2H)-quinazolineacetate, and, after added 0.97 g of potassium carbonate and 1.51 g of 2,4-dichlorobenzyl chloride, the mixture was stirred for 5 hours at 100° C. After cooling by allowing to stand, the reaction mixture was poured into 500 ml of water and the deposits were collected by filtration. They were recrystallized from ethanol to obtain 2.25 g of title compound. m.p. 192°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cncc(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromopyridin-3-ol (1.0 eq.), benzyl bromide (1.2 eq.), and silver carbonate (1.3 eq.) in toluene (0.1 M) was heated to 50° C. and stirred for 18 hours. After cooling to room temperature, the reaction mixture was filtered, eluting with ethyl acetate. The filtrate was concentrated en vacuo into a residue that was purified by a COMBIFLASH® system (ISCO) using 20% ethyl acetate in hexane to give 3-(benzyloxy)-5-bromopyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:18][C:19]1[N:20]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])=[CH:31][CH:30]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.4 g, 6.8 mmol), 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride (1.65 g, 6.8mmol) and potassium carbonate (7.2 g, 68 mmol) in dry DMF (10 ml) was stirred at 120° C. for 2 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate - benzene (300 ml, 2:1 v/v). The organic phase was washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated. Purification of the residual yellow solids by column chromatograghy on silica gel (100 g) eluting with CH2Cl2 /methanol=10:1 and recrystallization from ethyl acetate-hexane gave 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.0 g, 39%) as off-white solids.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=1[NH2:27].C(=O)([O-])[O-].[K+].[K+]>>[F:18][C:19]1[C:20]2[N:27]=[C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[NH:26][C:21]=2[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(F)c1N
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
Temperature: 140 °C
Yield: 61 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (6.72 g, 28 mmol) and 3,4-difluoro-benzene-1,2-diamine (4.00 g, 28 mmol) in polyphosphoric acid (130 g) was heated at 140° C. for 7.5 h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether, ethyl acetate and pentane to afford the title compound as a white solid (4.29 g, 62%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[ClH:13].[OH2:14]>>[ClH:13].[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:14])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: O
Agent: Cl
Product: N=C(N)c1ccc(C(=O)O)cc1
Reaction time: 9 h

Procedure:
4-Amidinobenzamide (commercially available one, 7.8 g) is dissolved in water (200 ml), and thereto is added conc. hydrochloric acid (200 ml), and the mixture is stirred at a temperature below 100° C. for 9 hours. The mixture is cooled, and the precipitated crystals are collected by filtration.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](O)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[N:23]1([NH:22][C:19]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NN1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NN1CCCCC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Yield: 24.7 %

Procedure:
5,6-Diphenyl-pyrazine-2-carboxylic acid (500 mg, 1.81 mmol) from Preparation A, step (a), was dissolved in DCM (4 ml) and DMF (150 μl). DMAP (22 mg, 0.18 mmol) and 1-aminopiperidine (218 mg, 2.17 mmol) were added and the solution was cooled to 0° C. A slurry of EDC (1.99 mmol, in 2 mL DCM and 100 μl DMF) was added dropwise. The reaction mixture was stirred at 25° C. After 17 hours additional 1-aminopiperidine (40 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol) was added, and the mixture was stirred for an additional 3 hours. The crude was diluted with DCM (5 ml) and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, ethyl acetate:hexane 2:1) gave the subtitle compound (160 mg, 25%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(CO)c(F)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: COc1ccc(C=O)c(F)c1OC

Procedure:
3.0 g of 2-fluoro-3,4-dimethoxybenzyl alcohol and 5.0 g of manganese dioxide are heated under reflux for 1 hour together with 50 ml of benzene. The insoluble constituents are subsequently filtered while washing with methylene chloride. The filtrate is evaporated and the residue is recrystallized from methylene chloride/hexane. There is obtained 2-fluoro-3,4-dimethoxybenzaldehyde of m.p. 52°-54°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].Cl.[NH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5]2=[O:12]
Reactant: COC(=O)CN
Reactant: O=C1OC(=O)c2cc(O)ccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Temperature: 200 °C

Procedure:
In a MW vial 5-hydroxyisobenzofuran-1,3-dione (561 mg, 3.42 mmol) and methyl 2-aminoacetate hydrochloride (386 mg, 3.08 mmol) were suspended in toluene (15 ml). The obtained mixture was heated under microwave irradiation at 200° C. for 5 hours. A mixture of the desired compound with an undesired byproduct (about 1:2 ratio) was obtained. After filtration, the obtained beige solid was purified by silica gel flash chromatography (petroleum ether/EtOAc 1/1 to EtOAc) to give 7 methyl 2-(5-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (78 mg, 0.332 mmol, 9.70% yield, MS/ESI+ 235.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 4-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (65 mg, 54%).