Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)C.Cl.C1COCC1>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6](=[O:18])[CH2:5][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-nitro-benzyl)-5-(4-nitro-phenyl)-3-oxo-pentanoic acid ethyl ester obtained in Example GG (18.2 g, 45.4 mmol), 6N HCl (250 mL), and THF (50 mL) was refluxed for 18 hours and cooled to room temperature. H2O was added, and the solution was extracted with EtOAc. The extracts were combined, washed with brine, dried (MgSO4), and concentrated. The residue was triturated with Et2O and filtered to give the title compound. 1H NMR (CDCl3) δ2.73 (t, 4 H), 2.96 (t, 4 H), 7.29 (d, 4 H), 8.09 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]([C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[CH3:1][N:2]([C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(c1ccccc1)c1cc(Nc2cccc(NC(=O)OC(C)(C)C)c2)ncn1
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccccc1)c1cc(Nc2cccc(N)c2)ncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
A mixture of tert-butyl 3-(6-[N-methyl-N-phenylamino]pyrimidin-4-ylamino)phenylcarbamate (1.17 g, 3 mmol) and TFA (50% in DCM, 10 mL) was stirred at RT for 4 hr. The reaction solvent was removed under vacuum. The crude product was mixed with 1 mL of 2N NaOH and 5 mL of EtOAc, was stirred for 30 min, was filtered, and was dried under vacuum to give 0.65 g (75%) of the title compound, an off-white solid. (IR-8) MS (m/z): MH+=292.
Reaction SMILES: [CH3:1][N:2]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH3:27])[C:3]([CH2:5][CH:6]([CH3:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)=[O:4].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][N:2]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH3:27])[C:3]([CH2:5][CH:6]([CH3:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]2)=[O:4]
Reactant: CC(COc1ccc2c(c1)CCC(=O)N2)CC(=O)N(C)C1CCCCC1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C
Yield: 36.6 %

Procedure:
3.3 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)-aminocarbonyl]-2-methylpropoxy}-3,4-dihydrocarbostyril and 3.4 g of 90% DDQ are added to 100 ml of dioxane and this mixture is refluxed for 9.5 hours and then cooled. After the reaction, the solvent is distilled off and the obtained residue is dissolved in chloroform and the organic layer is washed with aqueous saturated NaHCO3 solution, and with water, dried with anhydrous Na2SO4 and then treated with an active charcoal treatment. After distilling off the solvent, the resultant residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 10:1 chloroform-methanol (V/V)) and the crude crystals are recrystallized from benzene-ligron to produce 1.2 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals. Melting point: 146°-149° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:10]=[CH:11][N:12]=[C:13]([O:15][CH:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:14]=1)[C:4]#[C:5][CH3:6]
Reactant: Clc1cc(OC2CCCCCC2)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC2CCCCCC2)ncn1
Temperature: 25 °C
Yield: 105.3 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.15 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.6 ml of a tetrahydrofuran solution containing 0.43 g of 4-chloro-6-(cycloheptyloxy)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.52 g of 6-(2-butynyloxy)-4-(cycloheptyloxy)pyrimidine (the present compound (170)).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[O:8]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1CCCCC1Cl
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1CCCCC1N1C(=O)c2ccccc2C1=O

Procedure:
The amine required as precursor was prepared in accordance with GB1131191. 2-Chlorocyclohexanone was reacted with phthalimide to give 2-(2-oxocyclohexyl)isoindole-1,3-dione, which was ketalized with ethylene glycol in the presence of para-toluenesulfonic acid, giving 2-(1,4-dioxaspiro[4.5]dec-6-yl)isoindole-1,3-dione. Treatment with hydrazine hydrate to remove the phthalimideradical gave the desired 1,4-dioxaspiro[4.5]dec-6-ylamine. b) 1-(1,4-Dioxaspiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)thiourea
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12](O[Si](C(C)(C)C)(C)C)[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si](C(C)(C)C)(C)C)[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1.CC(O)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([OH:36])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
A mixture of 5 (1.486 g, 2.03 mmol), HOAc (20 mL), H2O (10 mL) and THF (10 mL) was stirred at 70° C. for 17 h. The reaction was then poured into 750 mL saturated NaHCO3 solution and the resulting mixture was extracted with ethyl acetate (4×200 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Flash chromatography (50% ethyl acetate/hexanes) gave 6 (497 mg, 1.03 mmol, 51%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:45][CH3:46])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=4[C:36]([NH:38][CH3:39])=[O:37])[C:17]4[CH:22]=[CH:21][N:20](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+]>CO.C1COCC1.CCOC(C)=O.[Na+].[Cl-]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:45][CH3:46])=[C:10]([NH:13][C:14]3[NH:19][C:18]4=[N:20][CH:21]=[CH:22][C:17]4=[C:16]([NH:33][C:34]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:35]=4[C:36]([NH:38][CH3:39])=[O:37])[N:15]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)[nH]c2nccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A solution of 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (130 mg, 0.2 mmol) in MeOH (10 mL) and THF (20 mL) was treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The resulting mixture was stirred at rt overnight, then diluted with EtOAc (100 mL) and saturated NaCl solution. The organic layer was washed with a saturated NaHCO3 solution, concentrated onto Celite and purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a beige solid (73 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3H) 2.80 (d, J=4.4 Hz, 3H), 3.12 (t, J=8.42 Hz, 2H), 3.78 (s, 3H), 4.10 (t, J=8.42 Hz, 2H), 6.27 (d, J=1.28 Hz, 1H), 6.86-6.98 (m, 3H), 7.28-7.37 (m, 1H), 7.55 (s, 1H), 8.34 (d, J=8.61 Hz, 1H), 8.55 (br s, 1H), 8.63 (s, 1H), 10.14 (s, 1H), 11.27 (s, 1H); ESIMS (M+H)+=489.98.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (59 mg, 0.59 mmol), acetic acid (0.053 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 372.0 [M]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccn3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloromethane (5 mL) was added freshly prepared picolinoyl chloride (56 mg, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant deep blue solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 3,3-dimethyl-2-(4-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 52%. MS (ESI+APCI) M+1=416.20.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].C1N2CCN(CC2)C1.C(N=C=O)CCC>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:1]=[O:2])(=[O:16])=[O:15]
Reactant: CSCc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Agent: C1CN2CCN1CC2
Agent: CCCCN=C=O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CSCc1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (2.5 ml, 35 mmol) was added portionwise into a nitrogen-purged mixture containing 6.8 g (31 mmol) of o-methylthiomethylbenzenesulfonamide, 0.1 g of DABCO, and 3.8 g (38 mmol) of n-butyl isocyanate in 60 ml of dry xylene, while the temperature was maintained at 130°-135° C. between additions. Stirring was continued for 1 hour at 130°-135° C. The mixture was cooled to room temperature and the solid was filtered off under nitrogen. The filtrate was concentrated to yield 9.0 g (theo 7.6 g) of oil: IR cm-1 2240 (N=C=O), no NH at ca 3300. The oil was taken up in 90 ml of dry methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:16]([OH:18])=[O:17])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[Mn]([O-])(=O)(=O)=O.[K+].[N+](C1C(C)=CC(C)=CC=1C)([O-])=O.S(=O)(=O)(O)O>[Zn].C(OCC)(=O)C.O>[C:16]([C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]2[NH:1][O:14][C:13](=[O:15])[C:12]=2[CH:11]=1)([OH:18])=[O:17]
Reactant: O=C(O)c1cc(C(=O)O)c([N+](=O)[O-])c(C(=O)O)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cc1cc(C)c([N+](=O)[O-])c(C)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(C(=O)O)c2[nH]oc(=O)c2c1
Reaction time: 1 h

Procedure:
To a stirred solution of 12.8 g. of nitrotrimesic acid (prepared by alkaline potassium permanganate oxidation of nitromesitylene) in 200 ml. of water containing 30 g. of sulfuric acid are added 6.5 g. of zinc dust in portions at such a rate so as to maintain a temperature of about 25° C. After the addition, the mixture is stirred for an additional 1 hr. After this time, 200 ml. of ethyl acetate are added and the mixture is rapidly stirred for 15 min. The reaction is then filtered by suction through a pad of filter aid. The organic layer is separated, dried and concentrated under reduced pressure, leaving 9.6 g. of crude product which is used directly in the next step. ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4C=CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg) in anhydrous DMF were added 2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 16 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The crude oil was purified by preparative-HPLC to obtain compound BW (17.1 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87˜5.76 (s, 2H), 4.59 (s, 1H), 4.11˜3.89 (m, 6H), 3.89˜3.76 (m, 3H), 3.72˜3.68 (m, 1H), 3.49˜3.40 (m, 3H), 2.03˜1.98 (m, 2H), 1.89˜1.84 (m, 1H), 1.80˜1.62 (m, 2H), 1.79˜1.51 (m, 1H); MS ESI (m/z) 506 (M+H)+, calc. 505.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.N>CC(C)=O.C(O)(=O)C.O.N1C=CC=CC=1>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCn1ccc(C=O)cc1=O
Agent: N
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCn1ccc(C=CC(=O)O)cc1=O
Temperature: 0 °C
Yield: 73.2 %

Procedure:
N-n-Butyl-4-formyl-2-pyridone (68.71 g), malonic acid (39.90 g), pyridine (225 ml) and piperidine (4.5 ml) were stirred under reflux for 6 hours. The reaction mixture was evaporated under reduced pressure to afford an oil, to which was added water and a small amount of ammonia ('880 solution) to aid dissolution. The solution was taken to pH 4 with acetic acid, the solvent volume was diminished under reduced pressure and acetone added to precipitate a solid. After cooling at 0° C. for a few hours the solid was collected by filtration, washed with acetone and dried in vacuo to afford β-(N-n-butyl-2-oxo-4-pyridyl)acrylic acid (62.06 g) as a white solid, m.p. 131°-134° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C4CC4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example E.14) (0.30 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.08 g, 26%). MS (ISP) 389.3 [(M+H)+]; mp 220-222° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25](Br)[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B1OC(C)(C)C(C)(C)O1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[Cl:37])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: CC1(C)OB(c2ccccc2Cl)OC1(C)C
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3Cl)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 229 mg (1.08 mmol) potassium phosphate to a mixture of 220 mg (0.49 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 17 mg (0.03 mmol) bis(triphenylphosphine)palladium(II) chloride in 2.2 ml toluene. Next, add 176 mg (0.74 mmol) (2-chlorophenyl)boronic acid pinacol ester and stir the mixture for 15 h at 80° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 101 mg (42% of theor.) of the desired product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.O=P(Cl)(Cl)[Cl:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Cl:14])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: [O-][n+]1cc(Br)cc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClC1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-6,7-dihydro-5H-[1]pyrindine N-Oxide (250 mg, 1.17 mM) in 3 mL of CH2Cl2 at room temperature was added POCl3 (0.131 mL, 1.4 mM) and triethylamine (0.202 mL, 1.4 mM). The reaction was stirred at room temperature for 2 hours then was extracted from saturated NaHCO3 solution into ethyl acetate, washed with saturated NaCl, dried over MgSO4, filtered, and concentrated to dryness. The product was used crude in the next step. 1H NMR (CDCl3): d 8.60 (s, 1 H), 7.80 (s, 1 H), 5.40 (d, 1 H), 3.00 (m, 2 H), 2.20 (m, 2 H)
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[I-].[Li+]>C(OCC)(=O)C>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][C:25]#[C:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([OH:4])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCNC(=O)OC(C)(C)C)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Yield: 56.2 %

Procedure:
A solution of 0.764 g (1.41 mmol) of methyl-4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)pheny]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate and 3.77 g (28.2 mmol) of lithium iodide in 30 mL of ethyl acetate was heated to reflux for 18 h. The resulting reaction was acidified, washed with water, an aqueous solution of Na2S2O3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0.5% methanol/dichloromethane to provide 0.417 g (56%) of 4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 527.2(M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:11])[NH:9][CH:10]=1.[H][H].[ClH:16]>CO.[Pd]>[ClH:16].[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[NH:9][CH:10]=1
Reactant: Cc1nc(/C=C/C(=O)N(C)C)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nc(CCC(=O)N(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (E)-N,N-dimethyl-3-(2-methyl-1H-imidazol-4-yl)-2-propenamide (340 mg) in methanol (10 ml) and HCl-saturated ethanol (2 ml) was added to a previously hydrogen-saturated suspension of 10% palladium on charcoal (50% paste with water) (35 mg) in methanol (10 ml) and the resulting suspension stirred at room temperature under hydrogen for 4 h. The mixture was filtered, concentrated in vacuo to ca. 5 ml and ethyl acetate (ca. 40 ml) was added, precipitating the title compound (275 mg) as white flakes, t.l.c. (System A 89:10:1), Rf 0.14. Addition of further ethyl acetate (40 ml) to the mother liquors precipitated further title compound (31 mg).