Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclopentyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of cyclopentylamine. LC/MS [9.55 min; 426 (M+1)]
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+].CCCCCC.CC>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: C#CC(O)(CF)CF
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-chlorobenzenesulfonyl chloride (2.1 g) were dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 4 hours while its temperature was raised to room temperature. A hexane/ethane mixed solvent (1/1) was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) and then recrystallized from methylene chloride/hexane to give the titled compound (2.2 g).
Reaction SMILES: B(O)O.[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:16]2[CH:4]=[CH:5][C:9]3[C:18](=[CH:19][CH:20]=[C:10]([O:12][CH3:13])[CH:8]=3)[CH:17]=2)[N:6]=1.[CH3:4][C:5]1[N:15]([C:20]2[CH:4]=[CH:5][C:9]3[C:18](=[CH:17][CH:16]=[C:10]([O:12][CH3:13])[CH:8]=3)[CH:19]=2)[N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2ccc3cc(OC)ccc3c2)n1
Product: CCOC(=O)c1cc(C)nn1-c1ccc2cc(OC)ccc2c1
Reaction time: 96 h
Yield: 37 %
Yield: 25 %

Procedure:
To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)+ 311] and ethyl 5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)+ 311] in a 1.5:1 ratio.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CS(C)=O.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Reactant: NCC1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(Br)ccc3nc21
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline (6.5 g, 0.021 mol), cyclohexanemethylamine (5.46 g, 0.042 mol) and DMSO (20 ml) is heated at 110° C. overnight. The reaction mixture is cooled, poured into water and basified with NH4OH. The mixture is extracted with CH2Cl2 (2×100 ml), and the combined CH2Cl2 extracts are washed with brine, then evaporated to about 20 ml. The solution is purified by column chromatography on silica gel eluting with ethyl acetate to afford 8.0 g (98.8%) of 1-ethyl-6-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 158°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[CH2:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.BrC1C=CC(N2C(=O)C=C(Cl)N(C3CC3)C2=O)=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([Cl:22])=[CH:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(Br)cc1
Agent: O=c1cc(Cl)n(C2CC2)c(=O)n1-c1ccc(Br)cc1
Solvent: O
Product: O=c1cc(Cl)n(-c2ccc(Br)cc2)c(=O)n1C1CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.8 g) obtained in Step 2 was added water (1.31 ml) and phosphorus oxychloride (17.0 ml) was added dropwise with stirring at room temperature. After the completion of the dropwise addition, the mixture was stirred at 110° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added to ice water by small portions and the mixture was stirred. The mixture was stirred at room temperature and extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1→chloroform:acetone=30:1) to give a 1:1.4 mixture (11.6 g, yield 93%) of 1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and 3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4,-dione 34 as a pale-yellow foamy oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[CH:13]=1)[C:8]([F:11])([F:10])[F:9].C(O)C.[OH-].[Na+].O.Cl>>[C:29]([CH:26]1[CH2:27][CH2:28][CH:23]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH:7]([NH:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])[C:8]([F:11])([F:9])[F:10])[CH:21]=[CH:20]3)[CH2:24][CH2:25]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CCC(Oc2ccc3cc(C(NCCC(=O)O)C(F)(F)F)ccc3c2)CC1
Reaction time: 1 h

Procedure:
3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid methyl ester (164 mg, 0.352 mmol) was dissolved in Ethanol (2 mL, 40 mmol) then treated with 1 M of Sodium hydroxide in Water (2 mL, 2 mmol). The mixture was stirred vigorously for 1 hour. pH was adjust to 3-4 with 6 N HCl and reaction was then extracted three times with EtOAc. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white ppt formed. The ppt. was removed via filtration to give a white solid that 99% pure by NMR and HPLC-traces of ethanol remain. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.83 (s, 9H) 0.93-1.10 (m, 1H) 1.11-1.27 (m, 2H) 1.27-1.42 (m, 2H) 1.73-1.89 (m, 2H) 2.19 (d, J=10.29 Hz, 2H) 2.67 (t, J=6.53 Hz, 2H) 3.03-3.18 (m, 2H) 4.22-4.37 (m, 1H) 5.33-5.51 (m, 1H) 7.13 (dd, J=8.91, 2.38 Hz, 1H) 7.21-7.29 (m, 1H) 7.46 (d, J=8.78 Hz, 1H) 7.76 (d, J=9.04 Hz, 1H) 7.85 (d, J=8.78 Hz, 1H) 7.93 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(OC)OC>C(O)(=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:21]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: COC(OC)(OC)c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc(-c3ccccc3)n(CC(OC)OC)c12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (922 mg, 3.6 mmol) from Step C of Example 13 was stirred in glacial acetic acid (2.5 mL) and (trimethoxymethyl)benzene (2.0 g, 10.9 mmol) at 70° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (silica gel, 80:20 hexanes/ethyl acetate) to give methyl 1-(2,2-dimethoxyethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate as a brown oil (1.0 g, 83%): 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.53-7.51 (m, 3H), 7.33 (t, J=8.0 Hz, 1H), 4.76 (d, J=5.0 Hz, 2H), 4.24 (t, J=5.0 Hz, 1H), 3.99 (s, 3H), 3.07 (s, 6H); MS (ESI+) m/z 341 (M+H).
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=O)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=O)C>>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:9])[O:13][C:11](=[O:12])[CH2:10]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC1CC(=O)OC(=O)C1

Procedure:
A 1 liter four-necked flask equipped with a mechanical stirrer, thermometer pocket and condenser, was charged with 3-isobutyl glutaric acid (250 g) and acetic anhydride (62.7 g). The reaction mixture was refluxed at 135°-145° C. for 2.5-3 hours, followed by distilling out the unreacted acetic anhydride at 147°-155° C., and then the distillation was continued under vacuum to ensure removal of traces of unreacted acetic anhydride. The residue was cooled to 25°-30° C. to obtain 220-225 g of 3-isobutylglutaric anhydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Yield: 65 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (69 mg, 65%) which was obtained as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH2:29])[CH3:28]>O1CCCC1>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:10]1[N:9]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=3)[N:7]=2)[CH:13]=[CH:12][N:11]=1)[CH3:28]
Reactant: COC[C@H](C)N
Reactant: Clc1nccc(-c2ncnc(Cl)n2)n1
Reactant: N#Cc1ccc(N)cn1
Solvent: C1CCOC1
Product: COC[C@H](C)Nc1nccc(-c2ncnc(Nc3ccc(C#N)nc3)n2)n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-4-(2-chloro-4-pyrimidinyl)-1,3,5-triazine (i.e., the product of Example 1, Step B) (100 mg, 0.43 mmol) in tetrahydrofuran (2.0 mL) was added 5-amino-2-pyridinecarbonitrile (86 mg, 0.72 mmol), and the resulting mixture was stirred at 40° C. for 3 h. To this mixture was added (S)-1-methoxy-2-propylamine (0.2 mL), and the resulting mixture was refluxed for 2 h. The solution was concentrated and purified using column chromatography on silica gel eluted with a gradient of 70% to 80% ethyl acetate in hexanes to give 84 mg of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN(C)CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCCNc1cc(Cl)ncn1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1 g, 6.7 mmol) and DIPEA (1.03 g, 8 mmol) in iPrOH (20 mL) was added N,N-dimethyl-propane-1,3-diamine (714 g, 7 mmol) at room temperature. The resulting mixture was stirred for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.15 g, yield: 80%). MS (ESI): 215 [M+H]+.
Reaction SMILES: C([C:3]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:5]=[CH:6][N:7](C)[CH3:8])#N.[BrH:21]>C(O)(=O)C>[CH3:20][O:19][C:17](=[O:18])[C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][CH:6]=[N:7][C:8]=1[Br:21]
Reactant: Br
Reactant: COC(=O)C(C#N)=C(C=CN(C)C)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Temperature: 25 °C
Yield: 83.5 %

Procedure:
80.0 g (0.28 mol) of 1-cyano-1-methoxycarbonyl-4-(N,N-dimethylamino)-2-(4-chlorophenyl)-1,3-butadiene was weighed, and 100 ml of acetic acid was added thereto and an acetic acid solution of 25% HBr was then gradually added dropwise thereto at room temperature under stirring. After the dropwise addition, the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into ice water to precipitate a crystal. The crystal thus precipitated was filtrated out and washed with water and was dried to obtain 75.0 g of a white crystal of the aimed product.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3](=[O:22])[CH2:4][C:5](=[O:21])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[CH:7][N:8]([CH3:10])[CH3:9].COC(OC)N(C)C.CN>O1CCCC1>[CH3:10][N:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:5](=[O:21])[C:4]([C:3](=[O:22])[C:2]([CH3:24])([CH3:23])[CH3:1])=[CH:9]1
Reactant: CN(C)C=C(C(=O)CC(=O)C(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: CN
Agent: COC(OC)N(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(C)(C)C)c(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
A 3.6 g. portion of impure 6,6-dimethyl-1-dimethylamino-2-(3-trifluoromethylphenyl)-1-heptene-3,5-dione was dissolved in 17 ml. of N,N-dimethylformamide dimethyl acetal and stirred under reflux at about 100° overnight using a sub-surface nitrogen bubbler. The mixture was then evaporated under vacuum to obtain 3.5 g. of a dark oil, which was dissolved in 120 ml. of tetrahydrofuran and reacted with 15 ml. of 40% aqueous methylamine at ambient temperature for 1 hour. The mixture was then evaporated under vacuum, and the resulting oil was chromatographed on a 300 g. silica gel column with 2:3 ethyl acetate:dichloromethane as the eluting solvent. The product-containing fractions were combined and evaporated under vacuum, and the residue was triturated under hexane to obtain 0.6 g. of the desired product, m.p. 86°-88°, showing the following peaks on nmr analysis in DMSOd6 : δ7.6-8.2 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 1.2 (s, 9 H, C(CH3)3).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.[F:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([I:30])[CH:24]=1.[CH2:31]([CH:34]1[CH2:39][CH2:38][CH:37]([CH:40]2[CH2:45][CH2:44][CH:43](C=CC=O)[CH2:42][CH2:41]2)[CH2:36][CH2:35]1)[CH2:32][CH3:33].Cl.[O:51]1C[CH2:54][CH2:53][CH2:52]1>O>[F:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([I:30])[C:24]=1[CH:52]([OH:51])[C:53]([CH:43]1[CH2:44][CH2:45][CH:40]([CH:37]2[CH2:38][CH2:39][CH:34]([CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36]2)[CH2:41][CH2:42]1)=[CH2:54]
Reactant: C1CCOC1
Reactant: CCCC1CCC(C2CCC(C=CC=O)CC2)CC1
Reactant: Cc1cc(F)cc(I)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: C=C(C1CCC(C2CCC(CCC)CC2)CC1)C(O)c1c(F)cc(C)cc1I
Temperature: -20 °C

Procedure:
An initial charge of 31.1 g (0.22 mol) of 2,2,6,6-tetramethylpiperidine in 350 ml of tetrahydrofuran is cooled down to −20° C. 135 ml of 1.6 M butyllithium in hexane (0.22 mol) are added dropwise at this temperature. The mixture is cooled down to -18° C. and 47.2 g (0.2 mol) of 1-fluoro-3-iodo-5-methylbenzene are added dropwise at this temperature. The reaction mixture is stirred for another hour at −80° C. and then treated with 52.5 g (0.2 mol) of 3-(4′-propylbicyclohexyl-4-yl)propenal. The mixture is allowed to warm to 0° C., hydrolyzed with water and diluted hydrochloric acid and then subjected to conventional work-up.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Temperature: 150 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
A mixture of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (3.54 g, 15.1 mmol), 1-fluoro-3-nitrobenzene (2.24 g, 15.9 mmol), potassium carbonate (6.26 g, 45.3 mmol) and N,N-dimethylformamide (30 mL) was stirred at 150° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.82 g, 37%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](O)=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:44][CH2:45][C:46]([CH3:51])([CH3:50])[C:47]([NH2:49])=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(=O)OCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](=[O:42])[NH:44][CH2:45][C:46]([C:47](=[O:48])[NH2:49])([CH3:51])[CH3:50])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(CN)C(N)=O
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.6 %

Procedure:
The compound of step 5 (0.176 g, 0.30 mmol) was dissolved in 2.5 ml of anhydrous DCM at 0° C. 3-Amino-2,2-dimethyl-propionamide (0.044 g, 0.38 mmol), EDIA (0.13 ml, 0.75 mmol) and TBTU (0.120 g, 0.38 mmol) were added and the solution was stirred at room temperature for 60 h. EA (15 ml) was then added and the solution was washed with water, 1 N hydrochloric acid, a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/MOH, 100:0, then 97:5, then 95:5) to give 0.188 g of the title compound as a greenish-brown wax.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O.CC(C)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CC(C)=O
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 61.8 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (3.16 g, 5.86 mmol) in 1,2-dimethoxyethane (40 mL) and water (20 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.87 g, 7.03 mmol), sodium carbonate (1.55 g, 14.66 mmol) and tetrakis triphenylphosphine palladium (0) (0.68 g, 0.59 mmol) at 80° C. for eighteen hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (15 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using 10% methanol in dichloromethane as an eluent to give a mixture of diethyl acetal, methyl ethyl acetal, and aldehyde. This mixture was reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.53 mmol) in acetone (100 mL) and water (10 mL) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solid was filtered and dried in vacuo to give the title compound (1.690 g, 62%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) 9.64 (d, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 8.06 (t, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30-7.38 (m, 2H), 7.27 (d, 1H), 7.12-7.20 (m, 2H), 6.94 (dd, 1H), 6.33-6.59 (b, 2H), 4.04 (s, 3H), 3.94 (s, 3H); RP-HPLC (Conditions d) Rt 7.36 min.; MS: MH+ 467.