Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([NH:30][C:31]([NH:42]C(OC(C)(C)C)=O)=[N:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:9][O:10][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][NH:32][C:31]([NH2:42])=[NH:30])=[CH:40][CH:39]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(=NCCc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N=C(N)NCCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,3,3-triphenylpropanol (11.54 g, 40 mmol), N,N'-Bis(t-butoxycarbonyl)-N"-2-(4-hydroxyphenyl)ethylguanidine (15.18 g, 40 mmol), and triphenyphosphine (1.54 g, 44 mmol) in THF (400 mL) was cooled to -15° C., and a solution of diethyl azodicarboxylate (7.66 g, 44 mmol) in 50 mL THF was added dropwise with stirring. The mixture was allowed to warm to room temperature, and then refluxed for 4 hr. The mixture was concentrated, and the residue taken up in toluene (300 mL). Triphenylphosphine oxide was removed by filtration, and the filtrate concentrated and chromatographed on silica gel with dichloromethane. N',N'-bis(t-butoxycarbonyl)-N-(2-(4-(3,3,3-triphenylpropoxy)phenyl)ethylguanidine was obtained as a colorless gum (8.0 g, 31%). This material was dissolved in isopropanol (50 mL) containing anisole (8 g) and anhydrous hydrogen chloride (10 g), and the solution heated until gas evolution was observed, at ca. 50° C. The solution was maintained at this temperature for 15 minutes, then concentrated in vacuo. The residue was stirred vigorously for two days with a mixture of ethyl acetate (200 mL) and 1.0N aqueous sodium bicarbonate, and the resulting white solid collected by filtration, and washed with water, acetone, ethyl acetate, and THF, to provide the bicarbonate salt, containing about 0.75 equivalents of water, as a white powder, mp 172°-176° C. (dec). This material was suspended in 250 mL water, and stirred vigorously while heating to 90° C. Gas evolution was observed, and the solid became gummy for a time, then once again became powdery. When gas evolution had ceased, the mixture was cooled, and the solid collected by filtration and dried in vacuo overnight. The title compound was obtained as the carbonate salt, a white powder, mp 150°-180° C. (dec) with slow heating, 180°-183° C. (dec) with rapid heating. Anal. calcd. for C30H31N3O·0.5CH2O3 : C, 76.22; H, 6.71; N, 8.74. Found: C, 75.79; H, 6.68; N, 8.87.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:15]([S:29](Cl)(=[O:31])=[O:30])=[CH:14]2.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:15]([S:29]([N:8]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:2][CH3:3])[CH2:9]1)(=[O:31])=[O:30])=[CH:14]2
Reactant: CCC1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methylene chloride solution (700 ml) of 2-ethylpiperazine hydrochloride (5.00 g) were added 5-chloro -1-phenylsulfonylindol-2-sulfonyl chloride (7.14 g) and triethylamine (11.16 ml) and the resulting mixture was stirred at room temperature for 3 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methanol:methylene chloride=1:100), whereby the title compound (5.86 g) was obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:13]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])[N:14]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccccc1
Agent: Cl[Sn]Cl
Product: Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccccc3)[nH]2)cc1
Yield: 35.4 %

Procedure:
2-(4-Nitrophenyl)-5-phenyl-N-(2-thiazolyl)imidazole-4-carboxamide (0.52 g) obtained in Example 51 and tin(II) chloride 6 hydrate (1.2 g) were reacted and treated in the same manner as in Example 59 to give 2-(4-aminophenyl)-5-phenyl-N-(2-thiazolyl)imidazole-4-carboxamide (0.17 g), melting point 257-258° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C=O)C.O.O.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>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc3ccccc3c2)cc1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
3-Bromo quinoline (2 g, 0.0096 mol) was dissolved in DMF:water (3:1, 20 mL), and potassium phosphate (6 g, 0.0288 mol) and 4-fluorophenyl boronic acid (1.6 g, 0.011 mol) were added at RT. The reaction mixture was degassed for 5 min, and Pd(PPh3)4 (0.55 g, 0.00048 mol) was added. The reaction mixture was heated by microwave at 80° C. for 1 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, the residue was purified by column chromatography (30% EtOAc:Hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a white solid (1.4 g, 66% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][C:2]2[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[C:4]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(COc2cc(Cl)nnc2OCc2ccc(OC)cc2)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2cc(SCc3ccc(Cl)cc3)nnc2OCc2ccc(OC)cc2)cc1
Yield: 100 %

Procedure:
A mixture of 6-chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 7; 550 mg, 1.42 mmol), (4-chlorophenyl)methanethiol (248 mg, 1.56 mmol), Pd2(DBA)3 (52.1 mg, 0.057 mmol), XANTPHOS (65.8 mg, 0.114 mmol) and Hunig's base (ethyl diisopropylamine; 404 mg, 3.13 mmol) was subjected to microwave irradiation at 120° C. for 1 hour. The resulting mixture was poured into water and extracted into ethyl acetate before the combined organics were washed with brine and then dried (magnesium sulphate). The resulting solution was evaporated in vacuo and purified by silica chromatography (eluting with 0-40% dichlormethane in petrol) to yield 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (201 mg, 1.42 mmol, 28% yield).
Reaction SMILES: O=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.C1COCC1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O.O>[N:6]1([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH:2]=[CH:3][CH2:4][C@@H:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC=CN1C(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of (R)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (D24) (14.3 g, 55.58 mmol) in toluene (100 ml) cooled at −50° C., LiEt3BH 1M sol in THF (58.4 ml, 58.36 mmol) was added dropwise maintaining the reaction temperature below −45° C. After complete addition the mixture was stirred at −45° C. for 30 min. DIPEA (42 ml, 239 mmol), DMAP (102 mg, 0.83 mmol) and TFAA (8.9 ml, 63.92 mmol) were added sequentially maintaining the reaction temperature below −45° C. After complete addition, the reaction mixture was warmed to 20-25° C. within one hour and kept for an additional 2 hrs at this temperature. The reaction mixture was slowly charged with water (8 ml) so that the temperature did not exceed 5° C. and diluted with EtOAc (50 ml). Aqueous and organic phases were then separated and the organics washed again with water (8 ml), dried over Na2SO4 and evaporated to obtain residue which was purified by Biotage SNAP-Si cartridge (50 g) eluting with cHex/EtOAc from 90/10 to 50/50. Collected fractions, after solvent evaporation afforded the title compound (D25) (10.4 g).
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[C:5]([O:17][C:18]([F:21])([F:20])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24])[C:3]1[CH:4]=[C:5]([O:17][C:18]([F:20])([F:21])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A mixture of ethyl 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2.19 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.05 g, yield 100%) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[ClH:20]>CO.O1CCOCC1>[ClH:20].[ClH:20].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
tert-Butyl(1-pyridin-2-ylpyrrolidin-3-yl)carbamate (2.5 g) was dissolved in methanol (4 mL) and was treated with 4M hydrogen chloride in 1,4-dioxane (8 mL). The mixture was stirred overnight at RT. The solvents were evaporated under reduced pressure. The residue was washed with ether and dried to give the desired product (2.1 g, 92%). LCMS: (M+H)=164.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(OCc3ccco3)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(OCc3ccco3)cccc2[nH]1
Reaction time: 24 h

Procedure:
The 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester 94 obtained above is mixed with a 1M-solution of KOH in EtOH (13.3 ml, 13.3 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4]([Br:17])[N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC.N#N>CN(C=O)C.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>[Br:17][C:4]1[N:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(Br)nc(-c3ccccn3)c2s1
Temperature: 80 °C

Procedure:
A solution of 1-(4,6-dibromothiazolo[5,4-c]pyridin-2-yl)-3-ethylurea (Intermediate 8) (0.25 g, 0.65 mmol) and 2-(tributylstannyl)pyridine (0.21 mL, 0.65 mmol) in DMF (10 mL) was purged with N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium (0) (0.075 g, 0.065 mmol). The reaction mixture was again degassed by purging N2 for 15 min then heated to 80° C. for 16 h. The solvent was distilled under reduced pressure, water (25 mL) added and extracted with EtOAc (3×100 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (100-200M, 2.50% MeOH-DCM) to afford the desired product that was finally triturated with ether (0.10 g, 40%). The regio chemistry was ascertained by NOE experiments.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][Cl:32].[OH-].[Na+].Cl>CN(C=O)C>[Cl:32][CH2:31][CH2:30][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCCl)cc2c1=O
Temperature: 50 °C

Procedure:
3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (5.9 g) was dissolved in DMF (120 ml). Potassium carbonate (27.6 g) and 1-bromo-2-chloroethane (9.99 ml) were added and heated at 50° C. for 18 hours. The reaction mixture was cooled to 40° C. and 2N NaOH (20 ml) was added and the mixture heated at 40° C. for 18 hours. The cooled reaction mixture was adjusted to pH 1 using concentrated hydrochloric acid to yield a brown oil. This oil was extracted with methylene chloride (×2), the organic solution was filtered through silicone treated filter paper (Whatman 1PS) and concentrated to yield 3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid as a brown oil (6.59 g); NMR Spectrum: (DMSOd6) 2.22 (s, 1H), 3.85 (m, 2H), 4.40 (m, 2H), 6.60 (m, 1H), 6.95 (m, 1H), 7.40 (m, 1H), 7.46 (m, 1H), 7.56 (m, 1H), 7.90 (m, 1H), 7.95 (m, 1H); Mass Spectrum: M+H+ 358.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:38][CH2:39][CH2:40][NH2:41])(=[O:37])[CH:34]([CH3:36])[CH3:35]>>[C:1]([NH:6][C@H:7]([C:29]([NH:41][CH2:40][CH2:39][S:38][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)C(=O)SCCN
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)C
Yield: 75 %

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-isobutyrylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 65%). 15 is collected in the form of a colorless foam with a yield of 75%. Rf (AcOEt/petroleum ether, 5/5): 0.6. [α]D20=+7.9° (c 1.27, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Product: CCC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and propionic acid chloride.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH2:8][OH:9])=[CH:6][N:7]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CN(c1ncc(CO)s1)C1CCCCO1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CN(c1ncc(C=O)s1)C1CCCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.2 %

Procedure:
MnO2 (3 g, 34.82 mmol) was added to a solution of (2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazol-5-yl)methanol (1.59 g, 6.96 mmol) in CHCl3 (50 mL). The resulting mixture was stirred at RT for 2 days. Then the solution was filtered through celite and concentrated, yielding 2-(methyl-(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde (1.5 g, 96%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([NH2:36])(=[O:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([NH:36][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[O:23])[CH2:20][CH2:21]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:35])[CH3:34]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.819 g, 8.27 mmol), acetamide (2.442 g, 41.3 mmol), cesium carbonate (4.04 g, 12.40 mmol), and xantphos (0.469 g, 0.810 mmol) were stirred in dry dioxane (59.1 mL) while argon was bubbled through the mixture for 15 minutes. After this time palladium acetate (0.139 g, 0.620 mmol) was added, and argon was bubbled through the solution for an additional 10 minutes. The round bottom flask was then fitted with a reflux condenser, flushed with argon, and heated to 100° C. gradually from room temperature while under a balloon of argon. After 3.5 hours at 100° C. the reaction mixture was cooled to room temperature. The reaction mixture was diluted with a 4:1 mixture of ethyl acetate and THF (300 mL) and water (100 mL). A bright yellow solid was removed by suction filtration and discarded. The organic layer was separated from the aqueous and washed with brine (200 mL). In addition, the aqueous layer was back-extracted with the ethyl acetate/THE mixture (100 mL), which was then also washed with brine (50 mL). The combined organic layers were dried over magnesium sulfate and evaporated to yield a peach-colored oil. It was stirred in dichloromethane (50 mL) for 1.5 hours, and a white solid formed which was collected by suction filtration and washed with more dichloromethane to give N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.328 g, 83% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.59 (s, 1H), 9.79 (s, 1H), 8.19 (d, 1H), 8.07 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.71 (dd, 1H), 2.02 (s, 3H), 1.62 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 485.1 (M+H+).
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[C:15]([N+:16]([O-])=O)=[CH:14][N:13]([CH3:19])[C:12](=[O:20])[CH:11]=1.[NH4+].[Cl-]>CCO.[Fe]>[NH2:16][C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[CH:11][C:12](=[O:20])[N:13]([CH3:19])[CH:14]=1
Reactant: Cn1cc([N+](=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1cc(N)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 4-(2-fluoro-4-iodophenylamino)-1-methyl-5-nitropyridin-2(1H)-one (960 mg, 2.47 mmol), NH4Cl (540 mg, 10.1 mmol) and Fe (453 mg, 8.1 mmol) in 70 mL of aqueous EtOH (70% by volume was heated to 90° C. for 2 hours. After cooled to room temperature, the solution was passed through a layer of celite, and the filtrate was concentrated under the reduced pressure to give the title compound as a tan-color solid which was used for the next reaction without further purification. (732 mg, 83% yield)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:17][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:13]([NH2:14])[CH:12]=[N:11][CH:10]=1
Reactant: Cc1cncc([N+](=O)[O-])c1N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cncc(N)c1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A suspension of Pd on C, (10%, wet, Degussa) (130.6 mg, 0.1227 mmol) with 1-methyl-4-(3-methyl-5-nitro-4-pyridyl)piperazine (290 mg, 1.227 mmol) in methanol (5.800 mL) was stirred at rt overnight under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a celite pad and washed with methanol and ethyl acetate and the filtrate concentrated in vacuo to leave 5-methyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a yellow oil (243 mg, 96%). MS (ES+) 207.1.