Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]([C@@H:14]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:15]([NH:17][N:18]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:19](=[O:40])[C@@H:20]([CH3:39])[NH:21][C:22]([O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[O:16])C/C=C/C1C=CC=CC=1)(O)=O.O1CCCCC1ON.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([N:18]([C:19](=[O:40])[C@@H:20]([CH3:39])[NH:21][C:22]([O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[NH:17][C:15](=[O:16])[CH2:14][CH2:45][CH:46]([CH3:48])[CH3:47])[CH:42]([CH3:43])[CH3:44]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.85 g of (E)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethoxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in 3 ml of dimethylformamide was treated with 0.60 g of O-(tetrahydro-2H-pyran-2(RS)-yl)hydroxylamine and 0.54 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. The ethyl acetate layer was then dried over magnesium sulphate and evaporated. The residue was triturated with hexaneldiethyl ether (2:1) to give 1.67 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethoxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][NH:5][CH2:6]2.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>O.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]>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:6]2
Reactant: CN1C2CCC1CNC2
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C2CCC1CN(c1cccc(C(F)(F)F)c1)C2
Temperature: 80 °C
Yield: 30.8 %

Procedure:
8-Methyl-3,8-diaza-bicyclo[3.2.1]octane (0.25 g, 1.98 mmol) (see, U.S. Pat. No. 3,951,980), 1-bromo-3-trifluoromethylbenzene (0.22 ml, 1.80 mmol), tris(dibenzylideneacetone)dipalladium(0)(0.016 g, 0.018 mmol), (s)-(−)-2,2′-bis(diphenylphosphino)-1-1″-binaphthyl (0.011 g, 0.014 mmol), sodium tert-butoxide (0.24 g, 2.52 mmol) and toluene (5 ml) were combined in a sealed tube and heated at 80° C. for 15 hours. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with water (1×100 ml), dried with magnesium sulfate and evaporated to a brown oil. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-methyl-3-(3-trifluoromethylphenyl)-3,8-diazabicyclo[3.2.1]octane (0.15g, 30.8% yield) as a golden oil. The oil was dissolved in 1N hydrochloric acid/methanol (30 mL) and concentrated to yield the hydrochloride salt as a pale yellow foam. 1H NMR DMSO-d6 δ: 11.30 (s, 1H), 7.41 (t, J=8.3 Hz, 1H), 7.20-7.03 (m, 3H), 4.02 (brd s, 2H), 3.75 (d, J=12.9 Hz, 2H),3.37 (d, J=12.0 Hz, 2H), 2.69 (d, J=5.0 Hz, 3H), 2.22-2.09 (m, 2H), 1.99-1.89 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filtered, washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene to this lawessons reagent (4.6 g, 11.5 mmol) is added and refluxed at 110° C. for 8h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 116 mg, 0.698 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6d as a brown solid (63%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:11]([O:18][CH2:19][C:20](Cl)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1>[CH2:11]([O:18][CH2:19][C:20]([NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1cccnc1N
Reactant: O=C(Cl)COCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cccnc1NC(=O)COCc1ccccc1
Yield: 38.1 %

Procedure:
To a slurry of 2-amino-nicotinamide (100 mg, 0.7 mmol) in THF (5 ml) was added dropwise benzyloxyacetyl chloride [19810-31-2] (127 μL, 0.8 mmol) in THF (2 ml) at 5° C. The reaction mixture was heated to reflux for 2 hours. Water was added, the phases were separated and the inorganic layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 as eluent yielded 2-(2-benzyloxy-acetylamino)-nicotinamide (76 mg, 36%), MS(m/e): 286.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[NH2:37][C:38]1[C:46]([Cl:47])=[CH:45][C:44](I)=[CH:43][C:39]=1[C:40]([OH:42])=[O:41].C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[NH2:37][C:38]1[C:46]([Cl:47])=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:39]=1[C:40]([OH:42])=[O:41]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Nc1c(Cl)cc(I)cc1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(Cl)c(N)c(C(=O)O)c3)cc12
Yield: 99 %

Procedure:
400 mg (0.793 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 32 mg (0.040 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct and 259 mg (0.872 mmol) of 2-amino-3-chloro-5-iodo-benzoic acid were placed in a microwave vial. To the vial was added 3 mL of acetonitrile and 2 mL of a saturated aqueous solution of sodium bicarbonate. The vial was sealed and purged with nitrogen and evacuated with vacuum (3×). The vial was irradiated in a microwave at 90° C. for 400 seconds. The resulting mixture was distributed between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated and then the material was triturated with ether to afford 430 mg (0.785 mmol, 51% yield) of 2-amino-3-chloro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid as an orange solid. 1H NMR (500 MHz, CD3OD) δ 8.47 (d, 1H), 8.03 (m, 3H), 7.94 (d, 1H), 7.89 (s, 1H), 7.65 (d, 1H), 7.46 (dd, 1H), 7.34 (m, 3H), 7.09 (d, 1H), 7.02 (t, 1H), 3.82 (s, 3H), 2.33 (s, 3H); MS: m/z 547.9 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=1)O)C1C=CC=CC=1.Cl>[OH-].[Pd+2].[OH-]>[F:25][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][CH3:24])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccc(Cc2ccccc2O)cc1F
Reaction time: 15 h
Yield: 92.3 %

Procedure:
To a (2-benzyloxyphenyl)-(3-fluoro-4-methoxyphenyl)-methanol (1.50 g, 4.43 mmol) methanol solution (29 mL), a 20% palladium hydroxide catalyst (150 mg) was added, and furthermore 2N—HCl (2 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 15 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (0.95 g, 92%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=O)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CON=C1C[C@@H](c2noc(C3CCN(C(C)=O)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 1-acetyl-4-piperidinecarboxylic acid, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=488.4.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C1C=CC=CC=1.[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[N+:24]([O-:26])=[O:25].S(=O)(=O)(O)O>O>[CH2:1]([O:4][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([N+:24]([O-:26])=[O:25])[C:12]([Cl:11])=[C:20]([N+:21]([O-:23])=[O:22])[CH:19]=1)[CH2:2][CH3:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Into a 1000 ml round-bottomed flask equipped with a stirrer, thermometer and Marcusson-condenser 180 g (3 moles) of n-propanol, and 380 g of benzene are weighed in, whereupon 493 g (2 moles) of 4-chloro-3,5-dinitro-benzoic acid and 20 g of concentrated sulfuric acid are added under stirring. The reaction mixture is heated to boiling on a water bath under stirring (86° C.) until no more water is distilled off. The water thus formed is collected in the Marcusson-condenser and removed if necessary. In the meantime the upper benzene/n-propanol phase is continuously re-introduced into the flask. The reaction having been completed the mixture is cooled to room temperature under stirring, the precipitated crystals are filtered off, washed with cold n-propanol and dried. Thus 490 g of the desired compound are obtained, yield 85%, purity 98%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:15]=1)=[N:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=2)([CH3:3])[CH3:2]>C1COCC1.[O-2].[Mn+4].[O-2]>[CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:15]=1)=[N:9][CH:10]=[C:11]([CH:13]=[O:14])[CH:12]=2)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc2ncc(CO)cc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)Nc1nc2ncc(C=O)cc2s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50 %

Procedure:
A mixture of the above-obtained (2-(isopropylamino)thiazolo[4,5-b]pyridin-6-yl)methanol (≦1.05 mmol) and manganese(IV) oxide (activated, 85%, 1.25 g, 12.2 mmol) in THF (12 mL) was stirred at rt for 3.5 hr. The insoluble material was removed by suction filtration through Celite® 545. The filtrate was concentrated under vacuum and dried over Drierite® under vacuum to give the title compound (0.115 g, 50% yield over two steps) as a pale solid.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[K+].[N:26]#[C:27]Br>CO>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:16][C:27]([NH2:26])=[N:18][N:17]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: Nc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a suspension of 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (105 mg, 0.33 mmol) (described in WO 2011/074560) in MeOH (4 mL) was added potassium bicarbonate (42 mg, 0.42 mmol) followed by cyanogen bromide (0.036 mL, 0.37 mmol) and the reaction mixture stirred for 3 h. The solvent was removed under reduced pressure and the residue purified on silica gel chromatography eluting with 0.5 to 8.5% MeOH/DCM to give Compound 89a (40 mg, 37% yield) as an orange solid. LCMS=1.75 min using analytical method (M), 309.0 (M+H). 1H NMR (400 MHz, CDCl3 containing CD3OD) δ 8.09 (d, J=1.5 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 4.59 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][N:14]=1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:36][C:37]1[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH2:41])=[O:40].FC(F)(F)C(O)=O>N1C=CC=CC=1.CN(C)C=O.ClCCl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]=[CH:15][C:16]([C:17]2[NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH2:41])=[O:40])[C:37]=3[N:36]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)cn1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)nc3)nc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)nicotinic acid (3 g, 10.6 mmol) in pyridine (10 mL) and N,N-dimethylformamide (50 mL) at ambient temperature was added 1,1′-carbonyldiimidazole (2.2 g, 16 mmol). The mixture was heated at 40° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (2.4 g, 10.6 mmol), stirred at ambient temperature, for 16 hours and concentrated. The residue was heated in acetic acid (100 mL) at 110° C. for 2 hours, cooled and concentrated. The residue was purified by flash chromatography on silica gel using ethyl acetate to provide the acyclic intermediate. This intermediate was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) and the mixture was stirred at room temperature for 16 hours and was concentrated. The residue was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) to provide the title compound. 1H NMR (methanol-d4) δ 2.04-2.36 (m, 3H), 2.49-2.74 (m, 1H), 3.39-3.72 (m, 2H), 4.98 (t, J=7.63 Hz, 1H), 7.17-7.49 (m, 1H), 7.69 (d, J=8.14 Hz, 1H), 7.81 (d, J=8.14 Hz, 1H), 7.99 (d, J=7.46 Hz, 1H), 8.64 (dd, J=8.31, 2.20 Hz, 1H), 9.42 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14](Br)=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].C[Zn+].[CH3:22]N1CCN(C)C1=O>C(N1C=CN(C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C.O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14]([CH3:22])=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Br)s2)CC1
Reactant: CN1CCN(C)C1=O
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(C)s2)CC1
Temperature: 50 °C

Procedure:
To a solution of cis/trans-4-(5-bromo-4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (371 mg, 1.12 mmol) and 2 M methyl zinc chloride solution in tetrahydrofuran (0.837 ml, 1.67 mmol) in a 5:1 mixture of tetrahydrofuran and 1,3-dimethyl-2-imidazolidinone (6 ml) was added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) chloride (15.2 mg, 22.3 μmol) at room temperature. The reaction mixture was heated at 50° C. for 2 h. After cooling to room temperature the reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (170 mg, 57%) as colorless oil, with a purity of 80% according to GC. MS m/e: 268 ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[S:36]1[CH:40]=[CH:39][NH:38][C:37]1=[S:41].O>C1COCC1.C(N(CC)CC)C>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][S:41][C:37]5[S:36][CH:40]=[CH:39][N:38]=5)=[CH:8][CH:7]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: S=c1[nH]ccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(CSc2nccs2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0002 mol), obtained in Example B14, and 2(3H)-thiazolethione (0.001 mol) in THF (1 ml) and triethylamine (0.1 ml) was stirred at room temperature for 18 hours, poured out into water and extracted with CH2Cl2/CH3OH. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over kromasil 60 μm (eluent: CH2Cl2/CH3OH; 90/10). The pure fractions were collected and the solvent was evaporated, yielding (70%) of 4(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)[4-[(2-thiazolylthio)methyl]phenyl]methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:585, 586 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:35])(=[N:24][S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[O:23])=[CH:18][C:17]=1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=O)C1C=CC=CC=1.Cl>CO>[CH2:36]([C:17]1[CH:18]=[C:19]([S:22]([CH3:35])(=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=2)(=[O:27])=[O:26])=[O:23])[CH:20]=[CH:21][C:16]=1[OH:15])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
500 ml of a 10% sodium carbonate solution was added to a solution of the oil of Step C in 250 ml of methanol and the mixture was stirred for 3 hours at 60° C. and was then cooled to room temperature. 100 ml of 20% hydrochloric acid were added to the mixture which was then extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure and the residue was triturated with petroleum ether to obtain 40 g of 2-hexyl-4-(S-methyl-N-tosyl-sulfonimidoyl)-phenol melting at 109°-110° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=1)=[CH:29][CH:28]=2)=[O:24])[CH3:21]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-ethoxycarbonyl-5-aminoindole were reacted to yield N2-(2-ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.84 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=3.6 Hz), 7.50 (d, 1H, J=9 Hz), 7.23-7.15 (m, 3H), 7.03 (bd, 1H, J=8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.38 (q, 2H, J=7.2 Hz), 4.22 (s, 4H), 1.41 (t, 3H, J=6.9 Hz); LCMS: ret. time: 23.58 min; purity: 100%; MS (m/e): 451 (MH+).