Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 2.41 g (7.18 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 2.4 mL of acetone and 2.4 mL of water was added 2.34 g (35.63 mmole) of sodium azide. The reaction mixture was heated at 70 degrees for 16 hours and then partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 55 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.44 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark amber oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:28]=3[N:27]=2)[CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[N:27][C:28]=2[CH:34]=1)=[O:36]
Reactant: O=C(O)c1ccc2[nH]c(-c3cccnc3)nc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(-c3cccnc3)nc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-3-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).
Reaction SMILES: [C:1]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:43])/[CH:37]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[C:24]([O:26]C(C)(C)C)=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].Cl>O1CCOCC1>[C:1]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:43])/[CH:37]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[C:24]([OH:26])=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)/C=C/C(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (200 mg, 0.334 mmol) was taken up in 3 mL of a 4 N HCl solution in dioxane and stirred at room temperature under an inert atmosphere of argon for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was portioned between 30 mL of EtOAc and 30 mL of water. The organic layer was further washed with brine until the pH of the water layer was close to neutral, dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA afforded (S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid. (90 mg; 50%). MS (EI) calcd for C31H46N2O6: 542.34. found 543 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[O:5][CH2:6][CH2:7][O:8][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: OCCOc1cc(F)cc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A solution of 2-(3,5-difluoro-phenoxy)-ethanol (2.5 g, 14.3 mmol) in pyridine (10 ml) was cooled with an ice bath and treated dropwise with methanesulfonyl chloride (1.7 g, 14.7 mmol). The ice bath was removed and the mixture was stirred for 16 hours at room temperature. The pyridine was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water, with 2N hydrochloric acid then three times with water, dried over magnesium sulfate and concentrated. The residue was crystallised in diisopropyl ether to give methanesulfonic acid 2-(3,5-difluoro-phenoxy)-ethyl ester (1.8 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1.CN(C)C=O>O>[CH:30]1([CH2:29][N:20]2[CH2:19][CH2:18][N:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=3)[CH2:22][CH2:21]2)[CH2:32][CH2:31]1
Reactant: ClCC1CC1
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1

Procedure:
A stirred mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 1.6 g of sodium bicarbonate, 1.7 g of chloromethylcyclopropane and 60 ml of dimethylformamide was heated at 85°-90° for 16 hours. Additional chloromethylcyclopropane (0.43 g) was added and the reaction mixture heated at 85°-90° for 8 hrs. The reaction mixture was then poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was purified by flash chromatography on silica gel utilizing ethyl acetate/diethylamine (3%) as the eluent. Concentration of the appropriate fractions gave 3-[4-(cyclopropyl)methyl-1-piperazinyl]-1-(4-fluorophenyl)-1H-indazole as a solid. The solid was dissolved in anhydrous diethyl ether and treated with ethereal hydrogen chloride to give the hydrochloride salt. The salt was recrystallized from ethanol-diethyl ether (twice) to give 2.6 g (40%) of 3-[4-(cyclopropyl)methyl-1-piperazinyl] -1-(4-fluorophenyl)-1H-indazole hydrochloride, mp 213°-215°.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(C(C)N=[N+]=[N-])nc3scc(C)n3c2=O)cc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.080 g, 0.25 mmol) and (4-methylphenyl)boronic acid (0.042 g, 0.31 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.011 g, 0.015 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, concentrated and then purified on silica gel (0-25% ethyl acetate/hexane) to give the desired product (50 mg). LCMS calculated for C16H16N5OS (M+H)+: m/z=326.1. Found: 326.0.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.C(Cl)(=O)O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:9]=[C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][N:4]1[CH2:3][C:2]([N:14]1[CH2:19][CH2:18][N:17]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:16][CH2:15]1)=[O:1]
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)Cl
Solvent: ClCCl
Product: O=C(Cn1sc2ccccc2c1=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 54.6 %

Procedure:
Compound 10 (81.5 mg, 0.29 mmol) was treated with 4-nitrophenyl chloroformate carbonochloridate (213 mg, 1.06 mmol) and DMAP (108 mg, 0.88 mmol) in anhydrous CH2Cl2 (4 mL) at room temperature for 16 h. The mixture was washed successively with saturated NaHCO3(aq.) and 1 M HCl(aq) until the solution became transparent. The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of CH2Cl2/MeOH (100:0.5 to 9:1) to give the title compound (70 mg, 56% yield). C20H18N4O6S; pale yellow solid; mp 114-118° C.; IR vmax (neat) 2923, 2854, 1725, 1655, 1520, 1346, 1259, 1163, 1111, 1056, 1024, 862, 748 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.22 (2H, d, J=10.2 Hz), 8.02 (1H, d, J=8.0 Hz), 7.62 (2H, t, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.40 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=10.2 Hz), 4.73 (2H, s), 3.70 (6H, br s), 3.62 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 165.4, 165.1, 155.5, 151.7, 144.7, 141.0, 132.1, 126.5, 125.4, 124.9 (2×), 123.0, 122.0 (2×), 120.2, 44.7, 44.5, 44.2, 43.8, 43.6; ESI-HRMS calcd for C20H19N4O6S: 443.1025. found: m/z 443.1042 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([NH:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[O:10])[CH:5]=[CH:4][N:3]=1.C(OC([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:8][C:7]1[C:2]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:3][CH:4]=[CH:5][C:6]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(N2CCNCC2)c1Cl
Yield: 26.6 %

Procedure:
A solution of 2,3-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.15 g, Example 10a) and 1-t-butoxycarbonylpiperazine (0.19 g) in dimethylsulfoxide (2 ml) was heated at 100° C. for 8 hours. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol and treated with 4M HCl in dioxan (4 ml). Once deprotection was complete the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.050 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:39])[N:37]=1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
tert-Butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (5.0 mg, 0.015 mmol) was mixed with 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step 2, 4.4 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4.1 mg, 49%). LCMS calc. for C28H32F2N5O3S (M+H)+: m/z=556.2. Found: 556.1.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].[F:14][C:15]([F:28])([F:27])[C:16](=O)[CH2:17][C:18]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)=O>C(O)C>[C:20]1([C:18]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:16]([C:15]([F:14])([F:27])[F:28])[CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: O=C(CC(=O)C(F)(F)F)C1=CCCCC1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2C2=CCCCC2)nc1
Yield: 18.3 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (128 mg, 0.54 mmol) and 4,4,4-trifluoro-1-(1-cyclohexenyl)-1,3-butanedione (100 mg, 0.45 mmol) were mixed in ethanol (8 ml). The resulting reaction mixture was heated at reflux temperature for 35 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by flash chromatography using methylene chloride to give the title compound (30.6 mg, 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[C:28](O)(=O)C>C(OCC)(=O)C>[N:4]1([CH2:5][C@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[N:1]=[CH:28]1
Reactant: CC(=O)O
Reactant: Cc1cccc(OC[C@H](CNc2ccccc2N)NC(=O)OC(C)(C)C)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(OC[C@H](Cn2cnc3ccccc32)NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the compound (85 mg) obtained in Step 2 were added methyl orthformate (1 ml) and acetic acid (50 μl), and the mixture was stirred at 60° C. for 1 hr. The mixture was diluted with ethyl acetate, and washed with 1N sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (60 mg).
Reaction SMILES: C(O[C:4]([CH:6]([C:28]([O:30]CC)=O)[C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])C.O.[NH2:34][NH2:35]>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:6]1[C:28]([OH:30])=[N:34][NH:35][C:4]=1[OH:5])=[O:27]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: O
Solvent: CCO
Product: O=C(Nc1cccc2c(-c3c(O)n[nH]c3O)ccnc12)c1c(Cl)cccc1Cl

Procedure:
A mixture or 4-[bis(ethoxycarbonyl)methyl]-8-(2,6-dichlorobenzoylamino)quinoline (200 mg) and hydrazine monohydrate (211 mg) in ethanol (2 ml) was refluxed overnight. After cooling, the resulting precipitates were collected by the filtration, and the residue was washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline as a solid. The obtained solid was treated with ethanol solution of hydrogen chloride, and the precipitates were collected and recrystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline hydrochloride (95 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([O:13]CC)=[O:12])=[C:6]([C:16]([O:18]CC)=[O:17])[N:5]=2.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([OH:13])=[O:12])=[C:6]([C:16]([OH:18])=[O:17])[N:5]=2
Reactant: CCOC(=O)c1cc2nc(C)oc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(C(=O)O)c(C(=O)O)nc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of diethyl 2-methyloxazolo[5,4-b]pyridine-5,6-dicarboxylate (5.42 g, 0.0195 mol) dissolved in absolute methanol (160 mL) is added a 10% aqueous sodium hydroxide solution (36.1 mL, 0.0974 mol). A white precipitate slowly forms. The reaction is stirred at room temperature for one hour, diluted with water (20 mL) to dissolve the precipitate, and concentrated in vacuo. The residue is dissolved in water and acidified to pH 2-3 with concentrated HCl. The resulting white precipitate is collected by filtration, washed with water, and air dried to give 2-methyloxazolo[5,4-b]pyridine-5,6-dicarboxylic acid in 61% yield, melting point 235°-236° C. (dec).
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])=O.[NH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[OH:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[CH2:22][NH:21][C:3]([C:4]1[CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]=1[CH3:6])=[O:8]
Reactant: O=C(CBr)c1cc(F)ccc1F
Reactant: NC[C@H]1CCCC[C@H]1O
Reactant: COC(=O)CC(C)=O
Product: Cc1c(C(=O)NCC2CCCCC2O)cc(-c2cc(F)ccc2F)n1CC1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-(2,5-difluorophenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3—(CH2)m—NH2 and cis-2-aminomethyl-1-cyclohexanol as R1R2NH, MS (ISP) 445.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CC(=O)CC.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][O:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccc(F)cc3)cc12
Yield: 68.8 %

Procedure:
A mixture of 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 101A) (125 mg, 0.29 mmol), potassium carbonate (120 mg, 0.87 mmol), potassium iodide (48 mg, 0.29 mmol) and 4-fluorophenol (65 mg, 0.58 mmol), in butanone (3.5 ml) was heated in a sealed tube at 130° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-100%) to yield the title compound (100 mg, 69%) as a yellow solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[CH:68][C:69]=1[O:70][CH3:71])[C:64](Cl)=[O:65]>>[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[CH:68][C:69]=1[O:70][CH3:71])[C:64]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:65]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 141 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4-dimethoxy benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:15][S:16](O)(=[O:18])=[O:17].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether (see J. Chem Soc., Perkin Trans. 1, 1992, 407-408) with 2 mL of dichloromethane in an ice-bath was added a solution of chlorosulfonic acid (0.73 mL, 11.0 mmol) in 2 mL of dichloromethane dropwise. The resulting mixture was stirred at 0° C. to room temperature for 2 hours, and then oxalyl chloride (11.14 mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF. The resulting mixture was heated to 40° C. for 1 hour and then allowed to cool to room tempereature over a 2 hour period. The reaction mixture was poured into ice-pH 7 phosphate buffer (50 mL), then extracted with EtOAc:Hexane (4:3) (3×150 mL). The combined organic layers were washed with brine (75 mL). The aqueous layer was extracted with EtOAc/Hexane(4:3) (150 mL). The organic layer was dried over Na2SO4, then evaporated by vacuum to give crude product as white solid. This solid was triturated with hexane and collected by filtration, then dried under high vacuum to give 1.555 g (57%) of 4-(4-methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-300° C. 1H-NMR (DMSO-d6) δ 2.34 (s, 3H), 6.91-6.99 (dd, J=7.7, 8.4 Hz, 4H), 7.24-7.27 (d, J=8.4 Hz, 2H), 7.61-7.63 (d, J=8.1 Hz, 2H).