Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].[NH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[CH2:25]([O:24][C:23]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:6])=[O:27])[CH3:26]
Reactant: CCCCCCCCSCCN
Reactant: CCOC(=O)Cl
Reactant: CCCc1c(OC)ccc(C(=O)O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCSCCNC(=O)c1ccc(OC)c(CCC)c1OC(=O)OCC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In the meantime, 6.00 g of 2-hydroxy-3-n-propyl-4-methoxy-benzoic acid was dispersed in 120 ml of methylene chloride, and the dispersion was cooled to -10° C. To the dispersion were added 9.93 ml of triethylamine and 5.45 ml of ethyl chlorocarbonate, and the mixture was agitated for 30 minutes. To the mixture was added the mixture of 2-aminoethyl-n-octylsulfide and hydrazide which had been dispersed in methylene chloride. The mixture was agitated at -10° C. to 0° C. for 3 hours. The reaction mixture was filtered, and the precipitate was washed with methylene chloride. The filtrate and the wash solution was combined, washed with water and then with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 6.28 g of 2-(2'-ethoxycarbonyloxy-3'-n-propyl-4'-methoxybenzoylamino)ethyl-n-octylsulfide.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:32]([CH:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=1)[C:35](OC)=O)=[O:33].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:35]=[C:34]([CH2:39][C:40]4[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=4)[C:32](=[O:33])[N:24]=3)=[CH:11][CH:10]=2)=[N:14][C:15]=1[C:20]([F:22])([F:23])[F:21]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)n2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)n4)cc3)nc2=O)cn1
Temperature: 80 °C
Yield: 2.55 %

Procedure:
To the solution of 4-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, trifluoroacetate (250 mg, 0.264 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (71.1 mg, 0.317 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (110 mg, 0.793 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (3.6 mg, 6.74 μmol, 2.55% yield). LCMS: rt=3.31 min, [M+H+]=534
Reaction SMILES: [NH:1]=[C:2]=[NH:3].C(OC(NC(NC(OC(C)(C)C)=O)=S)=O)(C)(C)C.[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[CH3:29].C(O)C(N)(CO)CO.C(O)(C(F)(F)F)=O>ClCCCl.ClCCl>[CH3:28][C:25]1[C:24]([CH3:29])=[C:23]([NH:22][C:2]([NH2:3])=[NH:1])[O:27][N:26]=1
Reactant: N=C=N
Reactant: Cc1noc(N)c1C
Agent: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(NC(=N)N)c1C
Temperature: 50 °C
Reaction time: 36 h

Procedure:
To PS-carbodiimide resin (Argonaut Technologies) (1.069 g, 1.71 mmol, 1.6 mmol/g) placed in a 20 mL vial was added anhydrous 1,2-dichloroethane (6.0 mL), N,N′-bis(tert-butoxycarbonyl)thiourea (235 mg, 0.85 mmol) in anhydrous 1,2-dichloroethane (2.0 mL), and 5-amino-3,4-dimethylisoxazole (63.9 mg, 0.57 mmol) solution or dispersion in anhydrous 1,2-dichloroethane (1.0 mL). The reaction mixture was shaken at 50° C. until the reaction completed, typically for 36 hours. The reaction mixture was brought to room temperature and PS-trisamine (317 mg, 1.14 mmol, 3.6 mmol/g) was added. The reaction mixture was shaken at room temperature for 24 hours. The resin was removed by filtration and washed with 1,2-dichloroethane (3.0 mL) and methanol (3.0 mL). The combined organic layers were dried in a Genevac at 40° C. The resultant crude reaction mixture was mixed with TFA in dichloromethane (25% vol., 5.0 mL) and shaken at room temperature for 6 hours followed by evaporation in Genevac 40° C. to give crude xxix-187 (152 mg, 99%).: MS m/z═155 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][NH:37]2)=[CH:33][C:32]=1[S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)[S:40]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:31]=1[CH3:30])[NH:37][N:36]=[CH:35]2)(=[O:42])=[O:41]
Reactant: COc1ccc(CNc2cccc(F)n2)c(OC)c1
Reactant: Cc1cc2[nH]ncc2cc1S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cccc(F)n2)S(=O)(=O)c2cc3cn[nH]c3cc2C)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Added N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (1.0 g, 3.87 mmol) to THF (19 mL) and cooled to −78° C. Added LHMDS (6.5 mL, 6.45 mmol), warmed to RT, stirred for 30 min, and cooled back to −78° C. Following addition of LHMDS, solution turned clear and pink in color. After warming to RT, solution became clear, yellow. At −78° C., added 6-methyl-1H-indazole-5-sulfonyl chloride (4-4, 594.8 mg, 2.58 mmol) in THF (6.5 mL) at −78° C. via syringe followed by THF rinse. Solution remained yellow in color. Allowed reaction flask to remain in bath and gradually warm to RT overnight. Following this duration, quenched with 40 mL saturated NH4Cl, diluted with 20 mL EtOAc. Separated layers, back-extracted aqueous with 3×10 mL EtOAc. Dried organics over Na2SO4, filtered, concentrated to give an orange oil. Purified by normal-phase ISCO (40 g column, 0-50% EtOAc:Hex) to give 4-5 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][CH:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOC1CCc2ccccc2C1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with rac.-2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 1:1 plus 2% ethyl acetate) to provide, after crystallization from diethyl ether-hexane, 0.79 g of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 86°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:13]([CH3:14])[CH3:12]
Reactant: CNC
Reactant: COc1ccc(F)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c(CN(C)C)c1
Yield: 97 %

Procedure:
2-Fluoro-5-methoxybenzaldehyde (2.62 g, 17.0 mmol), dimethylamine (2M in methanol, 17 mL, 34 mmol) and sodium cyanoborohydride (1.1.7 g, 18.7 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (2 mL) in methanol (100 mL) for 66 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to give (2-fluoro-5-methoxybenzyl)dimethylamine (3.02 g, 97%) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[C:19]([NH2:26])=[C:20]([NH2:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1>>[Cl:17][C:18]1[C:19]2[NH:26][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:25][C:20]=2[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cc(Cl)cc(Cl)c4[nH]3)cc2)S1

Procedure:
4,6-Dichloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,5-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=CN(C3CCN([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)CC3)C=2C2C=CN=C(NC)N=2)=CC=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)[CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCNCC1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCN(Cc2ccon2)CC1

Procedure:
Compound 14 was prepared from 4-[4-(4-fluorophenyl)-2-methyl-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidine (C31) according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(isoxazol-3-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}-N-methylpyrimidin-2-amine (5) in Example 5, except that extractions were carried out with dichloromethane, and the eluant employed for chromatography was 5% methanol in dichloromethane. The product was obtained as a solid. Yield: 10 mg, 0.024 mmol, 23%. LCMS m/z 419.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.95-2.00 (m, 2H), 2.15 (ddd, J=11.8, 11.8, 2.0 Hz, 2H), 2.27-2.37 (m, 2H), 2.65 (s, 3H), 3.01 (br d, J=11.6 Hz, 2H), 3.67 (s, 2H), 4.48 (tt, J=12.4, 4.0 Hz, 1H), 6.39 (d, J=1.7 Hz, 1H), 6.96 (dd, J=8.8, 8.8 Hz, 2H), 7.12 (dd, J=5.3, 1.5 Hz, 1H), 7.29 (dd, J=8.8, 5.4 Hz, 2H), 8.38 (d, J=1.7 Hz, 1H), 8.55 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1)[N:8]([CH3:27])[C:7]2=[O:28].IC1C=CC=C2C=1N=C([NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][C@@H:43]([NH:47][C:48](=[O:54])OC(C)(C)C)[CH2:42]1)N(C)C2=O.C[C@@H]1C2NC(B3OC(C)(C)C(C)(C)O3)=CC=2C(=O)N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:27][N:8]1[C:7](=[O:28])[C:6]2[C:11](=[C:2]([C:41]3[NH:40][C:44]4[C@@H:43]([CH3:42])[NH:47][C:48](=[O:54])[C:45]=4[CH:46]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(I)cccc2c1=O
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(Br)cccc2c1=O
Agent: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@@H]5CCC[C@H](NC(=O)OC(C)(C)C)C5)nc34)[nH]c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A mixture of (rac)-tert-butyl ((1R,3S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate and (rac)-tert-butyl ((1R,3S)-3-((8-iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509a, 1.49 g, 3.30 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 1.331 g, 3.96 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (0.117 g, 0.165 mmol), and potassium phosphate (2.102 g, 9.90 mmol) in 1,4-dioxane (26.4 mL)/water (6.60 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 1 h. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the aqueous layer was extracted with EtOAc (4×100); the organic layers were separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-8% 2 M ammonia in MeOH/DCM to give (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, 0.59 g, 0.582 mmol, 17% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.34 (m, 3H) 1.37 (s, 9H) 1.40 (d, J=6.65 Hz, 3H) 1.42-1.54 (m, 2H) 1.73-1.89 (m, 2H) 1.99-2.20 (m, 2H) 3.44 (s, 3H) 3.92-4.11 (m, 1H) 4.48-4.59 (m, 0.5; H) 4.60-4.74 (m, 0.5; H) 6.79-6.99 (m, 3H) 7.15 (t, J=7.73 Hz, 1H) 7.63 (d, J=4.30 Hz, 1H) 7.82 (d, J=7.04 Hz, 1H) 7.97 (dd, J=11.54, 7.82 Hz, 1H) 11.99 (br. s., 0.4; H) 12.09 (br. s., 0.6; H). MS (ESI, pos. ion) m/z: 507.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([O:27][CH3:28])=[O:29]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCCCn1c(=O)c2c(C)nc3cccc1n32
Yield: 78.9 %

Procedure:
To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.50 ml (6.5 mmol) of methyl chlorocarbonate. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride—methanol—ether to give 1.192 g of the desired compound (78.9%, colorless crystals), m.p.175-176° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:28](=[O:30])[CH3:29])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of compound 76 (101 mg, 0.25 mmol) in 5 mL of dichloromethane was added triethylamine (105 μL, 0.75 mmol) and acetic anhydride (26.0 μL, 0.28 mmol). After being stirred at room temperature overnight, the reaction solution was diluted with 50 mL of dichloromethane, washed with water, collected the organic layer, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (33% dichloromethane in ethyl acetate) to afford 74 mg (88.6%) of the title compound 25a as a light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH3:13][N:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]1[CH:22]=O.C(OC(=O)C)(=O)C.O>C(O)(=O)C.[Cl-].[Cl-].[Zn+2]>[C:7]1([C:4]2[S:3][C:2]([CH:1]=[CH:22][C:15]3[N:14]([CH3:13])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=3)=[N:6][N:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nnc(-c2ccccc2)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccccc2)s1
Yield: 55.9 %

Procedure:
17.6 g of 2-methyl-5-phenyl-1,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of ZnCl2 are heated in 100 ml of acetic acid and 50 ml of acetic anhydride for 7 hours at reflux temperature. After water has been added to the reaction mixture, the precipitated solid is recrystallized from glacial acetic acid. 17.5 g of a product melting at 257° C. is obtained, corresponding to 56% of the theory.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:19]1[CH:20]=[C:15]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2cc[n+]([O-])cc2)s1
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)s1
Reaction time: 8 h

Procedure:
A mixture of 1.90 g (6.33 mmol) of 4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine 1-oxide and 40 ml of phosphoryl chloride is heated under reflux. After 8 h, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 150 ml of dichloromethane and 50 ml of ice-water are added. The organic phase is separated off and once more washed with 50 ml of water, dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 1.35 g (65%) of the desired product; 1H-NMR(DMSO-d6) δ: 8.35 (d, 1H), 7.49 (m, 2H), 7.35 (s, 1H), 7.25 (d, 1H), 7.19 (m, 2H), 3.06 (q, 2H), 1.37 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[N:17]([CH2:33]OCC[Si](C)(C)C)[C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[N:55]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[CH:56]=[C:57]([C:59](O)=[O:60])[N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[N:55]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:68])([CH3:67])[CH3:69])[CH:56]=[C:57]([C:59]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:18]4[N:17]([CH3:33])[C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:41])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=4)=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)=[O:60])[N:58]=1)=[O:48])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCNCC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(C(=O)c4cn(COCC[Si](C)(C)C)c(C5CCCN5C(=O)OC(C)(C)C)n4)CC3)cc2)n1C)C(C)C
Reaction time: 18 h

Procedure:
(2-Methyl-1-{2-[5-(4-piperazin-1-yl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (28 mg, 0.047 mmol) and 2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid (20 mg, 0.047 mmol) in DMF (1 mL) were treated with HATU (20 mg, 0.052 mmol) and N-methyl morpholine (0.26 mL, 0.23 mmol). The mixture was stirred for 18 hours then diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (310 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 to afford crude 2-[4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-methyl-3H-imidazol-4-yl}-phenyl)-piperazine-1-carbonyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 978 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][CH2:11][CH2:12][OH:13])=[N:5]2.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C.[O:42]1CCC[CH2:43]1>>[C:27]1([CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:21]2[CH2:22][CH2:23][N:24]([C:43]([O:13][CH2:12][CH2:11][O:10][C:6]3[CH:7]=[CH:8][C:9]4[N:4]([N:3]=[CH:2][N:1]=4)[N:5]=3)=[O:42])[CH2:25][CH2:26]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: C1CCOC1
Reactant: OCCOc1ccc2ncnn2n1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCOc1ccc2ncnn2n1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-([1,2,4]triazolo[1,5-b]pyridazin-6-yloxy)ethanol (450 mg) was dissolved in tetrahydrofuran (20 ml), followed by addition of N,N′-carbonyldiimidazole (649 mg). The mixture was stirred at room temperature for 3 hours, followed by addition of 1-(diphenylmethyl)piperazine (1.07 g) and N-ethyldiisopropylamine (0.73 ml). The mixture was stirred at 60° C. for 17 hours and concentrated under reduced pressure. Ice-water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the objective compound were collected a and concentrated. The resulting crystals were recrystallized from ethyl acetate to yield the title compound (464 mg).
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:18]([C:20]1[C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[C:36]([C:33]([C:34]#[N:35])=[C:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])=[O:19])[C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)#[N:37]
Reactant: OCCN(CCO)CCO
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)OCCN(CCO)CCO)cccc21

Procedure:
A solution of 100.0 grams of triethanolamine and 58 milliliters of dry pyridine in 350 milliliters of dry dichloromethane was stirred at room temperature under a nitrogen atmosphere. A solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dry dichloromethane was added over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The reaction mixture was washed several times with water to remove the excess amines and the corresponding hydrochloride salts, dried with anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gave 5 grams of crude product. Purification by recrystallization from isopropanol afforded 4.5 grams of pure (1c), mp., 155.5°-156.5° C.