Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[CH3:11][O:12][C:13](Cl)=[O:14].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:14]
Reactant: COC(=O)Cl
Reactant: Nc1nc2cnccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2cnccc2s1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-aminothiazolo[4,5-c]pyridine (50 mg, 0.33 mmole) and 0.4 ml of methylchloroformate in 1 ml of dry DMF was added 0.4 ml of pyridine. The mixture was allowed to stand overnight at room temperature and aqueous NaHCO3 and ethyl acetate were then added. The organic layer was separated, washed with saturated aqueous NaCl solution, dried over Na2SO4 and evaporated in vacuo to give 54 mg (78%) of the title compound, which was recrystallized from CHCl3 --CH3OH to give pure crystalline solid. Mp 146°~152° C. (dec.).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([CH:11]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])[CH3:12])[CH:10]=1)(=O)C.OO.C([OH:26])C.Cl.[OH2:28]>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([CH:11]([S:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])(=[O:26])=[O:28])[CH3:12])[CH:10]=1
Reactant: CC(=O)Nc1ccc(C)c(C(C)Sc2cccc[n+]2[O-])c1
Reactant: CCO
Reactant: O
Agent: Cl
Agent: OO
Solvent: CO
Product: Cc1ccc(N)cc1C(C)S(=O)(=O)c1cccc[n+]1[O-]
Temperature: 39 °C
Reaction time: 0.33 h

Procedure:
To a stirred room temperature solution of 3.0 g (0.01 mole) of 2-[[1-(5-acetylamino-2-methylphenyl)ethyl]thio]-pyridine-N-oxide in 10 ml of methanol were added 0.12 g of Na2WO4 followed by 1 g of 35% hydrogen peroxide added over 20 minutes. The exothermic reaction was cooled using a room temperature water bath. The mixture was stirred for 20 minutes, and then treated dropwise with another 1.3 g of 35% H2O2. The mixture was warmed to 35-43° C. for two hours, and then left to stir at room temperature overnight. The mixture was then treated with 5 ml of ethanol, 10 ml of water, and 5 ml of concentrated HCl and heated on a steam cone for one hour. The mixture was cooled, diluted with 20 ml of water and filtered to remove a solid. The filtrate was made basic with concentrated aqueous ammonium hydroxide to give a tacky solid. This solid was taken up in 30 ml of water and 3 ml of concentrated HCl and some insoluble material was filtered off. The filtrate was basified to give a solid precipitate that was filtered off, washed with water, and left to dry overnight. The dry solid weighed 0.85 g and melted at 165-170° C. Recrystallization gave a solid with a melting point of 184-188° C. and having infrared and NMR spectra consistent with the proposed structure.
Reaction SMILES: CN(C)CCCCC(C1C=CC2C3C(=CC(C(=O)CCCCN(C)C)=CC=3)CC=2C=1)=O.[CH2:32]([N:34]([CH2:63][CH3:64])[CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:52]=[CH:51][C:50]2[C:49]3[C:44](=[CH:45][C:46]([C:53](=[O:62])[CH2:54][CH2:55][CH2:56][N:57]([CH2:60][CH3:61])[CH2:58][CH3:59])=[CH:47][CH:48]=3)[CH2:43][C:42]=2[CH:41]=1)=[O:39])[CH3:33].[CH2:65]([N:67]([CH2:70][C:71]([C:73]1[CH:85]=[CH:84][C:83]2[C:82]3[C:77](=[CH:78][C:79]([C:86](=[O:93])[CH2:87][N:88]([CH2:91][CH3:92])[CH2:89][CH3:90])=[CH:80][CH:81]=3)[CH2:76][C:75]=2[CH:74]=1)=[O:72])[CH2:68][CH3:69])[CH3:66].N1(CCCC(C2C=CC3C4C(=CC(C(=O)CCCN5CCCCC5)=CC=4)CC=3C=2)=O)CCCCC1>>[CH2:60]([N:57]([CH2:58][CH3:59])[CH2:56][CH2:55][CH2:54][CH:53]([C:46]1[CH:47]=[CH:48][C:49]2[C:50]3[C:42](=[CH:41][C:40]([CH:38]([CH2:37][CH2:36][CH2:35][N:34]([CH2:32][CH3:33])[CH2:63][CH3:64])[OH:39])=[CH:52][CH:51]=3)[CH2:43][C:44]=2[CH:45]=1)[OH:62])[CH3:61].[CH2:91]([N:88]([CH2:87][CH:86]([C:79]1[CH:80]=[CH:81][C:82]2[C:83]3[C:75](=[CH:74][C:73]([CH:71]([CH2:70][N:67]([CH2:65][CH3:66])[CH2:68][CH3:69])[OH:72])=[CH:85][CH:84]=3)[CH2:76][C:77]=2[CH:78]=1)[OH:93])[CH2:89][CH3:90])[CH3:92]
Reactant: CCN(CC)CCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN(CC)CC)ccc1-2
Reactant: CCN(CC)CC(=O)c1ccc2c(c1)Cc1cc(C(=O)CN(CC)CC)ccc1-2
Agent: CN(C)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(C)C)ccc1-2
Agent: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2
Product: CCN(CC)CC(O)c1ccc2c(c1)Cc1cc(C(O)CN(CC)CC)ccc1-2
Product: CCN(CC)CCCC(O)c1ccc2c(c1)Cc1cc(C(O)CCCN(CC)CC)ccc1-2

Procedure:
Following essentially the same procedure but substituting the appropriate molar equivalent amounts of 2,7-bis(5-dimethylaminovaleryl)fluorene, 2,7-bis(4-diethylaminobutyryl)fluorene and 2,7-bis(diethylaminoacetyl)fluorene for the 2,7-bis(4-piperidinobutyryl) fluorene used as a starting material above, results in the formation of α,α'-bis(4-dimethylaminobutyl)-2,7-fluroenedimethanol, α,α'-bis(3-diethylaminopropyl)-2,7-fluorenedimethanol and α,α'-bis(diethylaminomethyl) 2,7-fluorenedimethanol, respectively.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH3:19][OH:20]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:20][CH3:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: CO
Product: COC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α, α, α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride prepared as in Example 29 and 10 ml of methanol was held at reflux for 0.5 hours and was concentrated under vacuum to 80° (0.3 torr) to 2.72 g of oil, nD23.4° = 1.5404.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13].[OH:16]S(O)(=O)=O>>[F:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH2:11])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c(F)cccc1F
Product: NC(=O)Cc1c(F)ccc([N+](=O)[O-])c1F
Reaction time: 5 h

Procedure:
To a stirred mixture 2,6-difluorophenylacetonitrile (3.06 g, 20.0 mmol) in 30 mL of H2SO4 at 0° C. was added 12 mL of a 1:1 mixture of nitric acid and sulfuric acid. The reaction mixture stirred for 5 h and poured onto crushed ice. The resulting solid was filtered and air dried to give 2,6-difluoro-3-nitro-phenylacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[F:24].[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH:44]=O)=[C:33]([N:35]([C:39](=[O:41])[CH3:40])[C:36](=[O:38])[CH3:37])[N:34]=1)(=[O:27])[CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH2:44][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[F:24])=[C:33]([N:35]([C:36](=[O:38])[CH3:37])[C:39](=[O:41])[CH3:40])[N:34]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(F)c1)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Both diethyl N-(4-amino-3-fluorobenzoyl)-(L)-glutamate (2.21 g, 6.49 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (2.00 g, 6.49 mmoles) were stirred in absolute ethanol (50 mL) under nitrogen while glacial acetic acid (3mL) was added dropwise during 1 minute. After solution was achieved (1 hour), activated 3 Å molecular sieves (10 mL) were added and stirring was continued 5 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (408 mg, 6.49 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed. The reaction mixture was allowed to warm to ambient temperature and stir 16 hours. The reaction mixture was filtered and the solids rinsed with ethanol (100 mL). The filtrate was spin evaporated to a brown residue that was partitioned between ethyl acetate and water (100 mL each). The organic phase was separated, washed (1×100 mL 1:1 water/brine), dried (MgSO4), filtered, and spin evaporated to a small volume (20 mL). The solution was chromatographed on silica gel (175 g) using an ethyl acetate rinse (450 mL) followed by elution of the product with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a white solid; yield, 2.66 g (65%); mp 76°-84° C. (dec); 1H-NMR (DMSO-d6) δ 1.15 and 1.16 (2t overlapped, 6H), 1.64 (m, 2H), 2.00 (m, 2H), 2.11 (s, 3H), 2.20 (s, 6H), 2.27 (m, 2H), 2.40 (t, 2H), 3.10 (m, 2H), 3.9-4.1 (2q overlapped, 4H), 4.35 (m, 1H), 6.10 (m, 1H), 6.66 (t, JoH,H and JmF,H =9 Hz, 1H), 7.5-7.6 (m, 2H), 8.35 (d, 1H), 11.9 (v br d, 1H); uv (MeOH) 299 nm max (28000), 257 min (7500); mass spec (FAB) m/e 633 (23%), 430 (100), 388 (87).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(CO)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9-Formyl-2,7-di(Boc-amino)fluorene (0.47 g, 1.1 mmol) was dissolved in anhydrous methanol (MeOH) (5 mL) under an argon atmosphere. NaBH4 (1.2 eq, 1.3 mmol, 0.05 g) was added and the reaction was stirred at room temperature for five hours. The reaction was diluted with deionized water and acidified to pH 5 with glacial acetic acid. The reaction was extracted with ethyl acetate (2×100 mL) and the organic layers were washed with saturated NaHCO3 (4×20 mL) and brine (3×20 mL). The organic layers were dried over MgSO4, filtered and evaporated. The crude product, orange solid, was purified by flash chromatography: silica gel 60 Å gradient elution 1-5% methanol in chloroform (alternative gradient elution with 15-20% ethyl acetate in dichloromethane, “DCM”). Product was a yellow solid (0.39, 83%). 1H-NMR (CD3OD): δ (ppm) 7.9 (s, 0.5H, NH urethane); 7.7 (s, 2H, Ar); 7.6 (d, 2H, Ar); 7.4 (d, 2H, Ar); 4.0 (m, 1H, CH); 3.9 (m, 2H, CH2); 1.6 (s, 18H, Boc).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:14]([O-])=O.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cccc(-c2ccncc2)c1
Yield: 83 %

Procedure:
A Paar shaker bottle was charged with 0.2 g (0.85 mmol) of 4-(4-chloro-3-nitrophenyl)pyridine, 0.07 g (0.85 mmol) of sodium acetate, 0.02 g of 5% palladium-on-carbon, and 3 ml of glacial acetic acid. It was then charged with hydrogen to 40 psi, and the shaker was turned on. The reaction mixture was heated to 60°-70° C. and maintained at that temperature for two hours, after which the reaction was stopped and the catalyst removed by filtration. To the filtrate was added water and then 50% aqueous caustic to a pH greater than 7. The reaction mixture was extracted with methylene chloride. The methylene chloride fraction was washed, dried, and evaporated. Analysis of the reaction mixture showed that the process resulted in an 83% yield of 4-(3-aminophenyl)pyridine.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Clc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1Cl
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4-dichlorobenzyl chloride (0.218 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 217 mg of the product 204. 1H NMR (DMSO-d6) δ 11.40 (s, 2 H), 7.95 (d, 1 H), 7.78 (d, 1 H), 7.65 (d, 1 H), 7.20-6.90 (m, 6 H), 6.90-6.60 (m, 4 H), 5.78 (s, 2 H), 4.85 (s, 2 H); MS: m/z 413 (M++1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1([C:25]([F:28])([F:27])[F:26])[CH:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[NH:6][C:5]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:4]1.[C:31](=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CS(C)=O>[F:29][C:2]([F:30])([F:1])[C:3]1([C:25]([F:27])([F:28])[F:26])[CH:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:12][CH:11]=2)[N:6]([CH3:31])[C:5]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:4]1
Reactant: O=C(NC1NC(c2ccc(F)cc2)=NC1(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Reactant: C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1C(c2ccc(F)cc2)=NC(C(F)(F)F)(C(F)(F)F)C1NC(=O)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-yl]-4-fluorobenzamide (0.9 g, 2 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.83 g, 3 equiv.) and piperidine (0.51 g, 3 equiv.). The reaction mixture was heated at 145° overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by MPLC with 9:1 hexane-ethyl acetate to give two products. N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1-methyl-1H-imidazol-5-yl]-4-(1-piperidinyl) benzamide (160 mg, 15%) was isolated as a white solid: mp 128°-129° ; MS m/e 517 (M+ +H); 1H NMR (CDCl3 /TMS) δ 1.67(m,6H,(CH2)3), 2.93(s,3H,NCH2), 3.33(m,4H,CH2NCH2), 6.43-6.60(m,2H,NH,CH), 6.90)d,2H,J=7, Harom), 7.13-7.20(m,2H,Harom), 7.60-7.73(m,2H,Harom). N-[4,4-bis(trifluoromethyl)-4,5-dihydro-1-methyl-2-[4-(1-piperidinyl)phenyl]-1H-imidazol-5-yl]-4-fluorobenzamide (80 mg, 8%) was isolated as a white solid: mp 123°-124°; MS m/e 517 (M+ +H); 1H NMR (CDCl3 /TMS ( δ 1.67(m,6H,(CH2)3), 3.00(s,3H,NCH3), 3.30(m,4H,CH2NCH2), 6.37(d,1H,CH), 6.60(m,2H,NH), 6.90(d,2H,J=7,Harom), 7.13-7.22(m,2H,Harom), 7.53(d,2H,J=7,Harom), 7.80-7.90(m,2H,Harom).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1)=[O:12].[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1.C(OCC)(=O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[C:11]([CH:13]3[CH2:17][S:16][C:15](=[O:18])[NH:14]3)[O:12][C:2]=2[CH:7]=1
Reactant: COc1ccc(NC(=O)C2CSC(=O)N2)c(O)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccc(C)cc1
Product: COc1ccc2nc(C3CSC(=O)N3)oc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To 2-oxo-thiazolidine-4-carboxylic acid (2-hydroxy-4-methoxy-phenyl)-amide (50 mg) in p-xylene (3 mL) was added pyridinium p-toluenesolfonate (42 mg). The reaction mixture was refluxed for 2 h and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate and water was added. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 3% methanol-methylene chloride afforded 42 mg (90%) of the title compound as a solid. MS: 251 (MH+) HPLC tR: 1.60 min.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH3:35])[CH:26]=4)[CH:22]=[C:21]([C:36]([F:39])([F:38])[F:37])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:35][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:36]([F:37])([F:38])[F:39])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) and crystallization (MeOH/diethyl ether) to yield the title compound as a light yellow solid (0.14 g, 52%). MS (ISN) 532.3 [(M−H)−]; mp 260° C.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:51][CH3:52])=[C:33]([CH:50]=1)[O:34][C:35]1[CH:36]=[CH:37][C:38]2[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]3[CH2:49][CH2:48]3)=[O:46])[N:43]=2)[N:40]=1>CN(C)C=O.CN1CCCC1=O>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([O:34][C:33]4[CH:50]=[C:29]([NH:28][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=5)[CH:30]=[CH:31][C:32]=4[O:51][CH3:52])=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 65.5 %

Procedure:
Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (85 mg, 0.35 mmol), oxalyl chloride (38 μL, 0.44=mol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 64%) was obtained as a white powder.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12)=[O:2].[CH3:38]I>CN(C=O)C.C1COCC1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Pd]>[CH:1]([NH:3][CH2:4][C:5]1[N:6]([CH3:38])[CH:7]=[N+:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Reactant: CI
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3c[n+]4cn(C)c(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 134 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 2 ml of DMF was added 1.6 ml of methyl iodide, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The residue thus obtained was dissolved in 5 ml of THF and 5 ml of 0.1 M sodium phosphate buffer (pH 6.8), and 150 mg of 10% Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 1 hour. The catalyst was collected by filtration, and washed with a mixed solution of 2 ml of 0.1 M sodium phosphate buffer (pH 6.8) and 2 ml of THF. The filtrate was washed with 10 ml of ethyl acetate, and the aqueous layer obtained was purified by column chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1). The fraction containing the aimed product was concentrated under reduced pressure, and then lyophilized to give 58 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>CN(C)C=O.C(OCC)(=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95.9 %

Procedure:
Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (45 g, 0.33 moles) and 4-(2-chloroethyl)morpholine hydrochloride (18.3 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 5 days. The reaction mixture was poured into water (500 mL) and extraction with ethyl acetate (2×250 mL), washing of the combined organic phases with water (200 mL), drying over MgSO4 and evaporation afforded 16.8 g (96%) of methyl 4-(2-morpholin-4-ylethoxy)benzoate as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13](O)[CH2:14][CH3:15])[CH2:9][CH2:8]1.[C:17]1([CH:23](Br)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-:32].[Na+]>CN(C)C=O>[C:17]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:32][CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: CCC(O)N1CCN(c2ncccn2)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(OCCCN2CCN(c3ncccn3)CC2)c2ccccc2)cc1
Yield: 26 %

Procedure:
To a stirred solution of 1-(2-pyrimidinyl)-4-piperazinyl propanol 3 g. (0.013 mol) in 50 mol. of dimethylformamide was added 3.3 g. (0.013 mol) of diphenylmethylbromide and 2.9 g. (0.034 mol) of sodium bicarbonate. The reaction mixture was refluxed overnight, dimethylformamide was evaporated under reduced pressure, and the residue was extracted with methylene chloride (400 ml.). The methylene chloride extracts were collected, washed with water and evaporated, and the remaining residue was purified by HPLC to give 1.3 g. (26% yield) of the title compound. The free base which was converted to the (1:1) fumarate salt; m.p 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6](=[N:8][OH:9])[NH2:7].[C:15](OC(=O)CC)(=O)[CH2:16][CH3:17]>>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:15]([CH2:16][CH3:17])[O:9][N:8]=1
Reactant: NC(/C=C/c1cccc(Cl)c1Cl)=NO
Reactant: CCC(=O)OC(=O)CC
Product: CCc1nc(/C=C/c2cccc(Cl)c2Cl)no1
Yield: 58.2 %

Procedure:
7.0 g (0.03 tool) of (E)-2,3-dichlorocinnamamide oxime are initially introduced into 7 ml of propionic anhydride and the mixture is then stirred at reflux temperature for 2 hours. Subsequently, the whole batch is concentrated in vacuo, and the residue is stirred with sodium carbonate solution and extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is distilled off. 4.7 g (58.2% of theory) of (E) -3- (2,3 -dichloro-styryl) -5-ethyl-1,2,4-oxadiazole are obtained.