Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC[O:13][C:14]([CH3:16])=[O:15].[CH:17]1([C:22](=[O:35])[CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([CH2:33][CH3:34])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(OC)(C)C>[CH:17]1([C:22]([OH:35])([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH2:33][CH3:34])[N:28]=[C:29]([CH2:31][CH3:32])[CH:30]=2)[CH2:16][C:14]([OH:13])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCc1cc(CCC(=O)C2CCCC2)cc(CC)n1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CCc1cc(CCC(O)(CC(=O)O)C2CCCC2)cc(CC)n1
Temperature: -34 °C
Reaction time: 0.5 h

Procedure:
A clean 2-L, 3-neck flask was charged with LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) and purged with nitrogen. The flask was cooled to −34° C. An addition funnel was then charged with EtOAc (35 mL, 0.3583 mol) and this reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel could be maintained. After complete EtOAc addition another addition funnel was charged with the 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution (crude MTBE soln from prior reaction, theor. 73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 mL). The 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature could be maintained. Five minutes after complete addition, a reaction aliquot was removed and analyzed by HPLC, showing less than 1% 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one. Ten minutes after complete ketone addition, the bath was switched to 0° C. Once the internal temperature had warmed to −10° C., 1M NaOH (510 mL) was added. After complete NaOH soln addition, the reaction was heated to 50° C. After 21 hours the reaction solution was cooled below 30° C. and an aliquot of both layers was removed and analyzed for completion. The mixture was added to a separatory funnel with MTBE (350 mL) and the phases were mixed well and separated. An aliquot of the organic phase was analyzed by HPLC, verifying no significant product, and this layer was discarded. The aqueous phase was added to a flask with CH2Cl2 (350 mL). Concentrated aqueous HCl (about 100 mL) was slowly added to the aqueous phase until the pH=5. The mixture was added back to a separatory funnel and mixed well. The phases were separated and the aqueous layer was extracted a second time with CH2Cl2 (150 mL). The organic layers were combined and charged to a clean flask set up for distillation. The solution was distilled down to 370 mL then displaced with THF by addition of solvent portions followed by continued distillation down to 370 mL after each addition. When the distillation head temp. held steady at 65° C. for 30 min an aliquot was removed and analyzed by 1H NMR, showing a 12.5:1 ratio of THF:CH2Cl2. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: O=C=NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(F)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 45.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-fluoro-3-(trifluoromethyl)benzoyl isocyanate (Intermediate-101, 0.196 g, 0.84 mmol), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.090 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.70-7.76 (m, 1H), 8.19-8.23 (m, 3H), 12.76 (s, 1H); MS (m/z): 471.32 (M+H)+.
Reaction SMILES: C(=O)(O[CH2:6][C:7](=[CH2:9])[CH3:8])OCC.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=CC=CC=1)C>[Pd].O1CCCC1>[CH2:8]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]1=[O:17])[C:7](=[CH2:6])[CH3:9]
Reactant: C=C(C)COC(=O)OCC
Reactant: O=C1CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: C=C(C)CC1CCCCC1=O

Procedure:
A mixture containing ethyl methallyl carbonate (1.44 g, 0.010 mole), cyclohexanone (0.98 g, 0.010 mole), 5 percent palladium on carbon (1.0 g), triphenylphosphine (0.20 g, 0.76 mmole), and tetrahyrofuran (15 ml) was refluxed under N2 for 22 hours. Gas chromatographic quantification by means of an internal standard (ethylbenzene) showed 41.6 percent of the cyclohexanone has been consumed and that the desired product, 2-methallylcyclohexanone was formed in 49.2 yield based on unrecovered cyclohexanone. Preparative gas chromatography of the crude mixture gave a pure sample of the product whose structure was confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([OH:41])[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:41])[C:4]([OH:42])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NCC(O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino}-2-hydroxypropionic acid ethyl ester (0.99 g, 1.61 mmol) in ethanol (15 mL) and THF (15 mL) was stirred and 1 M sodium hydroxide (6 mL) was added. The mixture was stirred at 40° C. for 4 hours and acidified with 1 N hydrochloric acid. After evaporation in vacuo the residue was purified on semipreperative HPLC (Gilson system). The pure fractions were combined and evaporated in vacuo to afford 0.749 (79%) of the title compound as a solid.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH:13]1[NH:17][CH2:16][CH2:15][S:14]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:17]1[CH2:16][CH2:15][S:14][CH:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=1[O:8][CH3:7])=[O:4]
Reactant: COc1ccccc1OCC1NCCS1
Reactant: CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1OCC1SCCN1C(=O)C(C)Br
Reaction time: 1 h

Procedure:
α-Bromopropionyl chloride (0.97 ml) in methylene chloride (15 ml) is added dropwise to a mixture of 2-(o-methoxyphenoxy)methyl-thiazolidine (2 g) and triethylamine (1.35 ml) in CH2Cl2 (30 ml) at 0°-5° C. After 1 hour, the mixture is washed with water and the usual work-up gives 3-α-bromopropionyl-2-(o-methoxyphenoxy)methyl-thiazolidine as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH:12]=[CH:13][CH2:14]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:14][CH:13]=[CH:12][C:11]3[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1cccc(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(OCc3ccccc3)c1)CC2
Yield: 59 %

Procedure:
Prepared from 3-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 5 hours at 50° C. Yield: 59% of theory, Melting point: 78°-80° C. (ether).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[N:20]=[CH:21][N:22]([C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=4)[CH:23]=3)=[C:17]([CH3:33])[O:16][N:15]=2)=[CH:10][CH:9]=1>>[CH:1]1([NH:6][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:22]3[CH:23]=[C:19]([C:18]4[C:14]([C:11]5[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=5)=[N:15][O:16][C:17]=4[CH3:33])[N:20]=[CH:21]3)=[CH:25][CH:26]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCCC3)cc2)cn1
Yield: 76 %

Procedure:
As described for Example 71c, cyclopentylamine was converted, using 4-{4-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (56 mg, 0.17 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (54 mg, 76%) which was obtained as an off-white solid. MS: m/e=430.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)[CH3:9]
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cnc(Cl)nc1
Yield: 35.7 %

Procedure:
A solution of 2-chloro-5-ethylpyrimidine (1.15 g, 8.1 mmol) in 20 mL of carbon tetrachloride was treated with N-bromosuccinimide (1.50 g, 8.4 mmol) and a catalytic amount (about 1 mol percent based on reactants) of benzoyl peroxide and then heated to 75° C. After several hours and additional catalyst, the starting material was completely consumed. The solids were removed and the filtrate was concentrated. The resulting residue was further purified by flash column chromatography on silica gel using a mixture of ethyl acetate (EtOAc) and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 0.64 g (36%) of 5-(1-bromoethyl)-2-chloropyrimidine (A) as a clear liquid: 1H NMR (CDCl3) δ 8.70 (s, 2H), 5.15 (q, J=8.0 Hz, 1H), 2.10 (d, J=8.0 Hz, 3H); GCMS (FID) m/z 222 (M+). Some of the corresponding dibromo compound 0.44 g (18%) was also isolated, as a white solid: mp 84-85° C.; 1H NMR (CDCl3) d 9.00 (s, 2H), 3.00 (s, 3H); LC-MS (ESIMS) m/z 298 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([F:11])([F:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[BH4-].[Na+].Cl.[CH3:16]O>O>[CH3:16][O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]([F:11])([F:10])[CH2:3][OH:2]
Reactant: COC(=O)C(F)(F)CCC(=O)O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC(F)(F)CO
Reaction time: 2 h

Procedure:
To a solution of 2 g of 2,2-difluoroglutaric acid 1-methyl ester in 20 ml of methanol is added at 25° 250 mg of sodium borohydride and the mixture allowed to remain at 25° for 2 hrs. The solution is diluted with water and acidified to pH 1 with 1 N HCl and the methanol removed in vacuo. The residual suspension is extracted with methylene chloride and the extract dried with sodium sulfate and evaporated to dryness in vacuo. The residual oil is treated with ethereal diazomethane until the yellow color persists and the ether is removed in vacuo. There remains behind the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2C=CC(N)=NC2=O)[O:9][C@H:6]([CH2:7]O)[C@@H:4](O)[C@H:2]1O.[C:18](OC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>CN(C=O)C>[C:1]([NH2:10])(=[O:9])[C:2]1[CH:4]=[CH:6][CH:7]=[CH:19][CH:18]=1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 282.4 %

Procedure:
To a suspension of cytidine (100 g, 0.411 mol) in DMF (2.06 L) is added benzoic anhydride (102.4 g, 0.452 mol). The mixture was stirred at room temperature for 20 h. The DMF was removed in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by suction filtration and washed with diethyl ether (2×200 mL). Further drying in vacuo at room temperature gave the N4 benzamide (140.6 g, 98.3%). A portion of this material (139.3 g, 0.401 mol) was dissolved in anhydrous pyridine (1.2 L) and was treated with 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (141.4 mL, 0.441 mol) at room temp. The solution was stirred at room temperature overnight. The mixture was concentrated to near dryness in vacuo and coevaporated with toluene (3×200 mL). The residue was treated with EtOAc (1.8 L) and washed with HCl (2×200 mL, 0.05 N), NaHCO3 (5%, 2×400 mL). The organic layer was washed, dried (Na2SO4), filtered, and evaporated to dryness. Compound 16-1 (Compound 4-1 from U.S. Pat. No. 7,429,572) (256.5 g, >100%) was isolated as a white foam and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:16][CH:13]1[CH2:15][CH2:14]1)=[O:8]
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Reactant: NC1CC1
Solvent: c1ccccc1
Product: O=C(/C=C/c1cccc(Cl)c1)NC1CC1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 3-chlorocinnamoyl chloride (6 g) in dry tolune (100 ml) was added with stirring to a solution of cyclopropylamine (6 g) in dry benzene (50 ml). The reaction mixture was allowed to stand at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was thoroughly triturated with water containing a small amount of sodium carbonate, washed with water and filtered. Recrystallization of the resulting crude product from ethanol-water (1:10) gave trans 3-chloro-N-cyclopropylcinnamamide (5 g), m.p. 112°-113° C. Elemented analysis, nmr and ir data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([O:23][C:24](OC3C=CC=CC=3)=[O:25])[C:21]3[S:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][S:37][C:20]=3[C:19]2=[O:40])=[N:16][CH:17]=1>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([O:23][C:24]([N:8]3[CH2:9][CH2:10][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6][CH2:7]3)=[O:25])[C:21]3[S:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][S:37][C:20]=3[C:19]2=[O:40])=[N:16][CH:17]=1
Reactant: CCC(=O)N1CCNCC1
Reactant: COC1CSC2=C(SC1)C(OC(=O)Oc1ccccc1)N(c1ccc(Cl)cn1)C2=O
Solvent: CC#N
Product: CCC(=O)N1CCN(C(=O)OC2C3=C(SCC(OC)CS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 2 °C
Yield: 9.8 %

Procedure:
A solution of 1-propionylpiperazine (6.8 g) in anhydrous acetonitrile (50 cc) is added, at 20° C., to a suspension of 7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (11.15 g) in anhydrous acetonitrile (80 cc). The reaction mixture is heated under reflux for 6 hours. The acetonitrile is evaporated off under reduced pressure (20 mm Hg; 2.67 kPa). The residue is treated with water (100 cc) and extraction is carried out three times with methylene chloride (total 210 cc); the organic extracts are washed twice with distilled water (total 200 cc), dried over anhydrous sodium sulphate and evaporated to dryness. The resulting residue (14.7 g; oily) is dissolved in a mixture of chloroform and methanol (97:3 by volume; 50 cc). The solution is chromatographed on silica (0.04-0.063 mm; 400 g) contained in a column of diameter 6 cm, under a pressure of 140 kPa. Elution is carried out with the solvent mixture mentioned above under a pressure of 140 kPa. 1800 cc of eluate are collected and discarded, and then 600 cc of eluate are collected and evaporated to dryness under reduced pressure (20 mm Hg; 2.67 kPa). The resulting partially crystalline residue (11.0 g) is dissolved in a boiling mixture of acetonitrile (10 cc) and diisopropyl ether (50 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with diisopropyl ether (total 20 cc) and dried under reduced pressure (20 mm Hg; 2.67 kPa) at 20° C. The resulting product (4.1 g; m.p. 160° C.) is dissolved in boiling acetonitrile (60 cc). After cooling the solution for 2 hours at 2° C., the resulting crystals are filtered off, washed twice with diisopropyl ether (total 80 cc) and dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at 50° C. 7-(5-Chloropyrid-2-yl)-3-methoxy-8-oxo-6-(4-propionylpiperazin-1-yl)carbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (1.2 g), melting at 226° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: COCCBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Product: COCCOc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and 1-bromo-2-methoxy-ethane (0.031 mL). MS (m/e)=423.1 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]4)=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC1CCCC(C(=O)O)C1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC1CCCC(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)C1

Procedure:
Following the procedure of Example 14, making variations only as required to use 3-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (27% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.99, 6.99, 3.89, 3.79, 3.65-3.72, 3.56, 2.55, 1.20-1.86, 0.99, 0.92, 0.75, 0.47, 0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimethylformamide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Sc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1ccc(-c2ccccc2)cc1
Yield: 29.9 %

Procedure:
Prepared according to the method described in Example 1 from 4-phenylthiophenol (0.186 g), sodium hydride (0.044 g) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide (3 ml) at room temperature to give the title compound as a solid (0.100 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])(=[O:22])[CH:20]=[CH2:21].[OH-].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]2[C:8](=[O:13])[N:9]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:10](=[O:12])[NH:11]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCN1C(=O)NC(=Cc2ccc(OC)c(OC)c2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
20 g (80.6 mmol) of 5-(3,4-dimethoxybenzylidene)-hydantoin, 17.8 g (96 mmol) of 2-ethylhexyl acrylate and 0.90 g (1.6 mmol) of potassium hydroxide were added to 150 ml of dimethylformamide, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 200 ml of water and extracted with 500 ml of ethyl acetate. The extract was dried with sodium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized with toluene-n-hexane (1:1) and the precipitated crystals were dried to obtain 27.1 g of 2-ethylhexyl 4-(3,4-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidinepropionate (yield: 77.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23](=[NH:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:34]=[C:23]([C:24]5[CH:25]=[C:26]([S:30]([NH2:31])(=[O:32])=[O:33])[CH:27]=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (152 mg, 65%). MS (EI) 465.1 [(M)+]; mp 301° C.