Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[CH:12]1[C:17]([NH:18][NH2:19])=[CH:16][CH:15]=[C:14]([Cl:20])[CH:13]=1.OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([OH:8])=[O:7])=[C:9]([CH3:10])[N:18]([C:17]2[CH:16]=[CH:15][C:14]([Cl:20])=[CH:13][CH:12]=2)[N:19]=1
Reactant: CC(=O)C(CC(=O)O)C(C)=O
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Yield: 102 %

Procedure:
4.0 grams 3,3-diacetyl-propionic acid, 4.9 grams p-chlorophenylhydrazine-sulfate, 2.1 grams anhydrous sodium acetate and 30 milliliters glacial acetic acid were mixed and the mixture was heated to 60° C. for 3 hours. The reaction mixture was evaporated and water was added to the residue. The precipitate formed thereby was separated by filtration and recrystallized from a mixture of ethanol and of water. 5.5 grams 3,5-dimethyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 176°-177° C., were obtained, representing a yield of 82%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=S)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:23][OH:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Fc1cc(C(F)(F)F)ccc1C(=S)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ON=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzenecarbothioamide (2.50 g, 0.00663 mol), hydroxylamine hydrochloride (0.65 g, 0.00928 mol) and sodium bicarbonate (0.78 g, 0.00928 mol) was heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzeneamidoxime (2.35 g, 0.00625 mol) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:14]([O:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: CC(O)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(C)C(=O)c1ccccc1
Yield: 93.3 %

Procedure:
A mixture of 225 grams of 2-hydroxypropiophenone, 247 grams of allyl bromide, 415 grams of potassium carbonate and 5 grams of potassium iodide is heated to reflux for twenty four hours in 1 liter of acetone. After cooled, insoluble matters are removed by filtration, the filtrate is concentrated, the residue is dissolved in benzene, and the solution is washed with 10% sodium hydroxide solution. After washing with water, the solution is dried with anhydrous magnesium sulfate and benzene is evaporated therefrom. The resulting oil is distilled in vacuo to give 266 grams of 2-allyloxypropiophenone, colorless oil, b.p. 120° to 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH3:43][S:44]([CH2:46][S:47][CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:46](\[S:44]([CH3:43])=[O:45])/[S:47][CH3:48])=[CH:19][C:18]=3[CH:25]3[CH2:27][CH2:26]3)=[CH:14][CH:15]=2)=[CH:29][CH:30]=1
Reactant: CSCS(C)=O
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1)S(C)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
N-(4-Chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 0.381 mmol) was diluted with THF (3 mL) followed by the addition of N,N,N-trimethyl(phenyl)methanaminium hydroxide (0.0866 ml, 0.191 mmol) and methylsulfinyl(methylthio)methane (94.7 mg, 0.762 mmol). The reaction was heated to 70° C. and stirred for 2 hours. The reaction was cooled and loaded directly onto a silica gel column, eluting with ethyl acetate to yield (Z)—N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)benzamide (100 mg, 49.9% yield).
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:25]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[N:16]=1)[CH3:26]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 5, 1.75 g, 5.1 mmol) in methanol/THF (v/v, 1:1, 28 mL) was added 4N aqueous LiOH (4.6 mL, 18.4 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 1.3 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3) δ 7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.81-3.75 (2H, m), 3.47 (1H. br.s), 2.92 (2H, t, J=6.9 Hz), 2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H,
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:37][C:36]([O:35][CH3:34])=[O:39])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 120 h
Yield: 54.3 %

Procedure:
In DMF (15 mL) was stirred 4-hydroxy-1,3-benzenedicarboxylate dibenzyl ester (500 mg, 1.4 mmol) and potassium carbonate (276 mg, 2.0 mmol). To this was added methylbromoacetate (230 mg, 1.5 mmol) and the solution warmed to 50° C. and stirred 120 hours. The mixture filtered free of insoluble material and the DMF solution evaporated at reduced pressure to give a red oil. The oil was dissolved in ethyl acetate (50 mL) and washed successively with 10% citric acid (50 ML), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give an oil. The oil was purified by MPLC (90 g silica gel, 2:1[hexane:ethyl acetate]) to give 330 mg (54%) of a clear oil. MS: M+1=435.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([NH:21][OH:22])=[O:20])[C:12](=[O:28])[CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH3:30][O:31][NH2:32].C([O-])(=O)C.[Na+]>C(O)C>[OH:22][NH:21][C:19](=[O:20])[C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16][N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4](/[C:1](=[N:32]/[O:31][CH3:30])/[CH3:2])=[CH:5][CH:6]=2)=[CH:11][C:12]1=[O:28]
Reactant: CON
Reactant: CC(=O)c1ccc(-c2ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C(\C)c1ccc(-c2ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)cc1
Temperature: 70 °C
Reaction time: 0.13 h
Yield: 80.7 %

Procedure:
A suspension of 4-[4-(4-acetylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (105 mg, 0.258 mmol), O-methylhydroxylamine hydrochloride (86.2 mg, 1.03 mmol) and sodium acetate (107 mg, 1.03 mmol) in ethanol (10 mL, 0.025M) was heated in an oil bath at 70° C. for 3 hours. The volatiles were removed by rotary evaporation. The remaining material was redissolved in 1.5 mL DMSO and run on Shimadzu HPLC 30×100 mm reverse phase column. The material was eluted with 20-35% acetonitrile in water with 0.1% ammonium hydroxide modifier. The gradient was run for 8 min then held at 35% for an additional two minutes. The desired material eluted at about 30% acetonitrile. This solution was concentrated down by rotary evaporation yielding 90.7 mg (80.7%) of the title compound a white solid. LC/MS m/z 436 (M+1). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.13-2.21 (m, 1H) 2.21 (s, 3H) 2.39-2.48 (m, 1H) 3.11 (s, 3H) 3.70-3.81 (m, 1H) 3.94 (s, 3H) 4.12 (td, J=11.90, 5.00 Hz, 1H) 6.68 (dd, J=7.20, 1.83 Hz, 1H) 6.75 (d, J=1.95 Hz, 1H) 7.71-7.82 (m, 5H) 9.27 (br. s., 1H) 11.14 (br. s., 1H)
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][C:11]=3[CH:10]=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC=CC=1.[CH2:29](O)[CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:10]1[C:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][C:9]=1[C:7]1([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[O:31][CH2:30][CH2:29][O:8]1
Reactant: OCCO
Reactant: O=C(Cn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)Cc1cc(C3(Cn4ccnc4)OCCO3)ccc1-2

Procedure:
To a slurry of 10.0 g. of 2-(1H-imidazol-1-yl)-1-(9H-fluoren-2-yl)ethanone in 100 ml. of toluene were added 4.53 g. of ethylene glycol and 13.9 g. of p-toluenesulfonic acid. The mixture was heated overnight at reflux with the azeotropic removal of water. The reaction was poured into water and the resulting solid was removed by filtration. The solid was basified with 50 percent sodium hydroxide and extracted with ethyl acetate. The ethyl acetate was washed with water, followed by a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was crystallized from acetone to provide 8.64 g. of the title product, m.p. 163°-166° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[O:21][CH2:22][CH3:23]>C(OCC)(=O)C>[C:20](=[O:24])([O:21][CH2:22][CH3:23])[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]=[C:18]([NH2:20])[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH2:26](N)[CH2:27]N>O.C(O)CCCC>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]1[NH:20][CH2:26][CH2:27][N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=Nc1nc2ccccc2n1Cc1ccccc1
Reactant: NCCN
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCO
Solvent: O
Product: c1ccc(Cn2c(NC3=NCCN3)nc3ccccc32)cc1

Procedure:
2-(1-Benzylbenzimidazolyl)guanidine (3.65g, 0.0143 mol) was dissolved in water (600 ml) containing 5N hydrochloric acid (5.5 ml). The solution was cooled to 0° to 5°C and treated portionwise with sodium nitrite (1.0g) each hour for 3 hours. After a further 4 hours the reaction mixture was filtered and the microcrystals so obtained were heated under reflux in amyl alcohol (15 ml) with ethylenediamine (3 ml) for 6 hours. The cooled reaction mixture was evaporated to dryness. The resulting semi-solid was crystallised from amyl alcohol was then recrystallised from ethanol to yield 2-(1-benzylbenzimidazolyl)amino-2-imidazoline (1.0g) as colourless microcrystals m.p. 165°-166°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:30]1([CH2:35][C:36]([OH:38])=O)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][C:36]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(O)CC1CCCC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CC1CCCC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cyclopentylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 548.3 [M]+.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:38]([C:46]1[CH:54]=[CH:53][C:49]2[O:50][CH2:51][O:52][C:48]=2[CH:47]=1)[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[O:50]1[C:49]2[CH:53]=[CH:54][C:46]([C@H:38]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[C@H:2]([NH:1][C:63]([O:65][CH3:66])=[O:64])[C:3]([NH:5][C:6]3[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=3[CH2:12][CH2:13][C@H:14]3[O:19][CH2:18][C@@H:17]([CH2:20][O:21][C:22](=[O:29])[NH:23][CH2:24][C:25]([F:27])([F:26])[F:28])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]3)=[O:4])=[CH:47][C:48]=2[O:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (50 mg, 0.06 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methyl chloroformate (0.006 mL, 0.07 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=840.
Reaction SMILES: N1CCC[C@H:2]1[C:3](O)=[O:4].Br[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([N+:20]([O-:22])=[O:21])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1>C(O)C>[CH2:3]([O:4][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([N+:20]([O-:22])=[O:21])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1)[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1oc2ccc(CCBr)cc2c1-c1ccccc1
Solvent: CCO
Product: CCOCCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
A mixture of 1.04 g. (0.009 mole) of proline and 3 g. (0.009 mole) of 5-(2-bromoethyl)-2-nitro-3-phenylbenzofuran (prepared by reaction of 5-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran with phosphorus tribromide) in 50 ml. of ethanol is heated to its reflux temperature and maintained at reflux temperature for about 14 hours. The mixture is evaporated to provide a solid residue which is recrystallized from ethanol to provide 5-ethoxyethyl-2-nitro-3-phenylbenzofuran, m.p. 108°-109° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Product: CS(=O)(=O)c1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O=O.[K+].O=O.C1(C)C=CC(S(Cl)(=O)=[O:40])=CC=1>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:40]
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=O
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) is dissolved with stirring in methanol (40 ml). The resulting solution is cooled in an icewater bath while solid potassium superoxide (2.20 g, 31 mmol) is added slowly (with evolution of oxygen). After stirring for a further 15 minutes, a solution of p-toluenesulphonyl chloride (2.38 g, 12.5 mmol) in 30 ml methanol is added dropwise over 20-30 minutes. The reaction mixture is stirred for a further 30 min. After this time the mixture is filtered under vacuum. The residue is washed with methanol and the combined filtrate evaporated under reduced pressure. The resulting solid is slurried with water, filtered, and washed with water and ether, to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.6 g, 54 %) identical with authentic material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: c1ccsc1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)c1cccs1

Procedure:
Thiophene (a) is reacted with succinic anhydride (c) under Friedel-Crafts reaction conditions to afford 4-(2-thienyl)-4-oxobutyric acid (XII). Substitution of benzene (b) in the above reaction affords 4-phenyl-4-oxobutyric acid (XVII). ##STR18## The oxobutyric acids of formulas (XII) and (XVII) obtained in Step 1 above, are reacted with a suitable 1,2-dithiol (d), R3 and R4 are each either hydrogen or methyl, in an aromatic solvent such as benzene, toluene or xylene, in the presence of catalytic amounts of p-toluenesulfonic acid at a temperature range of 25° C. to 120° C. and, preferably, from 75° C. to 110° C. while azeotroping the water formed in the reaction. Alternatively, the reaction is conducted in a C2 -C5 alkanoic acid, preferably, acetic acid in the presence of an acid catalyst such as boron trifluoride/methanol, boron trifluoride/ether, ZnCl2 /Na2SO4, HCl/ether, and the like, at the temperature range specified above, to afford 2-(2-thienyl)-1,3-dithiolane-propionic acid (XIII) and 2-phenyl-1,3-dithiolane-2-propionic acid (XVIII), respectively. R3 and R4 are as hereinabove defined. ##STR19## The dithiolane propionic acids of formulae (IIIa) and (IIIb) are converted to the corresponding acid chlorides of formulae (XIV) and (XIX) with oxalyl chloride or thionyl chloride (with a small amount of DMF added if desired) in an inert anhydrous solvent selected from the group consisting of benzene, toluene, xylene, chlorobenzene, at a temperature range of about 0° C. to 30° C. and preferably 15° C. to 30° C. ##STR20##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 675.3 [(M+H)+]