Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[I:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[I:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1cccc(I)c1
Yield: 90.8 %

Procedure:
A mixture of potassium cyanide (4 g) and tetra-n-butylammonium bromide (0.32 g) in water (20 ml) was added to a solution of 3-iodobenzyl bromide (5.92 g) in methylene chloride (20 ml) and the mixture was heated to reflux for 2 hours. The organic phase was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent to give 3-iodophenylacetonitrile (4.4 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CS(O[CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][C@@H:48]([C:50]2[CH:61]=[CH:60][C:53]3[O:54][C:55]([CH3:59])([CH3:58])[O:56][CH2:57][C:52]=3[CH:51]=2)[O:47][C:46]1=[O:62])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:58][C:55]1([CH3:59])[O:54][C:53]2[CH:60]=[CH:61][C:50]([C@H:48]3[O:47][C:46](=[O:62])[N:45]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:1][CH2:2][C:3]4[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=4)[CH2:49]3)=[CH:51][C:52]=2[CH2:57][O:56]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c4)C(=O)O3)ccc2O1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A solution of 3-(hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (512 mg) in DMF (4 ml) under nitrogen was treated with sodium hydride (1.295 g, 60% in oil) and the mixture was stirred at 20° for 30 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (359 mg) in DMF (1 ml) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (25 ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (30 mm diameter column). Elution with EtOAc-cyclohexane (2:3) then (1:1) gave the title compound (400 mg). LCMS RT=4.43 min.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formylbenzoic acid (7.5 g), triethylamine (5.2 g) and p-methoxybenzyl chloride (7.6 g) in dimethylformamide (75 ml) was stirred at room temperature for 2 hours and then at 80° C. for 6 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extract was washed with aqueous sodium bicarbonate and then water, dried over anhydrous sodium sulfate and evaporated to give 4-formylbenzoic acid p-methoxybenzyl ester which was then converted into 4-carboxybenzoic acid p-methoxybenzyl ester by the procedure similar to that described in Example 185.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][C:11]([O:13]C)=[O:12].N1C=CC=CC=1.[OH-].[Na+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CBr
Reactant: Sc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Bromothiophenol (4.00 g, 21.6 mmol) was added to a solution of methyl 2-bromoacetate (2.20 mL, 23.3 mmol) and pyridine (1.88 mL, 23.3 mmol) in DMSO (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (300 mL) and the resulting solution was washed with water (2×250 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in THF (50 mL), aqueous 1 N NaOH solution (25 mL, 25 mmol) was added and the mixture was stirred at room temperature for 45 min. The mixture was concentrated and the aqueous solution was diluted with aqueous 1 N NaOH solution. The solution was cooled to 0° C. and was slowly rendered acidic (pH=2) by addition of aqueous 1 N HCl solution. The resulting suspension was filtered, the solid was washed with water and dried under reduced pressure to give the title compound (3.71 g, 71% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19](=[O:48])[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:21]=[C:22]([NH:24][C:25]([C:27]2[CH:28]=[N:29][N:30]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:31]=2)=[O:26])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19](=[O:48])[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[CH:21]=[C:22]([NH:24][C:25]([C:27]2[CH:28]=[N:29][N:30]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:31]=2)=[O:26])[CH:23]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(OCCN6CCCCC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 50 °C

Procedure:
To a solution of intermediate (11e), 5-hydroxy-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (150 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was added 1-(2-chloroethyl)-piperidine hydrochloride (62 mg, 0.33 mmol) and cesium carbonate (219 mg, 0.67 mmol). The reaction mixture was heated at 50° C. for 5 hours, and cooled to ambient temperature. The reaction mixture was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The title compound was purified by flash chromatography on SiO2 eluting with dichloromethane—5% methanol/dichloromethane (gradient) to afford the desired title compound as a pale yellow solid, 94 mg, 54%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[C:4]([NH2:16])[N:3]=1.C1(C)C=C(C)C=C(C)C=1S([NH:28]O)(=O)=O.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O>>[NH2:16][C:4]1[N:3]2[N:28]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][N:33]=3)[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=1
Reactant: Nc1cc(C(=O)c2ccccc2)cc(N)n1
Reactant: O=Cc1nccs1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Product: Nc1cc(C(=O)c2ccccc2)cc2nc(-c3nccs3)nn12

Procedure:
The title compound, MS m/e (%): 322 (M+H+, 100), was prepared in accordance with the general method of example 373 from (2,6-diamino-pyridin-4-yl)-phenyl-methanone, o-mesitylene-sulfonylhydroxylamine, and thiazole-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:5]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:3])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
Thionyl chloride (13.34 g) was added to 4.06 g of 4-phenoxybenzyl alcohol, and the mixture was stirred at 80° C. for 3.5 hours. After the completion of the concentration, the reaction mixture was extracted with ethyl acetate and with water. The organic layer was concentrated to give 4.31 g of 4-phenoxybenzyl chloride.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[S:15])[N:17]([CH3:16])[NH2:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNN
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [N-]=C=S
Solvent: CCCCC
Product: CN(N)C(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 10.0 grams (.0434 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 1.99 grams (.0434 moles) of methylhydrazine. The reaction was very exothermic and solids formed immediately. Pentane was added to form a slurry, the reaction mixture stirred for 30 minutes at room temperature and the pentane stripped from the slurry to leave a white solid weighing 10.7 grams (89% crude yield). The product melted at 118°-120° C. with decomposition and its infrared spectrum had a strong band at 1515 cm-1 ##STR22## moderate NH bands at 3225 cm-1 and the isothiocyanate at 2040 cm-1 was absent.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5][CH2:4]2)[CH2:2]1.[NH3:19]>>[NH2:19][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: N
Product: NCC1(O)CCNCC1

Procedure:
The synthesis of 1-oxa-4,9-diaza-spiro[5.5]undecan-3-ones is described in Scheme 8A (see R. D. Clark, J. M. Caroon, D. B. Repke, A. M. Strosberg, S. M. Bitter, M. D. Okada, A. D. Michel, R. L. Whiting, J. Med. Chem. 1983, 26, 855). N-protected 4-methylenepiperidine epoxides like benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate are opened by heating with a methanolic solution of ammonia to give the corresponding 4-aminomethyl-4-hydroxypiperidine. The spiro-bicyclic nucleus is formed by the following condensation with chloroacetyl chloride. After removal of the benzyloxycarbonyl group with HBr in acetic acid the spiropiperidine is acylated with 4-cyanobe-nzoyl chloride. The subsequent steps of alkylation with ω-halogenoalkanoates, formation of the amidine, and cleavage of the ester are carried out as described in the previous Schemes.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:7]=[N:8][C:9]([NH:12][NH2:13])=[CH:10][CH:11]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>ClCCl.CCCCCC>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][N:8]=2)[N:13]=1
Reactant: C/C=C/C#N
Reactant: NNc1ccc(Cl)cn1
Agent: [Na]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCO
Product: CC1CC(N)=NN1c1ccc(Cl)cn1

Procedure:
A mixture of 0.20 g. of sodium metal dissolved in 50 ml. of absolute ethanol, 5.0 g. of 3-chloro-6-hydrazinopyridine and 4.8 g. of crotononitrile is heated at reflux for 18 hours. The procedure of Example 5 is followed through the evaporation of the magnesium silicate filtrate to give a yellow gum. Trituration with hexane gives a yellow solid. The solid is dissolved in dichloromethane. This solution is concentrated by heating on a steam bath while adding hexane, then is cooled in a refrigerator to separate 3.3 g. of the product of the Example as pale yellow crystals, m.p. 168°-170° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:30][CH2:31][OH:32])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][N:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:32][CH2:31][CH2:30][N:22]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([C:17]2[O:16][N:15]=[C:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[N:18]=2)[CH:20]=[N:21]1)(=[O:3])=[O:2]
Reactant: OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Mesyl chloride (280 μL; 3.6 mmol) was added to a solution of 2-(4-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5-phenyl-1H-pyrazol-1-yl)ethanol (663 mg; 1.8 mmol), obtained from step 1, and triethylamine (502 μL; 3.6 mmol) in dry DCM (5 mL) at 0° C. The tube was sealed and allowed to warm to room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate and the organic fraction passed through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a pale yellow solid (785 mg; 97%). 1H NMR (CDCl3, 400 MHz) δ 8.31 (1 H, s), 7.69-7.64 (1 H, m), 7.59-7.81 (3 H, m), 7.50-7.45 (2H, m), 7.21-7.10 (2 H, m), 4.64 (2 H, t, J=5.2 Hz), 4.38 (2 H, t, J=5.2 Hz), 2.90 (3 H, s). LC/MS: 447 (M+H)+. HPLC (Method A) Rt=3.69 min (Purity: 99.4%).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:41]=[O:42]>C1COCC1>[OH:42][CH2:41][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:8]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:9]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(c2ccccc2)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(CO)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
tert-Butyl 4-((2,2-diphenylacetyloxy)methyl)piperidine-1-carboxylate (prepared as in Preparation intermediate 12 with 2,2-diphenylacetic acid replacing cyclohexylmandelic acid) (0.40 g, 0.98 mmol) in THF (5 mL) was treated with lithium hexamethyldisilazide (1.17 mL, 1.17 mmol, 1.0 M solution in THF) followed by formaldehyde (0.20 g, 50% w/w). The reaction mixture was stirred at RT for 16 hours then quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 30-60% ethyl acetate in petroleum ether (40:60) to afford the title compound (0.10 g, 23%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:29]([CH3:30])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Dissolve 28.2 g (0.2 mol) p-fluoronitrobenzene into 300 ml tetrahydrofuran. Add a solution of which 56.4 g (0.2 mol) N, N-octadecylmethylamine and 20.3 g (0.2 mol) triethylamine are dissolved in 300 ml tetrahydrofuran into the above solution, while stirring. After the completion of the adding heat and reflux it for four days. 60.6 g (0.15 mol) N, N-octadecylmethyl-p-nitroaniline is obtained by recrystalization of the solution using ethyl alcohol and water after concentrating the above solution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:35])=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=2[F:35])[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/N=C/CC1CCCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(CC2CCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 25.8 %

Procedure:
In a manner similar to the method described in Example 1c, [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was vented with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(Cl)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2ccc(Cl)cc2C1=O
Reaction time: 0.75 h
Yield: 85 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.3 g of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone in 200 ml of anhydrous dichloro-methane and 100 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.13 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was recrystallized from ethyl acetate/hexane. 8.29 g (85%) of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone were obtained as a white solid with m.p. 80°.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[C:20]3[N:19]=[CH:18][N:17]([CH3:21])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[C:20]2[N:19]=[CH:18][N:17]([CH3:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cn1cnc2c(Nc3cc(Cl)nnc3C(N)=O)cccc21
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)cccc21
Temperature: 120 °C
Yield: 32 %

Procedure:
A solution of 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (260 mg, 859 μmol) in N-methyl-2-pyrrolidinone (3.0 mL) was treated with tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (368 mg, 1.72 mmol), and the mixture was heated to 120° C. for 72 h. The solvent was evaporated under high vacuum and the residue was purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 5% of a 9:1 MeOH: NH4OH solution in CH2Cl2, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (132 mg, 32%) as a light brown foam. 1H NMR (CHLOROFORM-d) δ: 11.05 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.77 (s, 1H), 7.39 (br. s., 1H), 6.96-7.30 (m, 3H), 6.40 (br. s., 1H), 6.10-6.33 (m, 2H), 3.78 (br. s., 4H), 3.52 (br. s., 1H), 0.95-1.70 (m, 17H); LC-MS 481.0 [M+H]+.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)NCCCCc1cccnc1
Yield: 90 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis-(3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (25.85 g) and 3-pyridinebutanamine (10 g) in tetrahydrofurane (100 mL) was stirred for 18 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to afford 23.9 g of (E)-5,5-bis(3-fluorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 103°-104° C. Anal. Calculated for C26H24F2N2O: C, 74.62; H, 5.78; F, 9.08; N, 6.69 Found: C, 74.35; H, 5.99; F, 8.93; N. 6.59.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[N:20]O)[NH2:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:19]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:20]=1
Reactant: COc1ccc(C(N)=NO)cn1
Reactant: O=C(Cl)c1sccc1Cl
Product: COc1ccc(-c2noc(-c3sccc3Cl)n2)cn1

Procedure:
The title compound was prepared as in Example 16 from 3-chloro-thiophene-2-carbonyl chloride (0.150 g, 0.828 mmol) and 6-methoxy-pyridine-3-amidoxime (0.138 g, 0.828 mmol) as a white solid (166 mg, 63%). 1H NMR (DMSO-d6): 8.84 (d, J=2.4 Hz, 1H), 8.28 (m, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H).