Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][CH2:36][CH2:37][NH:38][C:39]1[N:47]=[C:46]([Cl:48])[N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl.O>[Cl:48][C:46]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:39]([NH:38][CH2:37][CH2:36][NH:35][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[N:47]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg of 4-(methylthio) benzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 290 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 4 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 336 mg of expected product is collected.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]#[N:20])=[CH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>O1CCCC1>[C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:18][CH:17]=2)#[N:20]
Reactant: N#Cc1cc2cc(C(CO)c3ccccc3)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(2-hydroxy-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXX (218 mg, 0.789 mmol) in tetrahydrofuran (10 mL) was added at 0° C. methanesulfonyl chloride (73 μL, 0.947 mmol) followed by triethylamine (0.16 mL, 1.183 mmol) and the resulting mixture was stirred at 0° C. for 3 hours. The precipitate which formed was filtered off and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography to give 240 mg of methanesulfonic acid 2-(2-cyano-1H-indol-5-yl)-2-phenyl-ethyl ester CCLXXI.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>C1COCC1.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C(COc1ccccc1)NC(c1ccccc1)c1cc([N+](=O)[O-])c2cccnc2c1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(NC(=O)COc2ccccc2)c2ccccc2)c(O)c2ncccc12
Yield: 61.8 %

Procedure:
N-[(8-hydroxy-5-nitroquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (4.0 g, 9.31 mmol), 10% Pd/C (420 mg) in 70 ml THF were hydrogenated at 42 psi for 20 h. The reaction mixture was filtered through Celite 545, dried over sodium sulfate and concentrated to afford 2.3 g of N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:18][C:3]=1[C:4](=[O:5])[NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 94.4 %

Procedure:
Prepared according to the method of Example 4 using 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and (2-amino-ethyl)-carbamic acid tert butyl ester (0.25 g) to deliver the sub-title compound as a brown oil (0.25 g).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccccn1
Agent: I
Solvent: CCO
Solvent: O
Product: N=C(NCc1ccccn1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide (U.S. Pat. No. 3,657,337) and 3.24 g. of 2-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 20 hours and diluted while hot with 75 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and filtration gives 5.00 g. of pale yellow crystals, m.p. 125°-140° C. Recrystallization from aqueous ethanol gives the desired compound as pale yellow crystals, m.p. 159.5°-161° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[OH:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1c(O)cccc1C(=O)CCC(=O)O
Reactant: NN
Solvent: O
Product: COc1c(O)cccc1C1=NNC(=O)CC1

Procedure:
3-(3-hydroxy-2-methoxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(3-hydroxy-2-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1.C(Cl)Cl>C(O)(=O)C>[N:23]1([C:21]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH:31]=[CH:35][CH:34]=[CH:33]3)=[CH:7][C:6]=2[NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Reactant: COC1CCC(OC)O1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(-n2cccc2)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCCCC1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a stirred solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-amino-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 24; 25 mg, 0.06 mmol) in glacial acetic acid (3 mL) was added 2,5-dimethoxytetrahydrofuran (8 μL, 0.06 mmol). The reaction mixture was heated to 120° C. for 45 min after which it was cooled to room temperature. The mixture was taken up to 4 mL of DCM and washed with water. The organic layer was removed, dried and purified by preparative reversed-phase HPLC (acetonitrile/water, 0.05% TFA) to afford the title compound (12 mg, 0.02 mmol, 43%). MS (ESI): m/z 468 [M+H]+, 490 [M+Na]+. HPLC (reversed-phase): RT=9.71 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.15 (s, 1H), 8.26 (dd, J=7.0 Hz, 1.0 Hz, 1H), 8.22 (dd, J=8.8 Hz, 1.0 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.8 Hz, 7 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.05 (m, 3H), 6.35 (t, J=2.2 Hz, 2H), 3.23 (bs, 4H), 1.61 (m, 2H), 1.48 (bs, 4H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C1C(C(O[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O)=CC=CC=1.Cl>O1CCCC1>[C:21]([O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: C=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 20 %

Procedure:
There was added dropwise with vigorous stirring under a nitrogen atmosphere, 62.9 grams (0.34 mole) of 4-chlorostyrene and 250 ml. of dry distilled tetrahydrofuran to 8.9 grams (0.37 mole) of magnesium metal turnings under enough tetrahydrofuran to cover the turnings. The exothermic reaction was controlled by external cooling to keep the temperature below 60° C. After the exotherm had subsided, the reaction mixture was heated at 60° C. for 0.5 hour until most of the magnesium had been consumed. Using a salt-ice bath, the reaction mixture was cooled to 0° C. and a solution of 44 grams (0.23 mole) of t-butyl perbenzoate in 80 ml. of tetrahydrofuran was added a such a rate to maintain the temperature between 0° C. and 5° C. After the addition had been completed, the temperature was allowed to rise to 25° C. with stirring over the course of 2 hours. Reaction mixture was then poured into 1000 ml. of a 3% aqueous hydrochloric acid solution. The oil which formed was extracted from the aqueous solution with 200 ml. portions of ethylether. The ether layers were washed twice with a 10% aqueous sodium hydroxide solution and then with water until the washings were neutral. The ether layer was then dried over sodium sulfate and the ether removed using a rotary evaporator. To the pale-yellow oil which remained was added a small amount of ionol as an inhibitor and the product fractionally distilled. There was obtained 20% yield of 4-t-butoxystyrene having a boiling point of 45°-46° C. at 0.03 millimeters. The proton NMR spectrum was recorded and is in agreement with the structure of the product. Elemental analysis calculated for C12H16O: %C, 81.82; %H, 9.09. Found: %C, 81.64; %H, 8.89.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[S:10]([NH2:13])(=[O:12])=[O:11])(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(F)cc(F)c1S(N)(=O)=O
Product: NS(=O)(=O)c1c(F)cc(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 49% yield, starting from 2-amino-4,6-difluorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: OCc1ccccc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCc1ccccc1C(F)(F)F
Yield: 92.4 %

Procedure:
A solution of 2.42 g (19.47 mmol) of 2-hydroxybenzyl alcohol in 100 ml of dry acetonitrile is mixed with 3.91 g (19.47 mmol) of 2-trifluoromethylbenzyl bromide and 2.96 g (21.42 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 5.08 g (87% yield) of a solid are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[C:10]([CH:2]3[N:1]([CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([C:24]5[N:25]=[C:21]([CH3:20])[S:22][CH:23]=5)[CH:27]=4)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]3)=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCC(N)c1cccc2c1OCCO2
Product: Cc1nc(-c2cccc(CN3C(=O)CCCC3c3cccc4c3OCCO4)c2)cs1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 420.98 g/mol.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([OH:10])[C@H:4]2[O:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=O)=O)=CC=1>CN(C=O)C>[C:48]([O:47][CH2:46][CH2:45][O:10][C@@H:9]1[C@H:4]2[O:3][C:2]([CH3:31])([CH3:1])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCO[C@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(tritylamino)tetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-ol (10.0 g, 24.0 mmol) in dry DMF (100 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.2 g, 29.0 mmol). After stirring for 30 min at 0° C., 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate (6.5 g, 24.0 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (100 mL). To the mixture was extracted 3×100 mL of EtOAc. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIf was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:17]#[N:18])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Cl-].[Na+].O>[O:11]=[C:10]1[CH2:15][CH2:16][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)([C:17]#[N:18])[CH2:8][CH2:9]1
Reactant: N#CC1(C2CCOCC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(C2CCOCC2)CCC(=O)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A solution of 10.3 g (40.8 mmol) of 8-(tetrahydropyran-4-yl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (5) in a mixture of 90 mL of acetic acid and 18 mL of water was heated at 100° C. for 24 h. The mixture was cooled to room temperature and slowly poured onto 1.2 L of cold saturated aqueous sodium bicarbonate solution. The mixture was diluted with 600 mL of brine and extracted six times with methyl-tert-butyl ether. The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was lyophilized from acetonitrile and water, taken up in water and lyophilized again to give 5.95 g of the ketone, which was used directly in the next step. Rt=0.82 min (Method O). Detected mass: 208.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[C:25]([F:24])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1c(F)cccc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3c(F)cccc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,6-difluorophenol were reacted as starting materials at 150° C. for 72 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (101.0 mg, 39.3%). Melting point: 204.7-206.4° C. (chloroform-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)=[NH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CNc1ccccc1-c1cccc(F)c1
Reactant: OC1CCNCC1
Solvent: COCCOC
Product: N=C(Nc1ccccc1-c1cccc(F)c1)N1CCC(O)CC1

Procedure:
A mixture of 3'-fluoro-2-biphenylylcyanamide (4.1 g) and 4-hydroxypiperidine (1.95 g) in 1,2-dimethoxyethane (30 ml) was heated at 90°-95° C. for 4 hours to give N-(3'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine as a colourless solid (m.p. 147°-148° C.) which was recrystallised from ethylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:15])[CH:11]=[C:12]([CH3:14])[CH3:13]>O=[Mn]=O.CCCCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CC(O)C1=C(C)CCCC1(C)C
Agent: O=[Mn]=O
Solvent: CCCCC
Product: CC(C)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 63 %

Procedure:
2,6,6-Trimethyl-1-[1-hydroxy-3-methyl-2-butenyl]-1-cyclohexene, prepared according to Example 6, (1.0 g.) with activated MnO2 (10 g.) in 30 ml. of pentane was mixed at room temperature during 63 h. After filtration and distillation 630 mg. (63%) of the desired ketone, B.p. 67°/0.001 Torr, were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccc(C#N)cc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-cyanobenzyl bromide (40 mmol, 7.84 g), methyl 3-hydroxybenzoate (40 mmol, 6.08 g) and potassium carbonate (60 mmol, 8.29 g) in 50 mL DMF was stirred at 60° C. overnight and the solution was cooled to room temperature. To it was added dilute citric acid followed by ethyl acetate. The organic layer was separated, washed with brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give a solid. The solid was washed with ether two times to give 6.2 g (60%) product. NMR (DMSO-d6): δ7.88 (d,2H);7.66(d,2H);7.58 (m, 2H); 7.46 (t, 1H); 7.32 (dd, 1H); 5.30 (s, 2H); 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][C@@H:11]1[CH2:15][C:14](=[N:16][O:17][CH3:18])[CH2:13][N:12]1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20].C(O)(=O)C>ClCCl>[CH3:18][O:17][N:16]=[C:14]1[CH2:15][C@@H:11]([CH2:10][C:9]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[N:12]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)=[O:20])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)Nc2ccccc2N)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C1C[C@@H](Cc2nc3ccccc3[nH]2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 66 %

Procedure:
A solution of N-(2-aminophenyl)-2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxy imino)pyrrolidin-2-yl]acetamide (Example 11, 21 mg, 0.05 mmol) and acetic acid (0.1 ml) in dichloromethane (1 ml) was stirred overnight. The organic phase was washed with NaHCO3. The organic phase was dried (MgSO4) and concentrated to afford (3EZ,5S)-5-(1H-benzimidazol-2-ylmethyl)-1-(biphenyl-4-ylcarbonyl)pyrrolidin-3-one O-methyloxime (14 mg). Yield: 65%. HPLC purity: 93%
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH2:10].[C:17]([NH:20][C:21]1[NH:25][N:24]=[C:23]([S:26](Cl)(=[O:28])=[O:27])[N:22]=1)(=[O:19])[CH3:18].[OH-].[Na+]>C(Cl)Cl>[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH:10][S:26]([C:23]1[N:22]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[NH:25][N:24]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(S(=O)(=O)Nc2c(Cl)ccc(C)c2Cl)n[nH]1
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A 250 ml, 1-necked flask equipped with a magnetic stirrer and filled with nitrogen gas was charged with 15 ml of dry pyridine and 8.8 g (0.05 mole) of 2,6-dichloro-3-methylaniline. To the stirred solution was added 11.3 g (0.05 mole) of crude 5-acetylamino-3-chlorosulfonyl-1,2,4-triazole over 10-30 minutes. The resulting dark green mixture, which had a mild exotherm during the addition, was heated to 100°-105° C. with stirring for 3-4 hours. It was then dispersed between a mixture of methylene chloride and dilute aqueous sodium hydroxide and the organic layer was removed. Acidification of the aqueous phase and filtraton and drying of the precipitate that formed gave the title sulfonamide as a tan solid melting at 284° (dec.). The yield was 60 percent of theory. A sample of this compound which was recrystallized from a mixture of methanol and water was a pale ivory powder melting at 285°-285.5° C. (dec.) and had the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]4[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:18]2)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1Cl
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c(Cl)cc1Cl
Yield: 369.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(2,4-dichloro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl) pivalamide (Intermediate-84, 0.150 g, 0.028 mmol), ethynylcyclopropane (0.038 g, 0.56 mmol), TBAF (0.268 g, 0.85 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.77 (m, 2H), 0.93 (m, 2H), 1.21 (s, 9H), 1.58 (m, 1H), 4.32 (d, J=6.3 Hz, 2H), 7.50-7.53 (m, 3H), 7.82-7.91 (m, 2H), 7.95 (s, 1H), 8.21 (m, 1H)