Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH2:16]([CH2:31][C:32](Cl)=[O:33])[CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19].[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:32](=[O:33])[CH2:31][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(O)CC1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCN1CCC(OC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)CC1
Yield: 17.2 %

Procedure:
In a 200-ml three-necked flask equipped with dropping funnel, thermometer and reflux condenser, there were placed 4.80 g of N-ethyl-4-hydroxypiperidine, 3.23 g of pyridine and 50 ml of benzene, and 11.60 g of farnesylacetyl chloride was added dropwise under reflux. After completion of the dropping, the mixture was refluxed for a subsequent 2 hour period and then cooled. Addition of 30 ml of 20% aqueous solution of sodium hydroxide, stirring, phase separation and silica gel column chromatography of the upper layer yielded 2.4 g of N-ethyl-4-farnesylacetoxy-piperidine as a pale-yellow liquid. The product was identified by proton NMR and mass spectrometry. The proton NMR data are shown in the following.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7]([O:55][Si](C(C)(C)C)(C)C)[CH2:6][C:5]1=[O:63])[CH:2]=[CH2:3].F.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7]([OH:55])[CH2:6][C:5]1=[O:63])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCC(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCC(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of the product of step (c) (40 mg) in acetonitrile (8 ml) was added 40% aqueous hydrofluoric acid (1 ml). After stirring for 1 hour at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The ether extracts were then dried (MgSO4), filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an increasing acetone gradient then gave the title compound as a foam (20 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:17]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(NC3=NN(c4ccccc4)CC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 65.2 %

Procedure:
A suspension of N-(4-benzyloxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (6.9 g) in ethanol (350 ml) was hydrogenated at atmospheric pressure over 10% palladium on carbon until hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated to small volume. The resulting precipitate was collected, washed with ethanol and dried to give the title compound, (3.32 g) mp 211°-14° (dec).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[C:17]([C:16]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:15]=2[CH3:14])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(C)c(C(=O)Cl)c1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: Cc1ccc(C)c(C(=O)N2N(C3CCCCC3)C(=O)C2(C)C)c1

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dimethylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1cc(C(O)CC)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
11.1 g (37 mmol) of 1-[4-(tert-butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-ol are placed in 100 ml of dichloromethane in a round-bottomed flask, and 32.8 g (377 mmol) of manganese dioxide are added. The medium is stirred overnight at room temperature. It is then filtered through Celite and rinsed with dichloromethane. The filtrate is evaporated and the residue is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10) to give 6.8 g (62%) of the expected product in the form of an orange-colored oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1ccc(CO)c(N)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C=O)c(N)n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 87.9 %

Procedure:
To a methylene chloride (8 mL) solution of (2-amino-6-methyl-pyridin-3-yl)-methanol (379 mg, 2.74 mmol) described in Manufacturing Example 170-1-3 was added manganese (IV) dioxide (1.19 mg, 13.7 mmol) at room temperature, which was stirred for 11 hours at room temperature. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (328 mg, 88%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:21])[NH:16]2)([OH:3])=O.[CH2:22]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:30]1([N:29]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)=[O:3])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: c1ccc(CNC2CCCCC2)cc1
Reactant: O=C(O)CCCCCCOc1cccc2c1CCC(=O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1CCc2c(cccc2OCCCCCCC(=O)N(Cc2ccccc2)C2CCCCC2)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
To a solution of 2.9 g of 5-(6-carboxyhexyloxy)-3,4-dihydrocarbostyril and 1.9 g of N-benzylcyclohexylamine in 100 ml of DMF is added gradually dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 10 ml of DMF at room temperature and under agitation. After this agitation, the mixture is further agitated at room temperature for 5 hours. After the reaction, the insolubles are filtered off and the mother liquor is concentrated. The residue is dissolved in chloroform and subjected to silica gel thin-layer chromatography (solvent: chloroform-methanol (8:1) to scrape out the portion with Rf value of 0.8. The silica gel is extracted with chloroform, and after distilling off chloroform, the residue is recrystallized from benzene-ligroin to obtain 1.1 g of 5-[6-(N-cyclohexyl-N-benzylaminocarbonyl)hexyloxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 49°-52° C.
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[O:20][CH3:21])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(OCC)(=O)C.[Pd]>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[C:9]([O:20][CH3:21])[CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1cc(C2CCCCC2)ccc1C(O)CCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C2CCCCC2)ccc1CCCC(=O)O

Procedure:
1 g of 4-hydroxy-4-(4-cyclohexyl-2-methoxyphenyl)-butyric acid is dissolved in 20 ml of ethyl acetate and hydrogenated in the presence of 100 mg of Pd on carbon (10%). When the hydrogen has been completely absorbed, filtration takes place. The filtrate is evaporated and the residue is recrystallised from CH2Cl2 -pentane. M.p. 104°-105°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([CH:19]=O)[CH:11]=2)[CH:9]=1)[CH3:2].[NH2:22][CH:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:21])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12](/[CH:19]=[N:22]/[CH:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2cc(C=O)nc(C(C)C)c2)c1
Reactant: CN1CCC(N)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(/C=N/C3CCN(C)C3=O)nc(C(C)C)c2)c1
Reaction time: 8 h

Procedure:
A solution of 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 116) (570 mg, 1.98 mmol) in DCM (10 mL) was treated with 3-amino-1-methyl-pyrrolidin-2-one (226.45 mg, 1.98 mmol) and magnesium sulphate (1193.7 mg, 9.92 mmol). The mixture was stirred overnight and then filtered and concentrated to give 3-[(E)-[4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-2-pyridyl]methylene-amino]-1-methyl-pyrrolidin-2-one as an oil. To a stirred solution of this material (759.25 mg, 1.98 mmol) in anhydrous THF (10 mL) under nitrogen at room temperature, was added phenyl vinyl sulfone (0.34 g, 2.02 mmol) and silver acetate (0.04 g, 0.01 mL, 0.2200 mmol). The resulting mixture was left to stir at room temperature for 2 h. The reaction mixture was filtered through Celite and the celite was washed with THF (approx. 20 mL). The filtrate was stirred under nitrogen in an ice bath and treated with potassium t-butoxide (2.33 mL, 3.96 mmol) over 5 minutes. After completion of the addition, the mixture was stirred at room temperature for 1 hr. Acetic acid (0.23 mL, 3.96 mmol) was added and the mixture was stirred for 5 minutes and then filtered through Celite and concentrated. The material was purified by chromatography using a Biotage Si—NH column, and eluting with 10-100% ethyl acetate in isohexane to give racemic 2-[4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one as a yellow gum (734.8 mg);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Reaction time: 16 h

Procedure:
1.0 g of the product obtained in Example 8 was dissolved in 5 ml of tetrahydrofuran, 4.7 ml of pivaloyl chloride was added and the mixture wasrefluxed for 16 h. The solvent was evaporated in vacuo and the residue was purified in a silicagel column by using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent. The product was crystallized from ether, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4].S(Cl)([Cl:17])=O>>[Cl:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([Cl:17])=[O:14])=[N:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4]
Reactant: O=C(O)c1ccc(C(Cl)=C(Cl)Cl)cn1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C(Cl)=C(Cl)Cl)cn1

Procedure:
The above reaction is repeated on 12.3 g. of 5-trichlorovinyl pyridine-2-carboxylic acid and 145 ml. of thionyl chloride affording a tan solid with a m.p. 89°-90° C. The crude 5-trichlorovinyl pyridine-2-carboxylic acid chloride are used without further purification in subsequent steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Nc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A mixture of 4-(3-fluorophenylamino)benzoic acid (0.040 g, 0.173 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.040 g; 0.173 mmol), HATU (0.072 g; 0.190 mmol) and N,N-diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 10% ethyl acetate in dichloromethane) to yield 0.027 g (39%) of the title compound as a colourless solid.
Reaction SMILES: NC1C=C[C:5]([N:9]2[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]2)=[N:6][C:7]=1N.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC.CO>C1(C)C=CC=CC=1>[N:9]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[NH:6][CH:5]=1
Reactant: Nc1ccc(N2CCC(O)CC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: c1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 127.9 %

Procedure:
To a stirring suspension of 5′,6′-Diamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (8.90 g, 39.7 mmol) and p-toluenesulfonic acid (1.63 g, 8.55 mmol, 0.2 eq) in toluene was added triethyl orthoformate (21.5 mL, 129 mmol, 3.0 eq) in two portions. The first (11 mL) was added in a fast dropwise addition manner the mixture stirred to 16 hr at 100° C. Methanol (10 mL) was added followed by the final portion of triethyl orthoformate (10.5 mL) and the reaction stirred an additional 1 hr at 110° C. The solution was cooled and concentrated to a dark solid. The resulting solid was triturated from Acetonitrile/Water (20:1) giving 6.0 g of benzimidazole as a brown powder. Benzimidazole (5.72 g, 26.2 mmol) was dissolved in DMF (100 mL) and imidazole (3.75 g, 55.1 mmol, 2.1 eq) followed by tert-butyl-diphenylsilylchloride (15.0 mL, 58.4 mmol, 2.2 eq) were added and the reaction stirred for 16 hr at 23° C. The reaction was quenched with sat'd NaHCO3 (20 mL) and then diluted (100 mL) with water. EtOAc (500 mL) was added and the layers partitioned. The organic was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by chromatography eluting with EtOAc/Heptane giving desired product as an oil, which was precipitated in Acetone to afford 5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine as an orange solid (4.75 g, 10.4 mmol, 40%). MS ESI m/z 457.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26][CH2:27][CH2:28]Cl>>[CH3:25][S:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9](\[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)/[CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: OCCC(=C(c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: CSCCCl
Product: CSCCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1

Procedure:
The compound is prepared by using the method described in the example 1a starting from 4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-en-1-ol (preparation described in U.S. Pat. No. 4,996,225) and 2-chloroethyl methyl sulfide.
Reaction SMILES: C(OC[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]([NH:21][OH:22])=[O:20])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:11]=1)C1C=CC=CC=1.FC1C=C(F)C=CC=1CN1C2=CN=C(C=O)C=C2C=C1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][N:12]1[C:13]2=[CH:14][N:15]=[C:16]([C:19](=[O:20])[NH:21][OH:22])[CH:17]=[C:18]2[CH:10]=[C:11]1[C:47]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: CCOC(=O)c1cc2cc(C=O)ncc2n1Cc1ccc(F)cc1F
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Product: CCOC(=O)c1cc2cc(C(=O)NO)ncc2n1Cc1ccc(F)cc1F

Procedure:
Ethyl 1-(2,4-difluorobenzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxyl ate. The title compound can be prepared by alkylation of ethyl 5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (prepared according to J.-F. Rousseau, R. H. Dodd, X. Doisy, P. Potier, Heterocycles 1989, 28, 1101-1113) and 2,4-difluorobenzyl bromide in a manner similar to step (a) in Example 1. (b) 1-(2,4-Difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound can be prepared by oxidation of ethyl 1-(2,4-difluoro-benzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate according to the procedure by R. H. Dodd, M. Le Hyaric, Synthesis 1993, 295-287. (c) Ethyl 1-(2,4-Difluorobenzyl)-5-hydroxycarbamoyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate. The title compound can be prepared from 1-(2,4-difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid following in a manner similar to step (c ) in Example 1.
Reaction SMILES: [C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:1](=[S:31])[NH2:2])[CH2:4][C:5]2=[O:17])=[CH:11][CH:12]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a cooled (0° C.) solution of 4-cyano-1-(4-fluorobenzyl)-4-phenylpiperidin-2-one (3.39 g, 10.9 mmol) in pyridine (77 mL) was added triethylamine (45.0 g, 0.77 mol). The reaction mixture was saturated with hydrogen sulfide gas, the reaction vessel was sealed and then brought to ambient temperature. After stirring for 24 hours, the reaction mixture was cooled (0° C.), the reaction vessel was opened, then the solvents were concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-70% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.68 (s, 1H), 7.35 (m, 4H), 7.26 (t, J=7 Hz, 1H), 7.13 (t, J=8.3 Hz, 2H), 7.04 (t, J=8.9 Hz, 2H), 4.48 (d, J=15 Hz, 1H), 4.35 (d, J=15 Hz, 1H), 3.16 (m, 2H), 3.93 (d, J=17 Hz, 1H), 2.82 (m, 1H), 2.51 (m, 2H) ppm. ES MS M+1=343.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].CN1CCOCC1>C(Cl)Cl>[C:26]1([O:25][C:23]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:21][CH2:20]2)=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)Oc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol) and phenyl chloroformate (40 mg, 0.26 mmol) in CH2Cl2 (3 mL) at 25° C. is added N-methyl morpholine (0.07 mL, 0.60 mmol). After being stirred at 25° C. for 3 h, the mixture is diluted with CH2Cl2 (10 mL), and washed with saturated sodium bicarbonate (1 mL) and water (2×5 mL). The organic layer is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid phenyl ester (69 mg, 81%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.Br[CH2:16][CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[K+]>C(O)C>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][CH2:2][NH:1][CH2:16][CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])[NH2:12]
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Reactant: OC(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1cc(OCCNCC(O)c2ccccc2)ccc1O

Procedure:
A suspension of 21.9 g of 5-(2-aminoethoxy)-salicylamide, 36.0 g of α-(bromomethyl)-benzyl alcohol and 30 g of potassium bicarbonate in 240 ml of ethanol is refluxed for 15 hours, with stirring. The reaction mixture is then cooled and filtered and the filtrate is evaporated. The evaporation residue is partitioned between 300 ml of ethyl acetate and 100 ml of water and the organic phase is separated off, dried over magnesium sulfate and evaporated. The residue is dissolved hot in as little ethanol as possible and made to crystallise, yielding α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)ethyl]-aminomethyl]-benzyl alcohol with a melting point of 174°-175° (from ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: BrCCCCSc1ccccc1
Product: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-(phenylmercapto)-butyl bromide (b.p. 96°-103° C. at 0.02 mm Hg; prepared from thiophenol and 1.4-dibromo butane).