Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH2:10][OH:11].[H-].[Na+].[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O.CN(C=O)C>[C:15]([Si:19]([CH3:21])([CH3:20])[O:11][CH2:10][CH2:9][O:12][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc(I)ccn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(I)ccn1
Reaction time: 2 h
Yield: 61.1 %

Procedure:
2-Fluoro-4-iodo-pyridine (607 mg, 2.72 mmol), ethylene glycol (760 uL, 13.6 mmol) and 60% sodium hydride (120 mg, 2.99 mmol) were sequentially added to 2 mL of anhydrous DMF at room temperature. The solution was then brought to 60° C. and stirred for 2 hours, then cooled down and diluted with 20 mL of water. The mixture was extracted 2 times with 30 mL of diethyl ether. The combined organic layers were washed with 10 mL of water, then 10 mL of brine and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the residue was dissolved in 2 mL of anhydrous acetonitrile. To this solution tert-butylchlorodimethylsilane (453 mg, 3.00 mmol) and triethylamine (459 μL, 3.30 mmol) were added and the mixture was stirred at r.t. for 3 days following evaporation under reduced pressure. The residue was taken up in 40 mL of a 1:1 mixture of diethyl ether and water. The organic layer was concentrated under reduced pressure and the residue purified on a 40 g silica column eluted with a gradient of 0-15% ethyl acetate in hexanes to yield 630 mg of the product as colorless oil. MS: (M+H)/z=380.0.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].S(=O)(=O)(O)O.[CH2:9]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-:25].[Na+].[Na+]>O>[CH2:9]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]([O:3][CH2:1][CH3:2])=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCC1CCCN1Cc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
Into a 3,000 ml roundbottom flask, was placed ethanol (479. g, 10.4 mol), followed by concentrated sulfuric acid (417 g, 4.17 mol). To the mixture was added 2-(1-benzylpyrrolidin-2-yl)acetonitrile (139. g, 695. mmol). The resulting solution was heated to reflux for 4 hours. After cooling to ambient temperature, the solution was diluted with 3,000 ml of water. Adjustment of the pH to 9 was accomplished by the addition of solid sodium carbonate. The resulting solution was extracted three times with 2,000 ml of ethyl acetate and the combined organic layers were concentrated to afford ethyl 2-(1-benzylpyrrolidin-2-yl)acetate, which was used without additional purification.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[CH:29]C(CO)=[CH:27][CH:26]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][C:7]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: COc1ccc(CO)cc1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1ccc(COC(=O)C(=O)c2ccc3c(c2)C2(C)CCN(C)C2N3C)cc1
Reaction time: 8 h

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (2.07 g) in anhydrous 4-methoxyphenylmethyl alcohol (40 ml) was added titanium (IV) ethoxide (0.54 ml) with stirring under nitrogen atmosphere. The reaction mixture was heated without reflexing for 8 hours. The 4-methoxyphenylmethyl alcohol was removed by distillation under high vacuum and the residue was dissolved in dichloromethane (200 ml). The residue was washed successively with two 100 ml portions of saturated aqueous NH4Cl solution, two 100 ml portions of saturated aqueous NaHCO3 solution and with brine, dried (Na2SO4), filtered and evaporated to yield an oil. The oil was purified by preparative HPLC (silica gel, 3% methanol in ethyl acetate as the loading solvent and eluent). A second preparative HPLC purification using 3% methanol in dichloromethane, yielded 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, 4-methoxyphenylmethyl ester (0.84 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.13 h
Yield: 42 %

Procedure:
A solution of 5-bromo-2-methylpyridin-3-amine (187 mg, 1.0 mmol) and diisopropylethylamine (523 uL, 3.0 mmol) in dichloromethane (5 mL) was cooled to 0° C., and then methanesulfonyl chloride (155 uL, 2.0 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 8 min and was then warmed to rt. After stirring for 1 h, the volatile materials were removed in vacuo. The residue was then dissolved in methanol (2.5 mL) and aqueous sodium hydroxide (2 M, 1.5 mL, 3 mmol) was added. The reaction mixture was stirred for 1 h 40 min at rt. Water was then added to the mixture which was subsequently extracted twice with dichloromethane. The combined organic extracts were extracted with aqueous citric acid (10%). The organic phase was discarded, and the aqueous phase was basified to pH ˜7.5 with aqueous sodium hydroxide (1 M). The aqueous mixture was extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (50% hexanes:50% ethyl acetate) to provide N-(5-bromo-2-methylpyridin-3-yl)methanesulfonamide (111 mg, 0.42 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 3.10 (s, 3H), 2.47 (s, 3H); MS (EI) for C7H9BrN2O2S: 265, 267 (Br isotopes, MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH2:9][C:5]([C:10](O)=O)([CH2:6][CH2:7]2)[CH2:4][CH2:3]1.Cl.[NH2:14][C:15]1[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[NH2:21]>>[OH:1][CH:2]1[CH:8]2[CH2:9][C:5]([C:10]3[NH:14][C:15]4[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=4[N:21]=3)([CH2:6][CH2:7]2)[CH2:4][CH2:3]1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C12CCC(O)C(CC1)C2
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C34CCC(O)C(CC3)C4)nc2n(CCC)c1=O
Yield: 44.9 %

Procedure:
Using the method described in Example 8, 4-hydroxy-bicyclo[3.2.1]octane-1-carboxylic acid (Kraus, W., et al. Liebigs Ann. Chem., 1981, 10, 1826) (0.50 mmol, 0.085 g) was reacted with 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (0.50 mmol, 0.132 g) to provide the desired product (0.081 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8]N=1)=[O:5])[CH3:2].[H-].[Na+].FC(F)(F)C1C=CC(C(=[O:33])C)=CC=1.C(OC(=O)C(OCC)=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6](=[O:33])[CH2:10][C:9](=[O:8])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Yield: 80 %

Procedure:
Preparation of 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester (compound 42A) Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of 1(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reaction was allowed to come to room temperature and then heated to 45° C. for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1×100 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxyl amine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1). Step 2. Preparation of [5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol (compound 42B) The title compound was prepared in a manner analogous to Example 40B using 42A. MS m/z 244 (M+1). Step 3. Preparation of 3-chloromethyl-5-(4-trifluoromethyl-phenyl)-isoxazole (compound 42C) The title compound was prepared in a manner analogous to Example 3B using 42B. MS m/z 262 (M+1). Step 4. Preparation of {2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 42 The title compound was prepared in a manner analogous to Example 1F using 42C and 2C. MS m/z 438 (M+1). Step 5. Preparation of {2Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid (compound 42) The title compound was prepared in a manner analogous to Example 1 using 42D. IR cm−1:1746, 1326; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 8.02 (d, 2H, J=8.0 Hz), 7.83 (d, 2H, J=8.0 Hz), 7.20 (s, 1H), 7.15 (s, 2H), 6.71 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.14 (s, 2H), 2.08 (s, 3H); MS m/z 424 (M+1). Anal. Calc'd for C20H16F3NO4S C, 56.73; H, 3.81; N, 3.31 found: C, 56.59; H, 3.58; N, 3.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH3:2].[CH2:15]([I:17])[CH3:16]>CC(C)=O>[I-:17].[CH2:1]([O:3][C:4]1[C:5]([C:9]2[CH:10]=[N+:11]([CH2:15][CH3:16])[CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH3:2]
Reactant: CCI
Reactant: CCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCOc1nsnc1-c1ccc[n+](CC)c1
Product: [I-]

Procedure:
A solution of 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)pyridine (0.90 g, 4.3 mmol) and ethyl iodide (2.03 g, 13 mmol) in acetone (4 ml) was stirred at 40° C. for 16 h. The pecipitate was collected by filtration giving the title compound to yield 1.34 g (86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[OH:24])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (500 mg), 2-amino-5-fluor-phenol (265 mg) and p-toluenesulfonic acid (75 mg) in dioxane (5 ml) was stirred at 140° C. for 15 minutes under microwave radiation. The reaction mixture was allowed to cool, filtered and the filtercake was washed with dioxane, MeOH and diethyl ether to give the desired product.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11].[OH-].[K+]>C(O)C>[C:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)OCCCl
Reactant: CC(C)(C)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)OCCNC(C)(C)C
Temperature: 60 °C
Reaction time: 120 h
Yield: 75.6 %

Procedure:
736 g of tertiarybutylamine and 500 g of 2-chloroethoxyethanol were placed in 2 liters of ethanol and heated at 60° C. overnight. The temperature was then gradually raised to 80° C. and held for 5 days. The reaction mixture was cooled to 50° C. and then treated with 247 g of KOH. After 1 hour at refluxing the reaction was cooled, filtered, vacuum stripped and distilled. The yield of the distilled product, which calculates as a 75.6% yield, was 491 g, and it had a b.p. of 117° C. at 10 mm. Analysis calculated for C8H19NO2 :% C 59.63; %H, 11.80, %N, 8.70; Found: % C, 58.99, %H, 11.82; %N, 8.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1C#Cc1ccccc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccccc1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (0.768 g, 4.74 mmoles) in dry DMF (10 ml) was added under stirring at room temperature with 60% NaH (189.6 mg, 4.74 mmoles) and the mixture was stirred for 1 hour, then dropwise added with 1-chloro-6-methoxy-5-phenylethynyl-phthalazine (700 mg, 2.37 mmoles), prepared as described in example 61, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 3:7). The separated product was taken up in ethyl ether and crystallised from 30 ml of ethyl acetate/CH2Cl2 to give 600 mg of the title compound (yield: 60%). m.p.: 217-219° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)(O)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:25][C:15]1[CH:14]=[C:13]([C:10]2[CH2:11][CH:8]([C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH:9]=2)[CH:18]=[CH:17][C:16]=1[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)CNC(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1

Procedure:
A solution of Example 20, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amide (3.71 g, 10.64 mmol) in trifluoroacetic acid (20 mL) and 1,2-dichloroethane (120 mL) was refluxed for 21 h and concentrated to give 8.6 g of crude 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-isobutylcyclobut-2-enecarboxamide trifluoroacetate salt and residual TFA as a dark red-brown oil. Diagnostic 1H NMR signals: (CDCl3) δ 7.48 (t, J=7.7 Hz, 1H), 7.23 (d, partially obscured by CHCl3 signal, 1H), 7.09 (dd, J=10.3, 1.5 Hz, 1H), 6.38 (d J=0.8 Hz, 1H), 4.33 (d, J=5.0 Hz, 1H), 3.77 (br s, 2H), 3.68 (d, J=4.6 Hz, 1H), 3.20-3.07 (m, 3 h), 2.98 (br s, 2H), 2.83 (dd, J=13.3, 1.7 Hz, 1H), 2.19-2.07 (m, 4H), 0.90 (d, J=7.1H, 6H).
Reaction SMILES: BrCCCCCCCCO.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[O:27]([CH2:34][CH2:35][OH:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][CH2:35][O:36][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: OCCOc1ccccc1
Agent: OCCCCCCCCBr
Product: c1ccc(OCCOCCCCCCCCOC2CCCCO2)cc1

Procedure:
The title compound, m/e=407.6 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran, which was reacted in step 2 with 2-phenoxyethanol, affording 2-(8-(2-phenoxy-ethoxy)-octyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 8-(2-phenoxy-ethoxy)-octan-1-ol. This was oxidized in step 4 to 8-(2-phenoxy-ethoxy)-octanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-4-dimethylamino-3-[8-(2-phenoxy-ethoxy)-octanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 6.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:24]([C:14]1[CH:15]=[N:16][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[CH3:12])=[O:25]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cnn(-c3ccccc3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (93 mg, 0.46 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide as a white solid (40 mg, 26%). LRMS (M+H+) m/z: calcd 336.16. found 336.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:16])([CH3:15])[C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[Cl:10]>CCOCC>[Br:1][CH2:13][C:12](=[O:14])[C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)([CH3:16])[CH3:15]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (1.84 ml) in ether (25 ml) was added dropwise over 1 hour at ambient temperature to a stirred solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (8.24 g) in ether (250 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 30 minutes then it was washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 1-bromo-3-(3,4-dichlorophenyl)-3 methylbutan-2-one as an oil (9.57 g) which was used without purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:33][CH2:32][CH:31]([CH2:34]I)[CH2:30][C:29]=2[CH:36]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:34][CH:31]3[CH2:30][C:29]4[CH:36]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=4[S:33][CH2:32]3)[CH2:3][CH2:4]2)=[O:9])=[CH:15][CH:14]=1
Reactant: Fc1ccc2c(c1)CC(CI)CS2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CSc3ccc(F)cc3C2)CC1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2.178 kg (10.5 mol) p-fluorophenyl 4-piperidinyl ketone hydrochloride (R. L. Duncan et al., J. Med. Chem. 13, 1 (1970)), 1.008 kg (9.96 mol) triethylamine and 25 1 dimethylformamide is added a solution of 3.053 kg (9.9 mol) (6-fluoro-3,4-dihydro-2H-1-benzothiopyran-3-yl)methyl iodide in 9 1 dimethylformamide with stirring at 23° C. over 45 min. The suspension is stirred for 3 days at ambient temperature. The reaction is filtered and the filtrate concentrated at 80° C./4 mbar. The resulting oil is poured into a mixture of 20 1 water and 24 1 ethyl acetate, cooled to 5° C. and basified to pH 10 with concentrated ammonium hydroxide. The organic layer is separated, the aqueous solution extracted further with ethyl acetate, and the combined organic solutions washed with water and brine, dried over sodium sulfate and activated carbon, filtered, and concentrated at 50° C./ 4 mbar. The residue is triturated with heptane, filtered, washed twice with heptane, dried in vacuo and dissolved in dichloromethane. The solution is filtered from the insolubles, stirred with 1.27 kg Kieselgel 60 for 30 min., then filtered and evaporated at 45° C./4 mbar to give the title compound as a solid, m.p. 121°-124° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][C:5]=2[CH:6]=1.[CH2:17](Br)[C:18]#[CH:19]>C(=O)([O-])[O-].[K+].[K+].CO>[CH2:19]([N:14]1[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:4]3[O:3][C:2]([CH3:1])=[CH:6][C:5]=3[CH:7]=2)[CH2:12][CH2:13]1)[C:18]#[CH:17]
Reactant: Cc1cc2cc(C3CCNCC3)ccc2o1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCN1CCC(c2ccc3oc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g (0.013 mol) of 4-(2-methyl-5-benzofuranyl)-piperidine (c.f. Example 12) and 2.4 g (0.02 mol) of 2-propynyl bromide are dissolved in a suspension of 10 g of potassium carbonate in 120 ml of methanol and the solution is stirred at room temperature. After 24 hours, a further 0.24 g of 2-propynyl bromide is added and the reaction mixture is stirred at room temperature for a further 24 hours. Thereafter, it is filtered, the residue on the filter is washed with ethyl acetate and the combined filtrates are evaporated to dryness under a waterpump vacuum. The residue is dissolved again in ethyl acetate and the solution is washed three times with water, dried over sodium sulfate and evaporated to dryness under a waterpump vacuum. The resulting residue is chromatographed on 200 g of aluminium oxide (eluting agent: methylene chloride), whereupon, after evaporating off the solvent, crystalline 1-(2-propynyl)-4-(2-methyl-5-benzofuranyl)-piperidine is obtained. The hydrochloride, prepared from the base in a conventional manner, melts at 185°-187°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH2:25][CH3:26].CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][C:19]=1[CH2:25][CH3:26]
Reactant: CCc1cc(O)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Cl
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-3-ethylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.