Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:24])[C@@H:14]3[C@H:17]([O:19][Si](C)(C)C)[CH3:18])[C:11]=2[C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH:7]=[CH:8][CH:9]=1)=[O:3].Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:24])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cccc(C(N)=O)c3)C[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cccc(C(N)=O)c3)C[C@H]12
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
[(2,2-Dimethylpropanoyl)oxy]methyl (5R,6S)-3-[3-(aminocarbonyl)phenyl]-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (11 mg) obtained in Step b) was dissolved in ethyl acetate (2 ml) and THF (2 ml), and thereto was added 0.1N hydrochloric acid under ice-cooling to adjust the pH value thereof to the range of from pH 2 to pH 3. The mixture was vigorously stirred for 20 minutes, and the reaction solution was diluted with ethyl acetate, and poured into a cold aqueous sodium hydrogen carbonate solution. The mixture was extracted and separated, and the organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (ethyl acetate/acetone=4/1) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-[3-(aminocarbonyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (9 mg).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].C(N(CC)CC)C.[C:32](OCC)(=[O:38])[C:33](OCC)=[O:34]>COC(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[NH:13][C:33](=[O:34])[C:32](=[O:38])[NH:6][C:7]=2[N:8]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: CCOC(=O)C(=O)OCC
Agent: COC(C)O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)c(=O)[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.0 g), triethylamine (0.42 ml) and diethyl oxalate (1.2 ml) in methoxyethanol (10 ml) was heated under reflux for 7 hours. The reaction mixture was stirred overnight at ambient temperature and a precipitate was collected and washed with water and ethanol to afford a crude product (0.70 g, m.p. 312-315° C.). The crude product together with another sample (0.34 g) similarly prepared was twice recrystallized from dimethylformamide to afford th e title compound, 0.40 g, m.p. 320-321° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[CH3:16].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:16][C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1cc(C)c(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c(C#C[Si](C)(C)C)s1
Reaction time: 3 h

Procedure:
Trimethylsilylacetylene (16 ml) is added to a solution of 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (16.9 q, example 1, step A), Pd(PPh3)2Cl2 (3.78 g), CuI (1.46 g) and triethylamine (16 ml) in DMF (15 ml). After 3 hours at room temperature, the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by filtration over a plug of silica gel eluting with dichloromethane to yield 1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g) as yellow solid. The compound is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([S:15]CC2C=CC(OC)=CC=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([SH:15])[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1c(SCc2ccc(OC)cc2)nc2c(F)c(F)c(F)cc2c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1c(S)nc2c(F)c(F)c(F)cc2c1O
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Ethyl 4-hydroxy-6,7,8-trifluoro-2-(p-methoxybenzylthio)quinoline-3-carboxylate (59.9 g) was added to a mixture of trifluoroacetic acid (500 g), trifluoromethanesulfonic acid (100 g) and anisole (92.5 g) at -23° to -20° C. with stirring over a period of 15 minutes. The mixture was stirred at -20° to -15° C. for 30 minutes and then at room temperature for 1.5 hour. After the reaction mixture was concentrated under reduced pressure, a piece of ice was added to the concentrate and the mixture was made alkaline with 10% aqueous sodium hydroxide. After insoluble materials were removed by filtration, the filtrate was washed with ether and made strongly acidic with concd. hydrochloric acid. The resulting powder was filtered to give the title compound (33 g), which was recrystallized from ethanol to give yellow crystals, m.p. 190° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH:7]=[C:8]([C:14](=O)[CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:25][CH3:26])[CH:4]=1)#[N:2].[NH2:27][C:28]([CH3:33])=[CH:29][C:30](=[O:32])[CH3:31]>C(O)(C)C>[C:30]([C:29]1[CH:7]([C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[O:25][CH3:26])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[NH:27][C:28]=1[CH3:33])(=[O:32])[CH3:31]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(=O)C(OCC)OCC
Reactant: CC(=O)C=C(C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(C)=O)C1c1ccc(C#N)cc1OC
Yield: 28.4 %

Procedure:
720 mg (1.992 mmol) of ethyl 2-(4-cyano-2-methoxybenzylidene)-4,4-diethoxy-3-oxobutanoate are taken up in 15 ml of isopropanol, 197.5 mg (4.84 mmol) of 4-amino-3-penten-2-one are added, and the mixture is heated at the reflux temperature overnight. The mixture is then concentrated and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 250 mg (28.6% of theory) of ethyl 5-acetyl-4-(4-cyano-2-methoxyphenyl)-2-(diethoxymethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate are obtained [LC-MS (method 11): Rt=2.48 min; [M+H]+ (EIpos): m/z=443].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CN(C)C=O.ClC(Cl)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:20][C:21]([CH3:22])=[O:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: CC(C(=O)O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC(=O)COC(=O)C(C)c1ccc(O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
After 49.9 g of 4-hydroxyphenylpropionic acid was dissolved in 160 ml of dimethylformamide, 21.8 g of potassium carbonate was added to the solution at room temperature. Then 29.1 g of monochloroacetone was added dropwise to the solution at 60° C. and the reaction with 4-hydroxyphenylpropionic acid was carried out at 80°-90° C. for 1 hour. After the reaction, dimethylformamide was distilled off from the reaction solution to give a residue. After the residue was dissolved in dichloroethane, the solution was washed with water. The layer of dichloroethane was removed and the solvent was distilled off to give 64.7 g (yield 97%) of acetonyl 4-hydroxyphenylpropionate. After recrystallization from isopropylether, the product was a colorless crystalline material having a melting point of 64.5° C.
Reaction SMILES: [C:1]1([CH2:7][OH:8])([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:9]([C:13]1[CH:14]=[C:15](O)[CH:16]=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10].O[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>>[C:9]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:6][CH2:5][C:1]1([CH2:7][O:8][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)[CH2:4][CH2:3][CH2:2]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: OCC1(CO)CCC1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3cccc(C(C)(C)C)c3)CCC2)cc1

Procedure:
Analogously to example 1, cyclobutane-1,1-diyldimethanol, 3-tert-butylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[1-(3-tert-butylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.[OH-].[Na+]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:2]([F:1])[CH:7]=2)[C:9](=[O:11])[CH3:10])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)c(F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
45.1 g of the ketone compound thus obtained, 50.3 g of 3,4-dichlorobenzyl chloride and 15.8 g of sodium hydroxide were mixed, heated with stirring at 100° C. for 6 hours. The reaction solution was left to cool to room temperature and then extracted by an addition of ethyl acetate and water. The organic layer was post-treated by a conventional method. Then, the product was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 65.0 g (yield: 85%) of 4-(3,4-dichlorophenyl)-3-(2-fluoro-4-biphenylyl)-2-butanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH:16]2[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C1COC(=O)N1)C1C=CC=CC=1>>[CH3:22][O:19][C:18]([CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Cl:21])[CH:11]=1)=[O:20]
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C(O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Product: COC(=O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Yield: 38 %

Procedure:
The mixture (650 mg) of 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step D was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (379 mg, two-step yield 38%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:10][O:9][C:8]3[C:11]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:13]=[CH:14][C:7]=3[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:10][O:9][C:8]4[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=[CH:14][C:7]=4[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1OCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 41 %

Procedure:
Using ethyl [(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 41%.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O)[CH3:28].C([N:48](CC)[C:49]([CH2:51]P(=O)([O-])[O-])=[O:50])C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:35]1([C:33]([C:32]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=2)=[CH:51][C:49]([NH2:48])=[O:50])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Reactant: CCN(CC)C(=O)CP(=O)([O-])[O-]
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC(N)=O)c2ccccc2)ccc1OC

Procedure:
The acrylamide was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol), diethylcarbamoylmethylphosphonate (0.25 g, 1.3 mmol) and lithium hexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 45% ethyl acetate/methylene chloride) to afford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: 1H NMR (CDCl3) δ 7.54-7.19 (m, 10H), 7.00-6.65 (m, 6H), 6.34 (s, 2H), 5.54 (s, 1H), 5.55 (s, 1H), 5.24 (s, 1H ), 5.04 (s, 1H), 4.16 (m, 4H), 3.92 (s, 3H), 3.87 (s, 3H), 1.60-1.33 (m, 6H); 13C NMR (CDCl3) δ 168.7, 168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2, 129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9, 111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C18H19NO3.0.35H2O. Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N, 4.45.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].CI.[CH2:17](Cl)Cl>CN(C=O)C>[CH3:17][O:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: ClCCl
Reactant: COC(=O)c1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of NaH (washed three times with dry THF to remove oil, 0.145 g, 1.1 eq) in dry DMF (5 mL, CaH2 dried), 420 mg of methyl 3-hydroxy- 6-aminobenzoate (E) was added in 3 mL of DMF immediately followed by MeI (443 mg [0.195 m], 1.2 eq), and stirred at room temperature under argon for 16 hr, at which time TLC indicated the absence of E. 200 mL of CH2Cl2 was added and the mixture was extracted with brine (5×100 ml); the organic solvent was evaporated; the crude product was added to 200 mg of NaOH in 5 mL of water; and the reaction mixture was heated at 70° C. for 2 hr. The reaction mixture was neutralized to pH 7.0 with dilute HCl and extracted with CH2Cl2 (5×25 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to yield crude product, which was applied to silica gel (230-400 mesh and eluted with EtOAc/MeOH, 50:1) to yield product 39, 206 mg (yield 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I:20][CH3:21]>C(OCC)(=O)C.C(O)C>[I-:20].[CH3:1][N+:2]([CH3:21])([CH3:19])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CI
Reactant: CN(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[N+](C)(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Product: [I-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl-(6-phenyl-5H-pyrrolo[2,3-b]pyrazin-7-ylmethyl)-amine [5.1 g, Reference Example 32] in ethyl acetate (100 mL) at 0° C. was treated with a solution of iodomethane (40 mL) in ethanol (150 mL). The resulting mixture was stirred at 0° C. for 2 hours. The precipitated solid was filtered then washed with ethyl acetate (10 mL) and then with diethyl ether (20 mL) to give the title compound as a yellow solid (4.5 g), m.p. 224-225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([F:15])[C:8]([F:14])=[CH:9][CH:10]=2)[C:5]=1[F:16])[CH3:2].C([Li])CCC.CCCCCC.[CH2:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][CH:45]=[O:46])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31].Cl>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]2[C:11]([CH:10]=[C:9]([CH:45]([OH:46])[CH2:44][C@H:41]3[CH2:40][CH2:39][C@H:38]([C@H:35]4[CH2:36][CH2:37][C@H:32]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]4)[CH2:43][CH2:42]3)[C:8]([F:14])=[C:7]2[F:15])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=O)CC2)CC1
Reactant: CCOc1ccc2ccc(F)c(F)c2c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC(O)c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A tetrahydrofuran (50 ml) solution of 2-ethoxy-1,7,8-trifluoronaphthalene (9.4 g) was cooled to −60° C. Then, a 1.58 M butyllithium/hexane solution (47 ml) was added dropwise to this solution, followed by stirring for 2 hours. A tetrahydrofuran (50 ml) solution of trans-4-(trans-4-butylcyclohexyl)cyclohexylacetoaldehyde (13.2 g) was added dropwise at −50° C. . After stirring for 2 hours, the reaction temperature was increased to 0° C. 10% hydrochloric acid was added to the reaction solution. The reaction solution was extracted with ethyl acetate, washed with brine, and concentrated. The residue was recrystallized from ethyl acetate, and 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]-1-hydroxyethyl]-1,2,8-trifluoronaphthalene was obtained.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.Cl[C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>O.C1COCC1.[Cu]>[CH3:23][C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([CH3:24])[C:21]#[CH:22]
Reactant: COC(=O)c1ccccc1N
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#CC(C)(C)Nc1ccccc1C(=O)OC
Temperature: 65 °C

Procedure:
To a solution of methyl anthranilate (5.54 g, 36.6 mmol), triethylamine (3.48 g, 34.5 mmol), cuprous chloride (0.21 g, 2.15 mmol), copper powder (0.163 g, 2.56 mmol) in H2O (4 mL) and THF (14 mL) was added 3-chloro-3-methyl-1-butyne (2.21 g, 21.6 mmol). After heating to 65° C. for 4 h the reaction was cooled, diluted with water and extracted using diethyl ether (three times). The combined organic layers were washed with water, dried using MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (5% EtOAc/hexanes-10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCCCCBr)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 96.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (525.0 mg, 1.83 mmol) and N-cyclopropyl-10-bromodecanesulfonamide (685.0 mg, 2.01 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-10-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]decanesulfonamide (964.0 mg) as a pale brown oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.5%).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])O)[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][S:14][CH2:15][C:16]1(OC)[CH:20]=[CH:19][CH:18](OC)[O:17]1.[O:25]1C=CCC1.C>O.C(OCC)(=O)C>[CH3:13][S:14][CH2:15][C:16]1[O:17][C:18]([C:3]2([OH:4])[C:5](=[O:6])[CH:7]([CH2:9][CH:11]([OH:12])[OH:25])[O:8][C:2]2=[O:1])=[CH:19][CH:20]=1
Reactant: COC1C=CC(CSC)(OC)O1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C1=COCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSCc1ccc(C2(O)C(=O)OC(CC(O)O)C2=O)o1
Reaction time: 1 h
Yield: 88 %

Procedure:
L-Ascorbic acid (8.8 g, 0.05 mole) was dissolved in 62 mL water that had been purged with nitrogen for 1 hour. Freshly distilled 2-methylthiomethyl-2,5-dimethoxy-2,5-dihydrofuran (9.5 g, 0.05 mole) was added dropwise with stirring over a period of 1 hour. The reaction mixture was not completely homogeneous. Twenty four hours after the addition of the dihydrofuran, the insoluble droplets were removed by treatment with methylene chloride. The aqueous fraction was frozen and freeze-dried to give 14.2 g (98%) crude product. The amorphous solid was dissolved in 100 mL ethyl acetate and was shaken with 3 g decolorizing charcoal and 3 g celite. After filtration, the solvent was removed under vacuum to give 12.7 g (88%) amorphous product, sinters 40°-42° C.
Reaction SMILES: [CH:1]1([N:4]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1>>[CH:1]1([N:4]([CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=3)[CH2:26][CH2:27]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]#[N:21])=[CH:17][CH:18]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1cnc(Cl)nc1
Reactant: N#CCc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-c4ccc(CC#N)cc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(4-cyanomethyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 3): tR=1.84 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)CCCC(F)(F)F
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0° C., was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0° C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid NaHCO3 (5 g) and stirred for 30 min. The mixture was filtered through MgSO4 and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgSO4 filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fritted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45 μm nylon membrane filter disk to provide Intermediate S-1G (6.6 g, 31.4 mmol 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (s, 9 H) 1.74-1.83 (m, 2 H) 2.00-2.13 (m, 2 H) 2.24 (t, J=7.28 Hz, 2 H).