Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Cl.[CH3:15]O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CO
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Agent: Cl
Product: COC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude (3-cyano-4-fluorophenyl)acetic acid (980 mg, 5.6 mmol) in methanol (10 mL) was added 5 M HCl/MeOH (10 mL). The reaction was stirred at ambient temperature overnight and concentrated. The residue was purified with preparative TLC to afford methyl (3-cyano-4-fluorophenyl)acetate. 1H-NMR (300 MHz, CDCl3) δ ppm 7.49˜7.55 (m, 2H), 7.17 (t, J=8.2 Hz, 1H), 3.71 (s, 3H), 3.63 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]3[CH2:20][CH:15]2[C:16](=[O:21])[O:17]3)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:22][CH2:23][N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].[OH2:31]>>[CH:25]([N:24]([CH:28]([CH3:30])[CH3:29])[CH2:23][CH3:22])([CH3:27])[CH3:26].[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]([OH:17])[CH2:20][CH:15]2[C:16]([OH:21])=[O:31])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O
Reactant: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Temperature: 40 °C

Procedure:
To a solution of 25 (800 mg, 2.73 mmol) in water (15 mL) in a 20 mL microwave reaction vessel was added DIPEA (1.2 mL, 6.8 mmol) and a stirrbar. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. After 1 min of pre-stirring, the reaction was irradiated for 40 min to a set temperature of 100° C. After cooling to 40° C., the transparent solution was concentrated in vacuo, and the residual brown oil co-evaporated 3× with MeCN to remove any residual water. The crude title compound, in the form of a DIPEA salt, was immediately taken forward to the next step. LC/MS>95%, m/z (ESI+)=312 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31]>O1CCCC1.[Cu]I.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>[NH2:35][C:34]1[CH:33]=[C:32]([C:30]#[C:31][C:2]2[C:3]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(N2CCOCC2)c(Br)cc1NC(=O)OC(C)(C)C
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)c(C#Cc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 20.4 %

Procedure:
tert-Butyl (5-bromo-2-methyl-4-morpholin-4-ylphenyl)carbamate (110 mg, 0.3 mmol), copper(I) iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) were stirred in tetrahydrofuran (0.5 mL) and triethylamine (50 μL, 0.4 mmol) was added. 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was heated to 80° C. for 1 hour. The mixture was filtered through celite and purified by preparative LCMS (pH 2). The product fractions were neutralized with saturated sodium bicarbonate solution, evaporated to remove acetonitrile and extracted with ethyl acetate. The extracts were evaporated to give the desired compound (25 mg, 31%). LCMS for C24H30N3O3 (M+H)+: m/z=408.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[S:23](=[O:25])(=[O:24])[N:22](CC[Si](C)(C)C)[C:21](=[O:32])[CH2:20]3)=[C:15]([O:33]CC3C=CC=CC=3)[CH:14]=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[OH:33][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[N:19]1[CH2:20][C:21](=[O:32])[NH:22][S:23]1(=[O:25])=[O:24])[CH2:12][C:3]1[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3cc4ccccc4cc3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc2ccccc2cc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
N-{3-[3-Hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-naphthalen-2-yl}-methanesulfonamide is prepared analogously to Example 4, Steps B and C, starting with 5-[4-(3-aminonaphthalen-2-ylmethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methanesulfonyl chloride: MS (M−H)−=460.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(Cl)c1cccc(Cl)c1Cl

Procedure:
A mixture of 2,3-dichlorobenzoic acid (39.4 g 0.2M) and thionyl chloride (100 ml) was heated to reflux for 21/2 hours. The cooled solution was evaporated down in vacuo and distilled under nitrogen. Yield 35.5 g (85%), b.p. 146°-148° C. at 31 mm of mercury pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 60c (1.4 g, 4.8 mmol) and SnCl2.2H2O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled to room temperature and was slowly added to saturated aqueous NaHCO3. The solid was filtered and washed with H2O. The solid was triturated with EtOAc and the filtrate was concentrated. The crude product 60d was used in the next reaction without purification. MS m/z (M+H+) 261.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclohexylamine (2.77 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum over the weekend. The solid was recrystallized from isopropyl alcohol-95% ethanol, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.75 g (73%) of crystal, mp 240°-241° C.
Reaction SMILES: [CH3:1][C:2]([NH2:10])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30](O)(=[O:41])[CH2:31][NH:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH3:1][C:2]([NH:10][C:30](=[O:41])[CH2:31][NH:32][C:33](=[O:34])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: CC(C)(NC(=O)CNC(=O)c1ccccc1)c1ccccc1
Yield: 89.9 %

Procedure:
1.0 g of α,α-dimethylbenzylamine and 1.95 g of triphenylphosphine were dissolved in 100 ml of anhydrous methylene chloride. 1.33 g of hippuric acid and 1.63 g of 2,2'-dipyridyl disulfide were added in that order to the solution, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction solution was washed with a 10% w/v aqueous solution of sodium hydroxide and then with 1N aqueous hydrochloric acid, and dried over anhydrous sodium sulfate After concentration of the reaction solution by evaporation under reduced pressure, the resulting residue was subjected to silica gel column chromatography for separation and purification (using as eluent a 1:1 by volume mixture of hexane and ethyl acetate), to give 1.97 g (yield 90%) of the title product melting at 156°-157° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(c1)CCO2
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a suspension of 10.3 g (62.37 mmol) of 5-nitro-2,3-dihydrobenzofuran in 50 mL of MeOH and 10 mL of dichloromethane was added 350 mg of 10% palladium on carbon and the mixture was placed under 55 psi of hydrogen gas. Hydrogen gas uptake was evident during the first 30 minutes. After 18 hours, the mixture was then filtered through diatomaceous earth and concentrated to afford 8.2 g of 2,3-dihydrobenzofuran-5-ylamine as a gray solid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]([OH:25])[C:23]#[N:24])[N:21]=2)=[CH:13][CH:12]=1>C1COCC1>[NH2:24][CH2:23][CH:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[O:18][CH:19]=1)[OH:25]
Reactant: N#CC(O)c1coc(-c2ccc(F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Trifluoroacetic acid (0.35 mL, 4.60 mmol) was added dropwise to a suspension of NaBH4 (0.174 g, 4.60 mmol) in dry THF (10 mL) at 0° C., followed by addition of 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (0.20 g, 0.92 mmol) also portionwise. The reaction mixture was stirred at room temperature for 8 h, and then concentrated under reduced pressure and diluted with ice-water. The mixture was acidified to pH ˜2 using 1.5N HCl at 0° C. and then heated to 50° C. for 20 min. The solution was basified with aqueous NH4OH solution and the organic product was extracted with CHCl3. The combined extracts were washed with brine and concentrated under reduced pressure to afford 2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol (120 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C11H11FN2O2: 222.08. found: 222.8 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([N:21]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][O:10]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.O.[Pd]>[CH2:1]([C@H:8]([NH:18][C:19]([N:21]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[CH2:9][OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(C)CCN(CCc1ccccc1)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN(C)CCN(CCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Yield: 89.8 %

Procedure:
To a solution of 1-[(1S)-1-benzyl-2-(benzyloxy)ethyl]-3-[2-(dimethylamino)ethyl]-3-phenethyl urea (Compound 2-1, 414 mg) in ethanol (4.5 ml), there was added 20% palladium hydroxide-on-carbon (100 mg) in the nitrogen gas atmosphere. This mixture was stirred for 3 days in the hydrogen gas atmosphere. The palladium-on-carbon was removed by the filtration through celite and the resulting filtrate was concentrated under reduced pressure to thus give the title compound (Compound 3-1, 299 mg).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:14]=[C:10]([C:11]([O:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Oc1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc(Br)ccc1O

Procedure:
80 ml of thionyl chloride was gradually added to a benzene suspension of 217 g of 5-bromosalicyclic acid and 113 g of phenol, followed by refluxing for ten hours under heating. After distilling off the benzene, ice-water was added to the residue, and the precipitate formed was collected by filtration, followed by drying. Yield: 210 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10](Br)[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].CC1(C)C(C)(C)OB([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])O1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[C:10]([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(Br)c1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionic acid ethyl ester and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[CH3:40][O:41][C:42](=[O:45])[CH2:43]Br>CO>[CH3:40][O:41][C:42](=[O:45])[CH2:43][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:2]=2[Cl:1])[CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)[CH3:17]
Reactant: CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)CBr
Solvent: CO
Product: COC(=O)CN(C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine (81 mg, 0.15 mmol) in methanol (15 ml) was treated with bromo-acetic acid methyl ester (46 mg, 0.30 mmol) diisopropylethylamine (46 mg, 0.36 mmol). The resulting solution was heated at 50° C. for 4 hours, cooled down and concentrated. The crude material was dissolved in EtOAc and washed with brine (1×), dried over sodium sulfate, and filtered. The filtrate was concentrated to afford title compound as an oil (70 mg, 76%). MS(ES) m/e 625.2 (M+).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:24])C=1>>[O:24]1[CH2:4][CH:3]1[CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH3:1]
Reactant: C=CC(C)Oc1ccccc1NC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)Nc1ccccc1OC(C)C1CO1

Procedure:
The compound was prepared from N-{2-[(1-Methyl-2-propenyl)oxy]phenyl}acetamide (549 mg, 2.67 mmol) and m-chloroperbenzoic acid (80%, 923 mg, 4.28 mmol) analogously to that described in Example 8 (ii). Purification was done on silica gel with petroleum ether/ethyl acetate 10/15 as eluent. This gave separation of the two diastereomeric pairs.
Reaction SMILES: COC(=O)C.[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8](O)=[O:9].[NH2:22][NH2:23]>CO>[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8]([NH:22][NH2:23])=[O:9]
Reactant: NN
Reactant: O=C(O)C(F)(F)c1ccc2ncccc2c1
Solvent: CO
Solvent: COC(C)=O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of difluoro-quinolin-6-acetic acid methyl acetate (670 mg, 2.83 mmol) in methanol (20 mL) was added anhydrous hydrazine (2 mL). The mixture heated to reflux for 2 h, cooled to room temperature, concentrated and dried in high vacuum to give a light orange solid (680 mg, 100%). 1H-NMR (DMSO): δ 9.02-9.01 (1H, dd, J=1.7 Hz), 8.56-8.54 (1H, d, J=9.3 Hz), 8.28 (1H, s), 8.17-8.15 (1H, d, J=8.8 Hz), 7.91-7.88 (1H, dd, J=2.0, 2.0 Hz), 7.66-7.63 (1H, q, J=4.0 Hz).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCCCOCC1CO1
Product: CCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 44.5 %

Procedure:
Using the method of Example 5, supra, 1-decyl glycidyl ether (235 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 175 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 394 (M+1, 1), 378 (6), 273 (97), 272 (100), 222 (9), 163 (37), 121 (61); 1H-NMR (CDCl3) δ7.49 (2H, d, J=8.5), 6.82 (2H, d, J=8.5 Hz), 3.78 (3H, s), 3.75 (1H, m), 3.45 (4H, m), 2.80 (1H, dd, J=11.7 and 4.0), 2.77 (1H, broad s), 2.64 (4H, m), 1.56 (2H, m), 1.26 (16H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.1); 13C-NMR (CDCl3) δ158.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.1, 55.1, 53.3, 46.4, 44.6, 31.8, 29.6, 29.5, 29.4, 29.3, 26.7, 26.6, 26.1, 22.6, 14.1; FT-IR (film) cm−1 3115 (broad s), 1612, 1512, 1245, 1121, 824.
Reaction SMILES: O.[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[C:10](/[CH3:26])=[CH:11]/[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20]C)[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24]C)(=[O:4])[CH3:3].CCOC(C)=O>C(C#N)(C)=O>[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[C:10](/[CH3:26])=[CH:11]/[CH2:12][C:13]1[C:14](=[O:24])[C:15]([CH3:23])=[C:16]([CH3:22])[C:17](=[O:20])[C:18]=1[CH3:19])(=[O:4])[CH3:3]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCOC(C)=O)c1C
Agent: CC(=O)C#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCC/C(C)=C/CC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
Ceric ammonium nitrate (270 mg, 0.498 mmol) was dissolved into H2O (0.75 mL) and AcCN (1.5 mL) and the solution chilled to 0° C. 77.9 mg of (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetate (0.223 mmol) in AcCN (1.5 mL) was added over 2 minutes and the dark orange solution stirred for 0.5 h. H2O (3 mL) and EtOAc (3 mL) were then added, the layers separated and the organics washed 2×2 mL H2O. The combined aqueous phase was back extracted 3×5 mL EtOAc and the combined organics washed 2×5 mL saturated NaCl solution and dried over anhydrous Na2SO4. The resulting yellow liquid was concentrated to a yellow oil and subjected to flash chromatography, which yielded 25.8 mg of (E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enyl acetate as a bright yellow oil (36.2%). 1H NMR (400 MHz, CDCl3) d 4.95 (t, J=6.4 Hz, 1H), 4.02 (t, J=6.8 Hz, 2H), 3.19 (d, J=6.8 Hz, 2H), 2.01 (m, 11H), 1.73 (s, 3H), 1.55 (m, 2H) 1.42 (m, 2H). 13C NMR (100 MHz, CDCl3) d 187.9, 187.0, 171.1, 143.0, 140.4, 140.3, 136.7, 119.9, 64.4, 39.1, 28.1, 25.6, 24.1, 20.9, 16.1, 12.3, 12.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>COC(C)(C)C>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
(α) A solution of 16.7 g (106 mmol) of 3-bromo-pyridine in 200 ml of tert-butyl methyl ether was cooled to -75° C. Thereto there was added dropwise within 45 minutes a solution of 66 ml (106 mmol) of n-butyllithium (1.6M in hexane) and the mixture was stirred at -75° C. for one hour. Subsequently, a solution of 10.0 g (52.8 mmol) of 1-benzyl-4-piperidone in 50 ml of tert-butyl methyl ether was added dropwise at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was left to warm to room temperature. Thereafter, it was hydrolyzed with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase was dried over magnesium sulphate and finally the solvent was evaporated under reduced pressure, with the product beginning to separate. From the evaporated mother liquor there were isolated by crystallization from a mixture of ethyl acetate and hexane a further 1.9 g, so that a total of 8.4 g (60% of theory) of 1'-benzyl-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol were obtained as a colourless solid; MS: 268 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.CCN(C(C)C)C(C)C>[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][N:28]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the stirred solution of 373 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride in 8 mL of N,N-dimethylformamide and 0.5 mL of Hunig's base was slowly added 104 mg of methanesulfonyl chloride. The solution was stirred at room temperature overnight. After removal of the N,N-dimethylformamide in vacuo, the residue was dissolved in 80 mL of ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to provide 233 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxylate in 58% yield. MS: 576.1 (M+H)+