Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]C)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].CN(CCCCCCCCCCCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:14]([Cl:13])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Nc1ccc(Cl)cc1
Agent: CCCCCCCCCCCCN(C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 4.61 g (25 mmoles) of methyl N-(4-chlorophenyl)-carbamate, 4.07 g (25 mmoles) of 3,4-dichloroaniline, 100 ml of toluene and 4.7 g (25 mmoles) of N,N-dimethyl-dodecylamine is reacted for 20 hours as described in Example 8, and then the mixture is allowed to cool. 4.60 g (58.4%) of N-(4-chlorophenyl)-N'-(3,4-dichlorophenyl)-urea separate from the mixture as a crystalline substance.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:44]=[N:43][N:42]([CH2:45][CH2:46][CH3:47])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:44]=[N:43][N:42]([CH2:45][CH2:46][CH3:47])[N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnn(CCC)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnn(CCC)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-propyl-1,2,3-triazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) was dissolved in methylene chloride (9.0 ml), and to the solution was added dropwise a solution of m-chloroperbenzoic acid (174 mg) in methylene chloride (9.0 ml) at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-propyl-1,2,3-triazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 276) (0.39 g).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]1[N:12]=[C:11]([NH:13][C:14](=[S:16])[S-:15])[CH:10]=[CH:9][CH:8]=1.C([NH+](CC)CC)C.C(O)C>CN(C)C=O>[OH:5][C:3]1([CH3:4])[CH2:2][S:16][C:14](=[S:15])[N:13]1[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cccc(N2C(=S)SCC2(C)O)n1
Temperature: 2 °C
Reaction time: 3 h

Procedure:
Chloroacetone (13.9 cc) is added to a solution of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (50.0 g) in dimethylformamide (250 cc) at a temperature between 15 and 23° C. The reaction is continued for 3 hours at 20°-23° C. After filtration and evaporation of the dimethylformamide under reduced pressure (0.1 mm.Hg) at 45° C., the residual oil is dissolved in ethyl acetate (500 cc); the organic solution is washed with distilled water (100 cc), dried over sodium sulphate, treated with decolorising charcoal (2 g) and evaporated. The crystals obtained (38.0 g; m.p. 150°-153° C.) are dissolved in boiling ethanol (520 cc). After 2 hours cooling at 2° C., the resulting crystals are separated by filtration, washed twice with ice-cold ethanol (total 80 cc) and dried under reduced pressure (0.1 mm.Hg) at 45° C. 4-Hydroxy-4-methyl-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (24.9 g), melting at 156° C., is obtained.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[N:11]1[CH2:15][CH:14]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:13][C:12]1=[O:23])([CH3:3])[CH3:2].[CH:24](C1CCC(C)CC1N1C(=O)CC(C(O)=O)C1)(C)[CH3:25]>>[N:18]1([C:16]([CH:14]2[CH2:15][N:11]([CH:5]3[CH2:6][CH:7]([CH3:10])[CH2:8][CH2:9][CH:4]3[CH:1]([CH3:2])[CH3:3])[C:12](=[O:23])[CH2:13]2)=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:25][CH2:24]1
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCC3)CC2=O)C1
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Product: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCCCC3)CC2=O)C1

Procedure:
1-(2-Isopropyl-5-methyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one was similarly prepared as described in Examples I, II, and III. 1-(2-Isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 5 g, 18.7 mmol) was used to provide 4-(azepane-1-carbonyl)-1-(2-isopropyl-5-methyl-cyclohexyl)-pyrrolidin-2-one (5.2 g, 15 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na+].[Cl-].NC(N)=N.C[O:13][C:14](=O)[CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:19][CH:18]=[C:17]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C[O-].[Na+].CO.CS(C)=O>[C:33]1([C:17]2[N:16]([CH2:15][C:14]([NH:4][C:3]([NH2:5])=[NH:2])=[O:13])[C:20]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:23][CH:22]=3)=[CH:19][CH:18]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(N2CCCCC2)cc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CS(C)=O
Product: N=C(N)NC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
Guanidine HCl (700 mmol, 66.5 mg) is dissolved in 1 mL of 0.5M NaOMe/methanol solution and rotated to dryness. The residue is subsequently dissolved in 400 uL dry DMSO. A white NaCl precipitate remained and the supernatant (free guanidine base in solution) is added to a vial containing [2-phenyl-5-(4-piperidin-1-yl-phenyl)-pyrrol-1-yl]-acetic acid methyl ester (170 mmol, 64 mg). The solution is agitated in a shaker at room temperature. The reaction is quenched with excess AcOH (75 uL), concentrated in vacuo. The residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]#[N:11])=[CH:7][CH2:8][CH2:9][C:2]1=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]#[N:11])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: N#CC1=CCCc2sccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: N#Cc1cccc2sccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A mixture of the crude 6,7-dihydrobenzo[b]thiophene-4-carbonitrile (88.3 g), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (120 g) and toluene (750 ml) was stirred at 80° C. for 2 hours then allowed to cool to ambient temperature. The resulting solid was removed by filtration and washed with toluene (500 ml). The filtrate and washings were combined, the solvent was removed in vacuo, and the residue was purified by Biotage flash chromatography over silica using 3-5% mixtures of ethyl acetate in petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to leave benzo[b]thiophene-4-carbonitrile (56.6 g) as a pale yellow solid which was used without further purification.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:39])=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+].Cl>CN(C=O)C.C(=O)(OC)OC.C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:39])=[C:29]4[C:33]=3[N:32]([CH3:1])[CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: C1CN2CCN1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(=O)OC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 94 °C
Reaction time: 72 h
Yield: 36.9 %

Procedure:
DABCO (45 mg) was added to a solution of 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E22) (71 mg) in DMF (2 mL) and dimethyl carbonate (2 mL). The reaction mixture was stirred at 94° C. for 3 days. Then the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the crude product as a brown solid. This solid was dissolved in THF (3 mL) and water (3 mL). Sodium hydroxide (40 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E23) (27 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.60 (2H, t), 3.03 (2H, t), 3.63 (3H, s), 5.45 (1H, m), 6.96 (1H, dd), 7.22 (1H, s), 7.42 (1H, dd), 8.57 (1H, d), 8.94 (1H, d), 12.11 (1H, br s). δF (DMSO-d6, 376 MHz): −120.4. MS (ES): C22H20ClFN4O4 requires 458; found 459.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Clc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(Cl)cc1

Procedure:
The title compound, white solid, m.p. 159° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][C@@H:5]([NH:35]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:8][CH:7]=1.C(O)C>[Pd].C(O)=O>[CH3:1][O:2][C:3](=[O:46])[CH2:4][C@@H:5]([NH2:35])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COC(=O)C[C@@H](N)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of (R)-3-benzyloxycarbonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid methyl ester (18.55 g), ethanol (750 ml) and formic acid (18 ml), under an atmosphere of hydrogen, was heated at reflux. The reaction was treated portionwise with 10% palladium on charcoal (3.0 g) over a period of 1 hour and then heated at reflux for a further 1 hour. The reaction mixture was filtered through a short pad of diatomaceous earth and the filter pad was washed three times with ethanol (75 ml) and water (75 ml). The combined filtrate and washings were evaporated. The residue was treated carefully with aqueous solution of sodium bicarbonate (600 ml, 0.6M) followed by stirring for 15 minutes. The resultant white solid was collected, washed twice with water (100 ml), then boiled in acetonitrile in the presence of activated charcoal (150 mg). The mixture was filtered through a short pad of diatomaceous earth while hot and the filtrate cooled in ice to yield the title compound (7.6 g) as a white solid m.p. 189-191° C.
Reaction SMILES: [CH3:1][N:2]([O:11]C(=O)C1C=CC=CC=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O>[OH:11][N:2]([CH3:1])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(OC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(O)C(=O)c1ccccc1

Procedure:
To a flask equipped with a stirrer and a heating mantle were added N-methyl-N-benzoyloxybenzamide (29.2 g, 0.119 mol) from above, 100 mL of water, and 10 g of sodium hydroxide. The mixture was stirred well and heated to 70°. A clear solution was obtained in 30 min. After a total of 45 min the solution was cooled and concentrated hydrochloric acid was added to bring the solution to pH 7. The mixture was extracted with methylene chloride, and the organic layer was dried, first with magnesium sulfate and then with 4 A molecular sieves. Evaporation of the solvent gave 14.7 g (81%) of colorless, liquid, N-hydroxy-N-methylbenzamide; nmr (CDCl3) 9.67 (broad s, CH, 1H), 7.7-7.1 (m, 5H), 3.20 (s, 3H). Attempts to vacuum distill the product were unsuccessful because of thermal decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:34])([F:33])[O:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]O)[CH:24]=[CH:25][CH:26]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:33])[F:34])[CH:22]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCCCC#Cc1cccc(OC(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2cccc(OC(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 38.1 %

Procedure:
To an ice cold solution of 50 mg (0.21 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590), 48 mg (0.21 mmol) 5-(3-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (example 3C]) and 70 μl (0.25 mmol) tributylphosphine (50 19 μmol) in 5 ml tetrahydrofuran were added 43 mg (0.25 mmol) N,N,N′,N′-tetramethyl azodicarboxamide. The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 34 mg (80 μmol, 36%) of the title compound as colorless oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:42][CH:43]1[CH2:45][CH2:44]1>C(#N)C>[CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][N:31]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Reactant: BrCC1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCN(CC3CC3)CC2)cc1
Reaction time: 8 h
Yield: 81341 %

Procedure:
To a solution of COMPOUND 27 (250 mg; 0.56 mmol) in acetonitrile (8 mL) was added triethylamine (92.7 μL; 0.67 mmol). The solution was cooled to 0° C. than bromomethylcyclopropane (53.5 μL; 0.56 mmol) was added. Reaction mixture was stirred overnight then was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 72 (229 g; 82% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.34-0.40 (m, 2H), 0.65-0.71 (m, 2H), 0.99-1.04 (m, 3H), 1.14 (t, J=6.83 Hz, 3H), 1.30-1.35 (m, 6H), 1.61-1.64 (m, 1H), 1.75-1.78 (m, 2H), 1.85-1.90 (m, 2H), 2.46-2.54 (br s, 1H), 2.95-3.03 (br s, 6H), 3.10-3.18 (br s, 2H), 3.37-3.44 (br s, 5H), 3.54-3.60 (br s, 2H), 7.27-2.31 (m, 3H), 7.50-7.53 (m, 3H), 7.64-7.68 (m, 2H). Found: C, 59.91; H, 8.10; N, 10.28. C32H46N4O×3.2HCl×1.1H2O has C, 60.13; H, 8.10; N, 8.76%. [α]D16=+12.4 deg [c 0.51, MeOH].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:19][CH2:18][C:15]2[CH:16]=[N:17][C:12]([C:11]([F:21])([F:10])[F:20])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(Br)ccn1
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccc(C(F)(F)F)nc2)ccn1
Yield: 72.4 %

Procedure:
4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), Cut (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:23]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([O:18][CH3:23])[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (543 mg, 22.6 mmol, 2.00 equiv) was carefully added to a solution of (2S,4R)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid (3-1, 3.00 g, 11.3 mmol, 1 equiv) in THF (100 mL) at 0° C., and resulting mixture was stirred for 20 minutes. Iodomethane (2.11 mL, 33.9 mmol, 3.00 equiv) was added, and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was then diluted with saturated sodium bicarbonate solution washed with ethyl acetate (2×100 mL). The aqueous layer was then acidified with 1 N HCl solution to pH 3 and extracted with ethyl acetate (100 ml). This organic layer was then dried over sodium sulfate and concentrated to provide (2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxy-2-pyrrolidinecarboxylic acid (3-2) as a light yellow oil. 1H NMR (400 MHz, CDCl3) major rotamer: δ7.40-7.25 (br m, 5H), 5.20 (s, 2H), 4.52 (t, 1H, J=7.4 Hz), 4.00 (m, 1H), 3.67 (dd, 1H, J=11.4, 2.8 Hz), 3.57 (dd, 1H, J=11.4, 4.6 Hz), 3.32 (s, 3H), 2.34 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[Li+].[CH3:10][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.Cl.CCOC(C)=O>[CH3:10][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1CCOCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1(C#N)CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-carbonitrile (2 g, 18.00 mmol) in THF (10 mL) at 0-5° C. was slowly added LHMDS (21.59 mL, 21.59 mmol). The mixture was stirred for 1.5 hr 0° C. Iodomethane (3.37 mL, 54.0 mmol) was added slowly and stirring was continued for 30 min at ˜0° C. and ˜2 hr at ambient temperature. The mixture was cooled to 0° C. and carefully diluted with 1N aqueous HCl (30 mL) and EtOAc (5 mL) and concentrated. The resulting residue was taken up in diethylether and the separated organic layer was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo providing crude 4-methyltetrahydro-2H-pyran-4-carbonitrile as an orange oil, which was directly used in the next reaction without further purification. Yield: 1.8 g. LCMS (m/z): 126.1 [M+H]+; Retention time=0.44 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:23])[CH2:20][CH2:19][O:18][C:17]([CH3:22])([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:23][CH3:24])[CH2:20][CH2:19][O:18][C:17]([CH3:21])([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Reactant: CI
Product: COC1(c2cccc(OCc3ccccc3)c2)CCOC(C)(C)C1
Yield: 89 %

Procedure:
Using the procedure described in Example 3, 4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g) was reacted with methyl iodide (0.25 ml) to give 4-(3-benzyloxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (1.06 g, 89%), as an oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][N:20]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[CH:27]([CH2:30][CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)[S:26][CH:25]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH3:21].C([O-])(O)=O.[Na+]>O1CCCC1>[CH3:19][N:20]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[CH:27]([CH2:30][CH2:31][CH2:32][OH:33])[S:26][CH:25]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH3:21]
Reactant: CN(C)CCN1C(=O)C(CCCO[Si](C)(C)C(C)(C)C)SC1c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)C(CCCO)SC1c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A 1M solution (15 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise to a solution of 3-dimethylaminoethyl-5-(3-t-butyldimethylsilyloxypropyl)-2-(3-pyridyl)thiazolidin-4-one (2.6 g, 6.02 mmol) of dry tetrahydrofuran (12 ml) under cooling with ice. Then the mixture was stirred at room temperature for 2 hours to complete the reaction. Saturated aqueous NaHCO3 (10 ml) was added dropwise to the product mixture, and the resulting aqueous layer was extracted 6 times with ethyl acetate. The extract was dried over MgSO4, and the solvent was removed under reduced pressure. The residual crude product was purified by medium-pressure liquid chromatography (Si-60® Art. 9385, eluent : hexane : ethanol : aqueous ammonia=3000:400:50), giving 3-dimethylaminoethyl-5-(3-hydroxypropyl)-2-(3-pyridyl)thiazolidin-4-one (1.7 g, 88% yield). IR (CHCl3) [cm-1 ]; 3400 (br), 1670, 1595, 1580, 1360. NMR (CDCl3) [δ ppm]; 2.16 (6 H, s), 4.10-4.15 (1 H, m), 5.86 (1 H, d, J=2 Hz).