Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:4]([I:10])[CH:5]=1
Reactant: Fc1cc(I)c(CBr)cn1
Reactant: OC1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCN(Cc2cnc(F)cc2I)CC1
Temperature: 80 °C

Procedure:
Combine 5-(bromomethyl)-2-fluoro-4-iodopyridine (0.2 g, 0.63 mmol), piperidin-4-ol (0.192 mg, 1.9 mmol), and diisopropylethylamine (0.22 mL, 1.27 mmol) in acetonitrile (3.0 mL). Heat the reaction mixture at 80° C. for 2 h and cool to RT. Remove the organic solvent to give crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol. Combine crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol (0.63 mmol), N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.15 g, 0.32 mmol, sodium carbonate (0.102 g, 0.96 mmol), 2-(di-tert-butylphospho)biphenyl (0.006 g, 0.06 mmol) and Pd(dppf)Cl2 (0.026 g, 0.1 mmol) in THF (3 mL) and water (1 mL). Heat the mixture at 120° C. for 10 min in a microwave reactor. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Purify by reverse phase chromatography (28% isocratic at 85 mL/min for 8 min on a 30×75 mm, 5 mm, C18 ODB MS XBridge™ column, Solvent A: water with 0.01 M ammonium bicarbonate, Solvent B: acetonitrile) to afford the title compound (91 mg, 52%). MS (ES) m/z 549 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][CH:14]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:13][CH:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][CH:14]([O:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:13][CH:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(OCC(=O)OC(C)(C)C)CC(C)N1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(OCC(=O)O)CC(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
1.11 g of N-benzyloxycarbonyl-4-tert-butoxycarbonylmethyloxy-2,6-dimethylpiperidine was dissolved in 5 ml of methylene chloride, and 2 ml of trifluoroacetic acid was added. The solution was stirred overnight at room temperature, and the resulting solution was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. From the fractions eluted with chloroform-methanol (9:1 v/v) was obtained 0.61 g of N-benzyloxycarbonyl-4-carboxymethyloxy-2,6-dimethylpiperidine, which was an oily product with no color (yield: 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5].C(OCC)(=O)C>[Pd].C(O)C>[CH3:32][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Yield: 81.1 %

Procedure:
A mixed solution of ethyl (2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate (400 mg, 0.89 mmol) obtained in Example 177 and 10% palladium on carbon (water content: 50%, 40 mg) in ethanol (3 mL)-ethyl acetate (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 326 mg (yield: 81%) of the title compound. Melting point: 136-138° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: N[C@@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
To a 10 mL vial was added N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.166 g), (3R)-3-pyrrolidinamine (0.127 g), triethylamine (0.083 mL) and acetonitrile (5 mL). The vial was sealed and heated at 100° C. for 30 minutes within a microwave. The reaction was cooled to room temperature and the resulting solid removed by filtration. This solid was purified (Varian SCX cartridge, using methanol and 10% ammonia in methanol as eluant) to afford the title compound (0.102 g).
Reaction SMILES: [O:1]=[Al-:2]=O.[Na+].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3].S([O-])([O-])(=O)=[O:12].S([O-])([O-])(=O)=[O:17].[Al+3]>>[OH2:1].[OH2:6].[OH2:12].[OH2:17].[Al:2].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6]
Reactant: O=[Al-]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Product: O
Product: [Al]
Reaction time: 3 h

Procedure:
An alumina hydrate was prepared by neutralization reaction of a sodium aluminate and aluminum sulfate in accordance with a method described in "Catalyst Preparation Chemistry" p. 207, by Ozaki, et al., published by Kodansha, 1980. To the amorphous and pseudo-boehmite alumina hydrate powder obtained by drying the alumina hydrate at 110° C. was dropwise added a sulfuric acid aqueous solution. Then, the mixture was kneaded, then adjusted in its water content and extrusion molded. The molded product was dried at 110° C. overnight by means of a dryer and calcined at 550° C. for 3 hours in an air stream, to obtain a sulfate ion-containing γ-alumina carrier. The content of the sulfate ion in the alumina was 8.4% by weight in terms of SO4. The sulfate ion-containing alumina carrier was impregnated with a nickel nitrate aqueous solution in a manner similar to that in the preparation of catalyst I, then dried at 110° C. and calcined at 500° C. for 3 hours in an air stream, to obtain a catalyst wherein NiO was supported in an amount of 10% by weight in terms of Ni (sulfate ion content based on total weight of catalyst after supporting of nickel oxide: 7.2% by weight in terms of SO4). Then, a butene oligomerization reaction was carried out under the same conditions as in Examples 12-17. The results are set forth in Table 11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15]C>N1CCCCC1.C(O)C>[CH2:12]([C:11]1[N:5]2[N:6]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:7]=[C:9]([CH3:8])[CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)CC(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCc1cc(C)nc2cc(C)nn12
Temperature: 80 °C

Procedure:
Add 5-methyl-2H-pyrazol-3-ylamine (217 mg, 2.17 mmol), nonane-2,4-dione (339 mg, 2.39 mmol) and piperidine (1 drop) to ethanol (10 mL) and heat at 80° C. overnight. Cool to room temperature and concentrate to dryness. Purify by silica gel column chromatography (0-20% ethyl acetate in hexane) to obtain a mixture of two isomers (2 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:17].O1CCOCC1>C(O)C>[ClH:17].[ClH:17].[NH:2]=[C:1]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N=C(c1ccc(C(=O)O)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Cyanonicotinic acid (4.15 g, 28.0 mmol) was dissolved in anhydrous ethanol (3.2 ml) and 4N hydrochloric acid/1,4-dioxane (30 ml), and the mixture was stirred in a closed system at room temperature for two nights. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (90 ml). Pyrrolidine (2.34 ml, 28.0 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. Pyrrolidine (3.51 ml, 42.0 mmol) was added again, and the mixture was stirred for 2.5 hours. The solvent was evaporated under reduced pressure, and water aid ethanol were added to the obtained residue. The precipitate was removed by filtration, ethanol was evaporated under reduced pressure, and the obtained aqueous solution was lyophilized to give the title compound without purification operation.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:10][C:2]1[O:18][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A 500-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a Claisen head with a condenser and a receiver connected to a cold trap and a vacuum controller was charged with 52.26 g of crude methyl 4-bromo-3-oxovalerate (ca. 0.250 mol) and 46.5 g of benzamide. A vacuum of 400 mbar was applied and the suspension was stirred at 90° C. for 18 h. After ca. 3 h the suspension had become a clear orange oil. After cooling to rt 300 ml of methanol and 1.0 g of p-toluenesulfonic acid monohydrate were added and the brown solution was stirred at reflux (ca. 73° C.) for 1 h. After this time 50 ml of methanol were distilled off, 50 ml of methanol were added and the mixture was heated at reflux for additional 30 min. After cooling and rotary evaporation (50° C., 8 mbar, 30 min), the residue was treated under argon with 150 ml of toluene and 125 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 1 h, the precipitated benzamide was filtered off with suction and the filter cake was washed twice with a small amount of ice-cold toluene and water. The combined aqueous phases were extracted in a separatory funnel with 100 ml of toluene. Thereafter the combined organic phases were washed twice with 30 ml, a total of 60 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 8 mbar, 1 h) to give 49.22 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 57.81 g) as a yellow oil, which was used without purification in the next step.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=O)[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[K+].[K+].Cl[CH2:26][CH2:27][O:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+]>CN(C=O)C.O>[C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]([CH2:26][CH2:27][O:28][C:29]3[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=3)[C:14](=[O:20])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCCl)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 120 °C

Procedure:
To a solution, heated at 80° C. for 2 hours, of 6-benzoyl-benzothiazolinone (6.7 mmol) in the presence of K2CO3 in 20 ml of DMF there is added ethyl 2-[4-(2-chloroethoxy)phenoxy]-2-methylpropanoate. The reaction mixture is heated at 120° C. for 5 days, cooled, hydrolysed using 100 ml of water and rendered alkaline using 1N NaOH. The precipitate obtained is filtered off and then recrystallised from cyclohexane to yield the title compound in the form of a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=O.Cl.[NH2:22][OH:23].CO>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=[N:22][OH:23]
Reactant: Cc1c(C=O)c2cc(Br)ccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2cc(Br)ccc2n1-c1ccc(O)cc1
Yield: 66 %

Procedure:
A mixture of 5-bromo-1-(4-hydroxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.16 g, 0.5 mmol), hydroxylamine hydrochloride (0.10 g, 1.4 mmol), methanol (10 mL) and pyridine (0.2 mL) was reacted according to the procedure used in Example 4 to afford a white solid (66%): mp 209-211° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.92-6.97 (3H, m), 7.20-7.25 (3H, m), 8.19 (1 H, d, J=1.9 Hz), 8.39 (1H, s), 9.94 (1H, br s), 10.76 (1H, s); MS m/z (M+H)+ 345/347 (1 Br). Anal. for C16H13BrN2O2·0.5H2O; Calc'd: C, 54.26; H, 3.98 N, 7.91. Found: C, 54.26; H, 3.68; N, 7.65.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[N:9]([CH2:12][CH:13]1[O:17][CH2:16][CH:15]([S:18][C:19]2[CH:25]([CH3:26])[CH:24]3[N:21]([C:22](=[O:30])[CH:23]3[CH:27]([OH:29])[CH3:28])[C:20]=2[C:31]([OH:33])=[O:32])[CH2:14]1)=[N+]=[N-].C(O[CH:38](OC(C)C)[N:39]([CH3:41])[CH3:40])(C)C>>[CH3:38][N:39]([CH:41]=[N:9][CH2:12][CH:13]1[O:17][CH2:16][CH:15]([S:18][C:19]2[CH:25]([CH3:26])[CH:24]3[N:21]([C:22](=[O:30])[CH:23]3[CH:27]([OH:29])[CH3:28])[C:20]=2[C:31]([OH:33])=[O:32])[CH2:14]1)[CH3:40]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Reactant: CC(C)OC(OC(C)C)N(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=CN(C)C)C3)C(C)C12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Three ml of sodium phosphate buffer, pH 7, is cooled to 0° C. and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 μl of N,N-dimethylformamide diisopropyl acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0° C. for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromato- graphy (C18 reverse phase tlc plates: 75% aqueous ethyl alcohol) to give 0.031 g of the desired product.
Reaction SMILES: ClC(OC(C)C)=O.C[N:9]1CCOCC1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].N.C(N(CC)CC)C>CN(C)C=O.CCOCC>[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([NH2:9])=[O:31])[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16]
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1M in toluene, 1.076 mL, 1.076 mmol) and then N-methyl morpholine (0.118 mL, 1.076 mmol) were added to a stirred mixture of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.233 g, 0.978 mmol) in dimethylformamide (4.7 mL) under nitrogen at −10° C. to −15° C. The reaction mixture was stirred for one hour at this temperature then ammonia (0.5 M solution in 1,4-dioxane, 3.91 mL, 1.956 mmol) and triethylamine (0.136 mL, 0.978 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was allowed to stir at −10° C. to −15° C. for one further hour then allowed to warm to room temperature. After 64 hours, ether (10 mL) was added and the precipitate was washed with ether (10 mL), acetonitrile (10 mL) and water (4×10 mL) to afford the title compound. Yield 105 mg, 0.443 mmol, 45%. LCMS (ES+), m/z 238 (M+H)+ at the solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (1H, s), 7.84 (1H, br s), 7.72 (1H, br s), 7.70 (1H, br s), 7.44 (1H, br s) 4.88 (2H, s).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1F
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2ccccc2F)cc1
Yield: 33.6 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(2-fluorophenyl) ethanamine (1.55 g) and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound (1.2 g) m.p. 111°-116° C. (benzene-heptane) as an ~40:60 mixture of diastereoisomers. τ(CDCl3) 8.95 (3H, d, J=6 Hz), 6.85-7.7 (7H, m, 2H disappears with D2O), 6.25 (3H, s), 5.1 (1H, m), 3.6 (1H, d, J=16 Hz), 2.5-3.2 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:7]=[C:8]([S:13][Si](C)(C)C)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(#N)C.CN(C)P(=O)(N(C)C)N(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([S:13][CH2:2][C:3]#[N:4])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: C[Si](C)(C)Sc1ccc(Cl)c(Cl)c1
Reactant: N#CCCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: N#CCSc1ccc(Cl)c(Cl)c1
Reaction time: 0.03 h
Yield: 96.9 %

Procedure:
3.5 ml (55 mmoles) of chloroacetonitrile were added to a refluxing solution of 11.0 g (44 mmoles) of 3,4-dichlorophenylthio(trimethyl)silane in a mixture of 25 ml of acetonitrile and 10 ml of hexamethylphosphoric triamide and the reaction was complete with 2 minutes. The residue obtained after evaporation of the acetonitrile was dissolved in ethyl acetate, and the solution was washed with water, dried and evaporated to dryness to obtain 9.30 g (93% yield) of (3,4-dichlorophenylthio)acetonitrile boiling at 127°-130° C./0.4 mm Hg and having a refractive index of nD25 =1.5920.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)C.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[C:33]2[CH:41]=[CH:42][CH:43]=[C:31]([C:30]([F:29])([F:45])[F:44])[CH:32]=2)[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
A sample of [(1R,3R,4S)-4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol) was dissolved in 1:1 CH2Cl2/DMF (2 mL). The resultant solution was charged successively with N,N-diethylisopropylamine (0.16 mL, 0.9 mmol), (3-trifluoromethyl-benzoylamino)-acetic acid (47 mg, 0.19 mmol, prepared as described in WO PCT 0250019), and BOP (116 mg, 0.26 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography afforded {(1R, 3R,4S)-3-(3-methyl-butyl)-4-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33 mg). MS found: (M+H)+=514.3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH:12]([CH3:14])[CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:25][CH2:26][CH3:27])[C:23]#[N:24].Cl.NO.[C:31](=[O:34])(O)[O-:32].[Na+].C1N=C[N:38](C(N2C=NC=C2)=O)C=1>CO.O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH:12]([CH3:14])[CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([C:23]1[NH:38][C:31](=[O:34])[O:32][N:24]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCC(C#N)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC(C)C3
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCC(c1noc(=O)[nH]1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC(C)C3
Temperature: 65 °C
Yield: 24.2 %

Procedure:
A solution of 2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanenitrile (0.082 g; 0.219 mmol) in methanol (1 mL) was treated with hydroxylamine hydrochloride (0.023 g; 0.331 mmol) and sodium bicarbonate (0.026 mg; 0.310 mmol) and the mixture was heated at 65° C. for 18 h. The volatiles were evaporated and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the crude N′-hydroxy-2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanimidamide which was mixed with carbodiimidazole (0.050 g; 0.308 mmol) in dioxane (2 mL) and heated at 100° C. for 45 min. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.023 g (25%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:29][C:30]#[N:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1

Procedure:
A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (compound of Example 13; 13.5 g, 67 mmol), anhydrous potassium carbonate (11.22 g, 81 mmol) and cyanomethyl phosphonic acid diethylester (15.6 g, 88 mmol) in THF (70 mL) was heated at reflux for 12 h. THF was evaporated and the residue was dissolved in chloroform (2×50 mL). The resulting solution was washed with water (2×50 mL) and brine (50 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to afford the title compound.