Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=NC([C:10]2[CH:34]=[CH:33][CH:32]=[CH:31][C:11]=2[C:12]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21]2[CH:26]=[N:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[O:13])=NC=1)C.Cl.[CH3:36]N(C1C=NC(C(F)(F)F)=CN=1)[C@H]1CCC[C@@H]1N.[CH3:54][C:55]1[N:59]=[C:58](C2C=CC=CC=2C(O)=O)[O:57][N:56]=1>>[CH3:54][C:55]1[N:59]=[C:58]([C:10]2[CH:34]=[CH:33][CH:32]=[CH:31][C:11]=2[C:12]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21]2[C:26]([CH3:36])=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][N:22]=2)=[O:13])[O:57][N:56]=1
Reactant: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: Cl
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ncc(C(F)(F)F)nc2C)n1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 452 mg, 1.74 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 355 mg, 1.74 mmol) except after the reaction was complete it was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit. The organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then recrystallised from MTBE/heptane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH3:22])[C:19]([C:18]([O:24][CH2:25][CH3:26])=[O:23])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2ccc(Cl)cc2c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)-(4-fluorophenyl)methanone (10.0 g) in 100 mL of toluene was added 8.3g (1.6 equivalents) of ethyl acetoacetate and 0.30 g of p-toluenesulfonic acid. The resulting mixture was heated to reflux with azeotropic removal of water. After one and one-half hours, the mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by flash chromatography over silica gel to give 10.18 g of 6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolinecarboxylic acid, ethyl ester as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=2)[C:8]=1[Br:33])C.[OH-].[K+].Cl>C1COCC1.O>[Br:33][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester (0.360 g, 0.667 mmol) and potassium hydroxide (0.125 g, 2.23 mmol) in THF (5 mL) and water (5 mL) was stirred at ambient temperature for four hours. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 78° C. for 12 hours to yield {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid as a light yellow solid (0.233 g, 68.3%): MP: 206–7° C.; mass spectrum (+EI, [M+H]+) m/z 511/513. 1H NMR (500 MHz, DMSO-d6): δ12.9–13.4 (br, 1H), 8.24 (d, 1H, J=9.01 Hz), 8.11–8.13(m, 2H), 8.07–8.09 (m, 1H), 7.74 (dd, 1H, J=8.78 Hz and 1.76 Hz), 7.46–7.51 (m, 3H), 5.02 (s, 2H), 2.33 (s, 2H), 0.76 ppm (s, 9H). Elemental Analysis for C26H23BrNO4S: Calcd: C, 61.06; H, 4.53; N, 0.00; Found: C, 61.17; H,4.64; N, 0.00.
Reaction SMILES: [CH:1]1([C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[CH:1]1([C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)[CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC[C@@H](c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 2-(R)-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid (290 mg, 0.8 mmol), prepared as in step 4, and triethylamine (0.14 ml, 1.0 ml) in THF (35 ml) at -25° C. was added dropwise ethyl chloroformate (0.1 ml, 1.0 mmol). Upon completion of addition, the mixture was stirred for 15 min. and warmed to 0° C. Sodium borohydride (150 mg, 4.0 mmol) was added followed by very slow addition of methanol (15 ml). The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, hexane-ethyl acetate 2:1) to afford 180 mg of 2-(R)-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)ethan-1-ol.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[OH-].[NH4+:17]>>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:17])[CH:11]=[CH:10]2
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccc2cc(C(F)(F)F)ccc2n1
Yield: 38 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)quinoline (1 g, 4.3 mmol) in ammonium hydroxide (50 ml) was stirred overnight at 130° C. The resulting mixture was then concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%˜2% methanol in dichloromethane to afford 6-(trifluoromethyl)quinolin-2-amine as an off-white solid (350 mg, 38%). (ES, m/z): [M+H]+ 212; 1H NMR (300 MHz, CDCl3): δ 7.97-7.86 (m, 2H), 7.71 (s, 2H), 6.85 (d, J=9.0 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(OCC)(O[CH2:15][CH3:16])(=O)=O>>[CH2:15]([O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:16]
Reactant: OCCOC1CCCCC1
Reactant: CCOS(=O)(=O)OCC
Product: CCOCCOC1CCCCC1

Procedure:
The 2-ethoxyethyl-cyclohexyl-ether was prepared in correspondence with the description of Example 1 from 72 g (0.5 mol) of 2-hydroxyethyl-cyclohexyl-ether and 54 g (0.35 mol) of diethyl sulfate.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]>>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: CN(C)CCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 78.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 266A, methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (200 mg, 0.38 mmol) and 3-bromo-N,N-dimethylpropan-1-amine (77 mg, 0.46 mmol) were converted to the title compound (180 mg, 78%). MS(ESI+) m/z 602.6 (M+H)+.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][CH2:2]1.N12CCN(CC1)CC2.C1(P([C:28]2[CH:33]=[CH:32]C=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Rh](Cl)(Cl)Cl.O>[CH:4](=[O:5])[CH2:3][CH2:2][CH3:1].[CH:4](=[O:5])[CH:33]([CH3:32])[CH3:28]
Reactant: O=C1CCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Rh](Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: O
Product: CC(C)C=O
Product: CCCC=O
Temperature: 87.77777777777777 °C

Procedure:
The following experiments illustrate the effect of water on the reaction rate and product distribution. Into a one-half gallon autoclave was charged 300 grams butyrolactone, 50 grams water, 2 grams 1,4-diazabicyclo(2.2.2)octane, 2 grams triphenylphosphine and 0.4 gram rhodium chloride. The autoclave was closed, purged with nitrogen and 104 grams of propylene were introduced. Thereafter equal volumes of carbon monoxide followed by hydrogen were introduced to raise the pressure 600 psi. The autoclave was heated to 190° F. and maintained at that temperature for 6 minutes, then cooled, depressured and opened. The liquid products were distilled to obtain 90.5 grams normal butyraldehyde and 21.7 grams isobutyraldehyde (ratio of 4.17).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(=O)O
Reactant: NCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 2,4-difluorobenzylamine (0.43 g, 3.0 mmol) in methylene chloride (30 mL) were added octanoic acid (0.43 g, 3.0 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.1 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4. Concentration in vacuo afforded 0.78 g (96%) of an oil, which solidified upon standing.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:27][C:28]1[N:32]2[N:33]=[C:34](Cl)[CH:35]=[CH:36][C:31]2=[N:30][C:29]=1[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[Cl:27][C:28]1[N:32]2[N:33]=[C:34]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:35]=[CH:36][C:31]2=[N:30][C:29]=1[C:38]([CH3:44])([CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 27.7 %

Procedure:
334 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 20 ml of N,N-dimethylformamide; 45 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 35 minutes. 310 mg of ethyl 2-[3,6-dichloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was then added, followed by stirring at 0° C. for 2 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected; the crystal precipitated was dissolved in 5 ml of ethanol; 160 mg of fumaric acid was added, followed by concentration under reduced pressure. Ethyl acetate was added to the residue; the mixture was washed with aqueous sodium bicarbonate and saturated saline, dried with magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue to cause crystallization; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 168 mg of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[CH2:32][C@:31]32[CH2:45][O:44]3)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[CH2:32][C@:31]2([CH3:45])[OH:44])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:46]=[CH:47][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@]2(C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred, suspension of lithium aluminum hydride (58 mg; 1.53 mmol) in anhydrous THF (10 ml) at 0° C. under argon was added dropwise a solution of 5′-O-(4,4′-dimethoxytrityl)-3′-C,O-methylenethymidine (385 mg; 0.692 mmol) in THF (10 ml). The reaction mixture was stirred at 0° C. for 1 h and the reaction quenched by slow addition of 10% NaHCO3, The resulting mixture was diluted with EtOAc (30 ml), washed with NaHCO3 (3×20 ml, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica (5% CH3OH in CHCl3) to yield 306 mg (79%) of 5′-O-(4,4′-dimethoxytrityl)-3′-C-methylthymidine as a foam.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][S:19]([NH:8][C:1](=[NH:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Reactant: N=C(N)c1ccccc1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
Reaction of benzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)BENZAMIDINE, m.p. 173°-175° C., by triturating with methanol.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C([C:16]1([CH2:26][O:27][C:28]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([F:40])[CH:29]=2)C2CC3C[CH:21]([CH2:25][CH:17]1C3)[CH2:22]2)#N.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCC1>>[N:6]1([S:10]([NH:13][C:32](=[O:33])[C:31]2[CH:35]=[C:36]([CH:37]3[CH2:39][CH2:38]3)[C:28]([O:27][CH2:26][CH:16]3[CH2:22][CH2:21][CH2:25][CH2:17]3)=[CH:29][C:30]=2[F:40])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.15-3.89 (m, 6H), 2.42-2.28 (m, 1H), 2.23-2.10 (m, 2H), 2.08-1.96 (m, 1H), 1.87-1.71 (m, 2H), 1.70-1.46 (m, 4H), 1.45-1.28 (m, 2H), 0.95-0.82 (m, 2H), 0.73-0.64 (m, 2H); MS (ES+) m/z 397.2 (M+1)
Reaction SMILES: NC[C:3]1([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]1.C([N:16](CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.O>[C:21]([NH:16][C:3]1([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC1(CO)NCC(O)C(O)C1O
Reactant: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(NC1(CO)NCC(O)C(O)C1O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.0 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine are dissolved in 20 ml of methanol/water (1:1), 1.45 ml of triethylamine are added and the mixture is cooled to -10° C. After adding 1.635 g of benzoyl chloride, the mixture is stirred at -10° C. for 30 minutes and then at room temperature for 20 hours. The solution is evaporated in vacuo and the residue is taken up in 40 ml of methanol/water (2:1). This solution is discharged onto a column 40 cm long and 3 cm wide which is filled with a cation exchanger in the H+ form. The column is first washed with 1 l of a methanol/water mixture (2:1) and is then eluted with 0.1% strength ammonia in methanol/water (2:1). The individual fractions are examined by thin layer chromatography to determine their content of the required compound. The fractions containing the desired product are collected and evaporated. The residue is dissolved in a little methanol and the solution is left to stand, whereupon crystallisation soon starts. The mixture is diluted with a little isopropanol and the crystals are filtered off and washed with isopropanol and diethyl ether. 0.8 g of 2-benzoylamino-2-hydroxymethyl-3,4,5-trihydroxypiperidine of melting point 154° to 156° C. is obtained.
Reaction SMILES: Br.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(N2N=C(c3cccnc3)CC2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C1CC(c2cccnc2)=NN1c1ccc(O)cc1
Yield: 64 %

Procedure:
To a mixture of 1 ml of 47% hydrobromic acid and 1 ml of acetic acid was added 267 mg of 1-(4-methoxyphenyl)-3-(3-pyridyl)-2-pyrazolin-5-one and stirred under reflux for 6 hours. After distilling off the solvent, water and aqueous NaHCO3 solution were added to the residue to adjust the pH value to 4 and extraction was made using ethyl acetate. After drying and concentrating the organic layer, the residue was recrystallized from ethanol to obtain 162 mg of Compound No. 10 as colorless crystals.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.N[C@H](C(N1CCC[C@H]1C(N[C@H](C([NH:86][C@H:87]([C:104]([O:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:105])[CH2:88][CH2:89][CH2:90]CNC(OCC1C=CC=CC=1Cl)=O)=O)C)=O)=O)CCCNC(=N)NS(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20]([N:86]1[CH2:90][CH2:89][CH2:88][C@H:87]1[C:104]([O:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:105])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
At 0° C. the solution of 18 mg (0.075 mmol) of HCl Pro-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 33 mg (0.077 mmol) Boc-Arg(Tos)-OH, 10 mg (0.074 mmol) of 1-hydroxybenzotriazole and 16 mg (0.077 mmol) of dicyclohexylcarbodiimide in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 5 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 30 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (10 ml×3), saturated NaCl in water (10 ml×3) and KHSO4 in water (5%, 10 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, filtered. The filtrate was evaporated to provide 37 mg (80%) of the title compound as a colorless powder. Mp 60–62° C., FAB-MS (m/e) 617[M+H]+.