Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:26])([F:25])[F:24])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=O)=[CH:15]2)(=[O:8])=[O:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.[C:49]([O:54][CH2:55][CH3:56])(=[O:53])[C:50]#[C:51][CH3:52].C(P(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:22][C:23]([F:24])([F:25])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:36][CH:51]([CH2:50][C:49]([O:54][CH2:55][CH3:56])=[O:53])[CH2:52][N:21]=1)=[CH:15]2)(=[O:8])=[O:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC#CC(=O)OCC
Reactant: NC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 27.7 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (2.14 g), Lawesson's reagent (2.14 g) and tetrahydrofuran (50 mL) was stirred at 50° C. for 1.5 hr, and heated under reflux for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give pale-yellow crystals. The obtained crystals were subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:2, volume ratio) to give yellow crystals. A mixture of the obtained crystals, ethyl but-2-ynoate (1.49 g), tributylphosphine (1.07 g), toluene (30 mL) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. ethyl but-2-ynoate (900 mg) and tributylphosphine (1.07 g) were added to the mixture, and the mixture was further stirred at room temperature for 2.5 days. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:3, volume ratio) to give the title compound (780 mg, yield 28%) as a brown oil.
Reaction SMILES: OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3[CH2:32][O:33][CH2:34][CH2:35][Si](C)(C)C)C)C=CC=1.Cl.[OH:41][C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1>CO>[CH3:32][O:33][CH2:34][CH2:35][O:41][C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: COCCOc1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 126 (300 mgs, 0.54 mmol) was treated with toluene 4-sulfonic acid 2-methoxy ethyl ester at 50 C for 42 hrs using the procedure described above for compound 127. The generated intermediate was then treated with 4N HCl in MeOH, using the procedure described for compound 121 (step D). m/z=487 (M+H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][CH:14]([N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12)[CH3:15]>C(OCC)(=O)C>[CH3:13][CH:14]([N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12)[CH3:15]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)C)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(1-methylethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 35%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of o-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 2-methyl-benzoate were obtained as a brownish oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 6), 232 (5.5), 173 (22.6), 119 (17.2), 91 (100), 82 (96).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:11]=1.[BH4-].[Na+].O>CC#N.CCOC(C)=O>[CH2:1]([N:19]1[CH2:18][CH:17]=[C:16]([C:12]2[N:11]=[C:10]([Cl:9])[CH:15]=[CH:14][N:13]=2)[CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Clc1ccnc(-c2ccncc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Clc1ccnc(C2=CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Benzyl chloride (460 μl, 4.0 mmol) was added to a stirred suspension of 4-chloro-2-(pyridin-4-yl)pyrimidine (prepared according to J. Med. Chem., 1982, 25(7), 837-842) (383 mg, 2.00 mmol) in MeCN (10 ml) and the mixture was heated at reflux for 30 h and then concentrated under reduced pressure. EtOH (5 ml) was then added, followed by NaBH4 (151 mg, 4.0 mmol), and the mixture stirred at room temperature for 30 min. Water (10 ml) and EtOAc (70 ml) were added, separated and the organics washed with H2O (20 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 3% MeOH/CH2Cl2 as eluent to yield 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine (325 mg, 57%): 1H NMR (360 MHz, CDCl3) δ 8.52 (1H, d, J 5.3), 7.40-7.23 (6H, m), 7.11 (1H, d, J 5.3), 3.66 (2H, s), 3.30-3.20 (2H, m), 2.80-2.63 (4H, m); m/z (ES+) 286, 288 (1:1, M+H+).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([O:40]CC2C=CC=CC=2)=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CCC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CCC(=O)O)c1
Yield: 87.2 %

Procedure:
Next, 0.68 g (1.03 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(2-benzyloxycarbonylethyl)phenyl](methyl)phosphono}butanoate was dissolved in 50 mL of a solvent mixture of methanol and water at 4:1 and mixed with 240 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(2-carboxyethyl)phenyl](methyl)phosphono}butanoic acid (0.31 g, yield 86%) as a colorless solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:51]1[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=1)[CH:48]([CH3:50])[CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:56]([C:54]3[N:55]=[C:51]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:52][CH:53]=3)=[O:57])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-isobutylthiazole-4-carboxylic acid (example 72, step d) (0.08 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. and the resulting yellow solution allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.24 g.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][N:11]=2)=[CH:6][CH:5]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:12]2[CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:9][CH:8]=3)=[N:11]2)=[S:31])=[CH:25][CH:24]=1
Reactant: FC(F)Oc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: FC(F)Oc1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1

Procedure:
A mixture of 5.8 g. of 3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline and 3.4 g. of 4-chlorophenylisothiocyanate in 200 ml. of anhydrous ethyl ether was refluxed for 6 hours to react them. After cooling the reaction mixture, the precipitated crystal (6.1 g.) was separated by a filtration. It was confirmed that the product was 1-(4-chlorophenylthiocarbamoyl)-3-(4-difluoromethoxyphenyl)-4-phenyl-2-pyrazoline (melting point of 158.0°-161.0° C.) by the NMR spectrum.
Reaction SMILES: [CH3:1][OH:2].[Na].Cl[C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:16](NC2C=CN(CCC(=O)N(C)C)N=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12].[OH2:37]>CS(C)=O>[CH:32]1([CH2:31][C@H:15]([C:7]2[CH:8]=[CH:9][C:10]([S:11]([CH3:14])(=[O:12])=[O:13])=[C:5]([O:2][CH3:1])[CH:6]=2)[C:16]([OH:17])=[O:37])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CO
Reactant: O
Reactant: CN(C)C(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: [Na]
Solvent: CS(C)=O
Product: COc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
In a round bottom flask under argon was placed methanol (50 mL) and to it was added in small portions sodium metal (1.15 g, 45.35 mmol). This was stirred at 25° C. for 1 h. It was then concentrated in vacuo and azeotroped with acetonitrile. To this solid residue under argon was then added 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO200058293, Example 12, 3.00 g, 9.07 mmol) in dimethylsulfoxide (25 mL). This was then stirred and heated at 75° C. for 1 h. Let the solution cool back to 25° C. and then diluted it with water (120 mL). The solution was then filtered through celite and washed with water. The pH of the filterate was then adjusted pH=2 using a 1 N aqueous hydrochloric acid solution. It was then extracted with ethyl acetate (200 mL) and dried using sodium sulfate. The solution was filtered and concentrated in vacuo. The crude racemic material was then separated into the chiral components by supercritical fluid chromatography (SFC) on a Berger MultiGram II Supercritical Fluid Chromatography (SFC) system (Mettler-Toledo AutoChem Berger Instruments, Newark, Del.) (Chiral column: Daicel OJ-H, 250 mm×30 mm i.d., 5 μm-particle size, temperature: 35° C., flow rate of 70 mL/min, and 100 bar back pressure, 12% of a 1:1 ethanol/acetonitrile as mobile phase modifier and UV Detection: 220 nm) to afford (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (second compound to elute, 1.31 g, 44%) as a white foam: [α]31589=−47.4° (c=0.23, methanol); ES-HRMS m/e calcd for C16H22O5S (M+H)+ 327.1261, observed 327.1262; 1H NMR (300 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.36-1.81 (m, 8H, 4×CH2), 2.00 (m, 1H, CH), 3.22 (s, 3H, SO2CH3), 3.66 (t, J=7.7 Hz, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 7.10 (dd, Jm=1.4 Hz, Jo=8.1 Hz, 1H, Ar), 7.22 (d, Jm=1.4 Hz, 1H, Ar), 7.74 (d, Jo=8.1 Hz, 1H, Ar), 12.56 (s, 1H, CO2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][N+:13]([O-:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Under a nitrogen atmosphere, 4-(tert-butyldimethylsilyloxymethyl)pyridine (1.1 g, 5 mmol) synthesized in Production Example 84 was dissolved in dichloromethane, and m-chloroperbenzoic acid (1.9 g, 14.5 mmol) was added slowly thereto under an ice cooling. The mixture was heated slowly to a room temperature and then stirred overnight. After the completion of the reaction was confirmed by HPLC, an excess of m-chloroperbenzoic acid was removed by a sodium thiosulfate solution. The remaining mixture was washed with 2-N sodium hydroxide 3 times. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (1.2 g, 100%) was obtained as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:29][CH2:30][CH2:31][OH:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:31][OH:32])=[O:17])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
5-[(2,5-Difluorophenyl) (phenylsulfonyl)methyl]-4-meth ylpyridine-2-carboxylic acid (90 mg, 0.22 mmol), 2-aminoethanol (27 μl, 0.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.34 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), and triethylamine (92 μl, 0.66 mmol) were dissolved in methylene chloride (15 ml), and the resulting solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (30 mg, 0.067 mmol, 30%) as a white amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:20][C:21]([O:23]CC)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:8][CH:7]=1)=[O:4].[NH3:26].C(O)C>>[F:18][C:14]([F:19])([CH:15]([F:17])[F:16])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:20][C:21](=[O:23])[NH:26][CH2:2][C:3]2=[O:4])=[CH:7][CH:8]=1
Reactant: N
Reactant: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCO
Product: O=C1CN(c2ccc(OCC(F)(F)C(F)F)cc2)C(=O)CN1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The resulting N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (1.9 g) was dissolved in 20 ml of 10.5% ammonia-ethanol and the solution was stirred at 60° C. for four hours. After cooling, the crystals separated out therefrom were collected by filtration and washed with cold ethanol to give 1.5 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].O.[Se](=O)=[O:12]>O1CCOCC1>[C:1]([C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=[Se]=O
Reactant: Cc1ncccc1C#N
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1C=O
Yield: 9.7 %

Procedure:
To a solution of 3-cyano-2-picoline (166 mg, 1.41 mmol) in dioxane (3 mL) was added water (0.2 mL) and selenium(IV) oxide (228 mg, 2.05 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1 then 1:1) to afford the title compound (18 mg, 10%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.69 (dd, 1H, J=9, 6 Hz), 8.20 (d, 1H, J=9 Hz), 9.00 (d, 1H, J=3 Hz), 10.13 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
(S)-2-t-butoxycarbonylamino-succinic acid 4-benzyl ester (545 mg, 1.69 mmol) was dissolved in tetrahydrofuran (THF) to which N-methylmorpholine (NMM, 0.19 mL, 1.77 mmol) and isobutyl chloroformate (0.23 mL, 1.77 mmol) were added at 0° C., followed by stirring at that temperature for 30 min. After 30 min, the resulting white solid salt was removed by celite filtration, and a solution of sodium borohydride (96 mg, 2.53 mmol) in distilled water (2 mL) was added to the resulting clear filtrate without further concentration at room temperature. After stirring for 1 hour at room temperature, THF was distilled under reduced pressure. The reaction was diluted with ethyl acetate and was terminated by the addition of 1N HCl. The organic layer was extracted with ethyl acetate and was purified by column chromatography (ethyl acetate:hexane=1:1) to afford 468 mg (yield: 90%) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: CSc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cnc(NC(=O)c2cccc(OC(C)=O)c2)s1
Yield: 64.6 %

Procedure:
Following the procedure for the synthesis of example 85, intermediate 511 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 512 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 77 (0.681 g, 65%) as a tan solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.[CH2:17]([NH2:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:17]([NH:24][CH2:12][CH2:13][CH2:14][CH2:15][N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1CCCCCN1
Reactant: BrCCCCBr
Reactant: CCCCCCCN
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCCCCCCNCCCCN1CCCCCC1=O
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 0.88 g of 60% sodium hydride and 200 ml of dry toluene was incorporated dropwise with a solution of 2.26 g of azacycloheptane-2-one in toluene, heated under reflux for one hour, thereafter incorporated with 17.3 g of 1,4-dibromobutane, further refluxed for 18 hours and then filtered to remove insoluble materials to obtain a filtrate. The thus obtained filtrate was washed with water, dried, freed from the solvent by distillation off at reduced pressure and then finally distilled to obtain an oily substance. A mixture of 3.92 g of the thus obtained oily substance, 1.82 g of n-heptylamine and 50 ml of benzene was incorporated dropwise with 2.64 g of 1,8-diazabicyclo [5,4,0] undecene-7 (DBU) in benzene and agitated at room temperature for a whole day. The thus obtained reaction mixture (liquid state) was washed with water, dried, freed from the solvent by distillation off at reduced pressure and then finally distilled to obtain 3.16 g of colorless 1-[4-(n-heptylamino) butyl] azacycloheptane-2-one having the following appearance, column temperature and analysis: