Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NNc1ccc(Cl)cc1)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1oc(-c2cccs2)nn1-c1ccc(Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of N′-(4-chlorophenyl)thiophene-2-carbohydrazide (20 g, 79.3 mmol), triethylamine (10 mL) and carbonyldiimidazole (16.2 g, 100 mmol) was refluxed in THF (100 mL) for 1 hour. The crude product obtained after the removal of the solvent was triturated with water, filtered, and dried, followed by recrystallization from ethyl acetate/hexanes to provide 3-(4-chloro-phenyl)-5-(thiophene-2-yl)-1,3,4-oxadiazol-2(3H)-one (18 g, 64.7 mmol, yield 81%). The HPLC purity of the final product was 99.9%. LC-MS [M+H] 279.9 (C12H7ClN2O2S+H, expected 279.72). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH2:15][CH:16]=[O:17])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH2:15][CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: COc1nnc(N=C=O)s1
Reactant: CCNCCC=O
Solvent: c1ccccc1
Product: CCN(CCC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-ethylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: C([N:8]([C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:8][C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H](C)[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1

Procedure:
A mixture of methyl (2S ,3R,αS)-3-(N-benzyl-N-α-methylbenzylamino)-2-methyl-3-phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium-on-carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a balloon of hydrogen for 24 h. The catalyst was removed by filtration followed by evaporation and co-distillation with toluene to provide the title compound as a white solid. MS (m/z): 194.2 (M+H)+; C11H15NO2 requir. 193.3.
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][N:41]([CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 55 °C
Yield: 30.9 %

Procedure:
Method A. 3-Cyclopentylacrylonitrile (8, 14.6 g, 0.12 mol, 1.20 equiv) and DBU (18.2 mL, 0.12 mol, 1.2 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (19, 30.0 g, 0.1 mol) in acetonitrile (45 mL) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to room temperature for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with water (3×200 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product (20) as a thick oil. The crude product was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 13.0 g, 42.14 g theoretical, 30.8% yield) as a white solid. For 20: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[NH3:23]>C(O)CO.O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:23])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: N
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Into a 10 mL sealed tube, was placed 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (150 mg, 0.40 mmol). To this was added Cu2O (30 mg, 0.21 mmol), followed by a saturated solution of NH3 in ethylene glycol (4 ml). The resulting solution was stirred at 70° C. for 3 hours, then diluted with 30 mL of H2O and extracted three times with 20 mL of EtOAc. The organic layers were combined and dried over Na2SO4. Removal of the volatile components under reduced pressure afforded the product 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (50 mg, yield 40%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(NC(NC3CCN(C4C=CC=CN=4)CC3)=O)CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:119]([O:121][C:122]([C:124]1[CH:125]=[CH:126][C:127]([N:130]2[CH2:135][CH2:134][CH:133]([NH:136][C:137](N3C=CN=C3)=[O:138])[CH2:132][CH2:131]2)=[N:128][CH:129]=1)=[O:123])[CH3:120]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:119]([O:121][C:122]([C:124]1[CH:125]=[CH:126][C:127]([N:130]2[CH2:135][CH2:134][CH:133]([NH:136][C:137]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:14]4[N:22]=[C:21]5[C:17]([N:18]=[CH:19][N:20]5[C@@H:23]5[CH2:27][C@H:26]([N:28]6[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]6)[C@@H:25]([OH:35])[C@H:24]5[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:15]=4)[CH2:10]3)=[O:138])[CH2:132][CH2:131]2)=[N:128][CH:129]=1)=[O:123])[CH3:120]
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)n3ccnc3)CC2)nc1
Agent: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)N[C@@H]3CCN(c4nc(NCC(c5ccccc5)c5ccccc5)c5ncn([C@@H]6C[C@H](n7cc(CO)cn7)[C@@H](O)[C@H]6O)c5n4)C3)CC2)nc1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 76) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with 4-[(imidazole-1-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ethyl ester. MS (ES+) m/e 436 (MH+/2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccccc1-c1nc[nH]c1-c1ccccc1Cl
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 23.6 %

Procedure:
4,5-Bis(2-chlorophenyl)imidazole (1.2 g) (Chem. Ber., 1959, 92, 338-343) and ethyl 8-bromooctanoate (2.1 g) were reacted in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 4,5-bis(2-chlorophenyl)-1-(7-ethoxycarbonyl-heptyl)imidazole (0.45 g, 23.7%) as an oil. NMR d (CDCl3) 1.0-1.8(11H, m, 4×CH2, CH3), 2.2(2H, t, CH2C=O), 3.8 (2H, m, N--CH2), 4.1(2H, q, CH2OC=O), 7.1-7.45 (8H, m, ArH), 7.69 (1H, s, N=CH) ppm
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.[C:20]([O-:23])(=[O:22])C.[K+].[I-].[K+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(=O)C>[F:17][CH2:16][C:4]1([CH2:18][F:19])[CH:3]=[C:2]([C:20]([OH:23])=[O:22])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CC(=O)[O-]
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 120 °C
Reaction time: 9 h
Yield: 80.9 %

Procedure:
A mixture of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran (1.72 g), potassium acetate (2.00 g), potassium iodide (0.85 g), triphenylphosphine (27 mg), palladium acetate (11 mg) and N,N-dimethylacetamide (10 ml) was stirred under a CO atmosphere at 120° C. for 9 hours. To the reaction mixture, 2 N HCl was added and the precipitating crystals were recovered by filtration. To the recovered crystals, ethyl acetate was added and the insoluble matter was filtered off; the filtrate was washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was dissolved in a saturated aqueous solution of sodium hydrogencarbonate and washed with dichloromethane; to the resulting aqueous layer, concentrated HCl was added to render it acidic and the precipitating crystals were recovered by filtration. The recovered crystals were dissolved in ethyl acetate, dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was recrystallized with an ethyl acetate/hexane mixed solvent to give 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid (1.25 g) having a melting point of 162-163° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][C:17]#[N:18])[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#CCc1cc(Cl)cc2cc(C(=O)O)[nH]c12
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of 81 mg (0.3 mmol) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (5 ml) at RT was added 39 mg of LiOH.H2O. The reaction mixture was stirred at 40° C. for three hours and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 71 mg (98%) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 232.9 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.[CH2:36]([N:38]([CH2:41][CH2:42]Cl)[CH2:39][CH3:40])[CH3:37]>CN(C)C=O.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:37][CH2:36][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Reactant: CCN(CC)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In one portion 2.1 g (6.4 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.8 g (7.0 mmol) of potassium t-butoxide in 35 ml of dimethyl formamide which was cooled to 0°. After stirring for 15 min 2.5 ml (7.5 mmol) of a 3 M toluene solution of diethylaminoethyl chloride was added. The mixture was warmed to room temperature and stirred for 3 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. Purification of the residue by column chromatography (25 g, silica gel; eluent 4:1 methylene chloride:ether) gave an off-white solid, mp 130°-131°.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH:4]=[CH2:5].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH:2]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][CH:4]=[CH2:5])=[CH:23][CH:22]=1
Reactant: C=CCC(O)c1ccc(C#N)cc1
Reactant: Oc1ccc(OC2CCCCO2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (4.93 g, 28.5 mmol) and 4-(tetrahydro-2H-pyran-2-yloxy)phenol (8.3 g, 42.7 mmol) in dry THF (200 mL) was treated with tributylphosphine (8.85 mL, 42.7 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (10.77 g, 42.7 mmol). After addition was complete, the reaction mixture was stirred at 0° C. for 10 min, before being stirred at rt overnight. The precipitate of tributylphosphine oxide was removed by filtration and the filtrate was concentrated in vacuo to give 24.6 g of crude product. This was purified by chromatography on silica gel, eluting with IPA:EtOAc:heptane (5:5:90), to give 4.6 g (47%) of the subtitle compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54](=[O:58])[CH2:55][CH2:56][NH2:57])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:53][C:54](=[O:58])[CH2:55][CH2:56][NH:57][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: COc1nnnc(OC)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCC(=O)OCc2ccccc2)C1

Procedure:
rac-N-(t-butoxycarbonyl)piperidine-3-carboxylic acid (Can. J. Physiol. Pharmacol. 57, 1979, 763) in THF was activated with chlorodimethoxytriazine and N-methyl-morpholine and then coupled with β-alanine benzyl ester p-toluenesulphonate (J. Org. Chem. 17, 1952, 1564) and N-methylmorpholine to give rac-N-[[1-(t-butoxycarbonyl)-3-piperidinyl]carbonyl]-β-alanine benzyl ester, m.p. 57°-59° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH3:32])=[C:9]([CH:30]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[H-].[Na+].[CH3:41][N:42]=[C:43]=[S:44]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH3:32])=[C:9]([CH:30]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:19]([S:21]([NH:24][C:43]([NH:42][CH3:41])=[S:44])(=[O:23])=[O:22])[CH:20]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=S
Reactant: COCCOc1ccc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)cc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Product: CNC(=S)NS(=O)(=O)c1cc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)ccc1OCCOC

Procedure:
The preparation was carried out analogously to Example 1 using 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)benzenesulfonamide. Instead of potassium carbonate, sodium hydride was used as base in the reaction with methyl isothiocyanate analogously to Example 5. The product had a melting point of 61° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].CN1CCOCC1.[CH3:23][C:24]1[C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=[C:26]([C:35]([F:38])([F:37])[F:36])[N:25]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH:7][C:32](=[O:33])[CH:31]=[CH:30][C:29]1[C:24]([CH3:23])=[N:25][C:26]([C:35]([F:36])([F:37])[F:38])=[CH:27][CH:28]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 0.08 h
Yield: 58.8 %

Procedure:
To a suspension of 3-fluoro-4-methansulfonylaminobenzylamine hydrochloride (67 mg, 0.26 mmol) in THF (5 mL) was added N-methylmorpholine (43 μL, 0.39 mmol). After stirring for 5 minutes, 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 73 mg, 0.26 mmol) were added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-fluoro-4-methanesulfonylaminobenzyl)-3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylamide (66 mg, 58.8%) as a solid.
Reaction SMILES: ClC1C=C([C@@H]2[C@@H](C3C=CC(Cl)=CC=3)N([C@@H](CC)CO)C(=O)[C@](CC(OC)=O)(C)C2)C=CC=1.C(P(CCCC)(CCCC)=CC#N)CCC.FC(F)(F)S(N)(=O)=O.[Cl:57][C:58]1[CH:59]=[C:60]([C@@H:64]2[C@@H:69]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=3)[N:68]([C@@H:77]([CH2:87][CH3:88])[CH2:78][NH:79][S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[C:67](=[O:89])[C@:66]([CH2:91][C:92]([O:94]C)=[O:93])([CH3:90])[CH2:65]2)[CH:61]=[CH:62][CH:63]=1.[Li+].[OH-]>C1(C)C=CC=CC=1.C(O)C>[Cl:57][C:58]1[CH:59]=[C:60]([C@@H:64]2[C@@H:69]([C:70]3[CH:71]=[CH:72][C:73]([Cl:76])=[CH:74][CH:75]=3)[N:68]([C@@H:77]([CH2:87][CH3:88])[CH2:78][NH:79][S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[C:67](=[O:89])[C@:66]([CH2:91][C:92]([OH:94])=[O:93])([CH3:90])[CH2:65]2)[CH:61]=[CH:62][CH:63]=1
Reactant: CC[C@@H](CNS(=O)(=O)C(F)(F)F)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: NS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC[C@@H](CNS(=O)(=O)C(F)(F)F)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A reaction vial under argon was charged with methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (0.048 g, 0.1 mmol; Example 186, Step A), 2-(tributylphosphoranylidene) acetonitrile (0.036 g, 0.15 mmol) and trifluoromethanesulfonamide (0.022 g, 0.15 mmol) in toluene (0.5 mL). The reaction mixture in the reaction vial was sealed and stirred at 110° C. for 1 h. Column chromatography on silica gel gave a mixture of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetate with an unknown impurity. This mixture was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[F:27][C:21]1[CH:20]=[C:19]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH2:17]2)[CH:24]=[C:23]([F:25])[C:22]=1[F:26]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 16 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.1 g) in THF (100 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether; 55 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 16 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.91 g of the title compound. The property value of the compound is as follows.