Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:35]([NH:38][NH:39][C:29]([C:27]1[NH:28][C:24]([C:14]2[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=[C:12]([O:11][C:10]3[CH:32]=[CH:33][C:7]([C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[CH:8][C:9]=3[F:34])[CH:13]=2)=[CH:25][CH:26]=1)=[O:30])(=[O:37])[CH3:36]
Reactant: CC(=O)NN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (126 mg, 0.27 mmol) synthesized in Example (66g) and acetohydrazide (40 mg, 0.54 mmol) were dissolved in dichloromethane (5 mL), and HATU (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) were added at room temperature, followed by stirring under nitrogen atmosphere for 1 hour. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=5%) to afford the desired product (87 mg, yield 62%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([CH3:37])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[C:10]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=4[S:21](=[O:35])(=[O:34])[N:20]=3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:39]>O>[CH:1]1([CH2:7][C:8]2([CH3:37])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O-:18])=[C:10]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=4[S:21](=[O:34])(=[O:35])[N:20]=3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:39]
Reactant: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A suspension of the product of Example 41I (0.968 g) in water (5 mL) and treated with 0.997N sodium hydroxide solution (1.78 mL, 1.77 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.602 g, 60%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.75 (m, 6H) 1.10 (m, 1H) 1.38 (m, 7H) 1.75 (m, 1H) 2.22 (m, 1H) 2.95 (m, 3H) 7.31 (m, 3H) 7.45 (m, 3H) 8.05 (m, 1H) 9.87 (m, 1H) 15.55 (m, 1H). MS (ESI−) m/z 542 (M−H)−.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.2945 mmol), 3-methoxytetrahydro-4H-pyran-4-one (110 mg, 0.88 mmol) and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (65 mg after converting to TFA salt) and isomer 2 (45 mg after converting to TFA salt). LCMS calculated for C24H36F3N5O3: (M+1) 500; found 500.1 for both isomers.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: CC(C)(CN)c1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)cs1
Yield: 38 %

Procedure:
This compound was synthesized from 2-methyl-2-(4-phenylthiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 38%). 1H NMR (400 MHz, MeOD) δ 8.52 (t, J=1.8 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.92-7.90 (m, 2H), 7.69 (s, 1H), 7.67-7.63 (t, J=7.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.28-7.26 (m, 1H), 3.79 (d, J=6.3 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O2S: 472.12. found: 473.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11]>C(O)CC(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(=O)NC1CCNCC1
Solvent: CC(C)CCO
Product: CC(=O)NC1CCN(c2ccc(C#N)cn2)CC1
Temperature: 140 °C
Yield: 58.5 %

Procedure:
6-Chloronicotinonitrile (300 mg, 2.1 mmol) and 4-acetylaminopiperidine (610 mg, 4.33 mmol) were taken in isoamyl alcohol (15 mL) and the mixture was heated to 140° C. for 2 h. Reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CHCl3) to afford N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)acetamide (300 mg, yield 57%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=2.4 Hz, 1H), 7.83-7.80 (m, 2H), 6.95 (d, J=9.3 Hz, 1H), 4.32-4.28 (m, 2H), 3.89-3.80 (m, 1H), 3.14-3.07 (m, 2H), 1.80 (m, 2H), 1.78 (s, 3H), 1.33-1.24 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:48][C:49]1([OH:53])[CH2:52][NH:51][CH2:50]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:51]3[CH2:52][C:49]([OH:53])([CH3:48])[CH2:50]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: CC1(O)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1(O)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.250 g, 1.0 eq.) was charged along with dichloromethane (5.0 mL, 20 V). The reaction mixture was cooled to 0° C. and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.149 g, 1.1 eq.) and 3-methyl azetidin-3-ol HCl (0.096 g g, 1.1 eq.). DIPEA (0.101 g, 1.1 eq) was added to this reaction mixture dropwise at the same temperature. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in 20 mL ice-water slurry. Organic layer was separated and aqueous layer was extracted with dichloromethane (2×10 mL) to ensure complete extraction. The organic layer was washed with brine solution and dried over anhydrous Na2SO4 and concentrated by rotary evaporation under reduced pressure (35° C., 20 mm Hg) to afford 0.280 g of crude compound. (cis: 61.9%, trans: 16.46%)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3]1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3]1
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1

Procedure:
In 59 ml of methylene chloride are dissolved 11.8 g of 1-benzyl 2-ethyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate, 11 ml of 3,4-dihydropyrane and 2.0 g of pyridinium p-toluenesulfonate. The solution is heated under reflux for one hour. The reaction mixture is added to 50 ml of saturated aqueous solution of sodium bicarbonate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 12.9 g of 1-benzyl 2-ethyl (2S,4R)-4-(tetrahydro-2H-pyran-2-yloxy)-1,2-pyrrolidinedicarboxylate as a colorless oily product.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH-:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH2:4]
Reactant: CC(C[NH-])Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CN)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of commercially available 2-methyl-3-phenylpropylamide (4.32 g, 26.5 mmol) and lithium aluminium hydride (1.3 g, 34.3 mmol) in tetrahydrofuran (184 ml) was stirred at room temperature for 5 h. The reaction mixture was poured into saturated aqueous sodium sulfate and extracted with dichloromethane followed. The combined organic extracts were dried (sodium sulfate) and evaporated to provide the amine as an oil. For alternative preparations see: Dornow and Fust, Chem. Ber. 87, 984 (1954).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=[O:13].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.CCOCC>[CH2:17]([O:16][C:9](=[O:15])[CH2:10][CH2:11][C:12](=[O:13])[CH:14]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: CCOC(=O)CCC(C)=O
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCOC(=O)CCC(=O)C=Cc1ccccc1
Yield: 94.7 %

Procedure:
Benzaldehyde 69a (5.40 g, 50 mmol) and ethyl levulinate 97 (7.21 g, 50 mmol) were dissolved in benzene (25 mL) then glacial acetic acid (6 mL) and piperidine (2 mL) were added. The solution was stirred and refluxed under a Dean-Stark trap under argon for 5 hr. The solution was cooled and diluted with ether and washed twice with 2M HCl, 5% NaHCO3 brine and evaporated to give an oil 11.0 g, 95%. 1H NMR (300 MHz, CDCl3) δ 1.27, 3H, t(J 7.1); 2.69, 2H, t(J 6.7); 3.02, 2H, t(J 6.7); 4.16, 2H, q(J 7.1); 6.77, 1H, d(J 16.2); 7.37-7.43, 3H, m; 7.51-7.60, 2H, m; 7.60, 1H, d(J 16.4). 13C NMR (CDCl3) 14.2, 28.2, 35.2, 60.7, 125.8, 128.3, 128.9, 130.5, 134.4, 142.9, 172.9, 198.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
114 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(3,4-dichlorophenyl)piperazine (64 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [S:1]1[C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH:41]([NH2:43])[CH3:42]>C(Cl)Cl>[CH3:12][O:11][C:9]([C:2]1[S:1][C:5]([C:6](=[O:8])[NH:43][CH:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)[CH3:42])=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(N)c1cccs1
Reactant: COC(=O)c1ccc(C(=O)[O-])s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccs2)s1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 500 mg (2.7 mmol) of methyl thiophen-2,5-dicarboxylate in CH2Cl2 (20 ml) is treated with 617 mg (4 mmol) 1-hydroxybenzotriazole hydrate and 772 mg (4 mmol) N′-(3-dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride and stirring is continued at ambient temperature for 1 hour. 410 mg (3.2 mmol) of 1-thiophen-2-yl-ethylamine are added to the reaction mixture which is subsequently stirred at ambient temperature overnight. The product is isolated after acidic work-up and purification on silica gel as waxy solid in 84% yield (0.67 g).
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+]>C1COCC1>[C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
(E)-Methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate (200 mg, 0.41 mmol) was taken up in 5 mL of THF along with 2 mL of a 5 N NaOH. The resulting reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure to remove the THF, and diluted with water (10 mL). The aqueous layer was acidified to pH=2 with 3 N HCl and then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 190 mg of (E)-4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoic acid (97% yield). MS (EI) calcd for C28H40N2O4: 468.30. found 469 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCN([C:24]2[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][CH:28]=2)CC1.C(OC1C=CC(NN)=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)(=O)C.C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:24]3[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][C:28]=3[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C=C1CCC=C1N1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=C1CCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, and a nitrogen inlet was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 mole equiv.), ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (22.02 kg, 1.104 mole equiv.), ethanol (51.2 kg, 2.429 mass equiv.), and acetic acid (36.8 kg, 1.746 mass eq.). After the reactor contents are allowed to stand for 10 minutes, agitation and then heating to 60° C. to 65° C. (60° C. target) was started. While stirring at that temperature, samples of the reaction mixture were taken over intervals of approximately 30 minutes and analyzed by HPLC for (4-(benzyloxy)phenyl)hydrazine, ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When (4-(benzyloxy)phenyl)hydrazine HPLC % area was <1, TFA (11.6 kg, 101.7 mol, 1.200 mole equiv., 0.550 mass equiv.) was charged over approximately 1 hour while the stirred reaction mixture was maintained at 60° C.±5° C. with reactor jacket cooling. As stirring at 60° C. to 65° C. was continued, the hydrazone and imine content of the reaction mixture was monitored by HPLC. After stirring at 60° C. to 65° C. for at least 12 hours the imine content of the reaction mixture was <5% area by HPLC, and the stirred reaction mixture was cooled to 20° C. to 25° C. over approximately 3 hours. Stirring was maintained at that temperature to allow isomerization of the Z isomer to the desired E isomer. The E isomer crystallizes from the reaction mixture. The Z isomer and E isomer % area content of the reaction mixture was monitored by HPLC during this period of stirring at 20° C. to 25° C., which was continued until the Z-isomer content of the reaction mixture was <15% area by HPLC.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].Cl.[Cl:27][CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>COCCOC>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22]([NH:31][CH2:30][CH2:29][CH2:28][Cl:27])(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: NCCCCl
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl
Yield: 97.5 %

Procedure:
CF3(CF2)5(CH2)2SO2Cl (10 g), 3-chloropropyl amine hydrochloride (4.1 g), and 1,2-dimethoxyethane (20 g) solvent were added to the round bottom flask equipped with mechanical stirring under nitrogen. Solution of triethylamine (4.5 g) in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 min at 20-30° C. at 250 rpm. Stirred for 12 h after the addition is completed. The reaction was monitored by GC to ensure the complete conversion 1. The final reaction mixture with pH of about 5 was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane (7 g) and combined filtrate was evaporated in vacuum to obtain 11.0 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl. The product was additionally dissolved in hot toluene (8 g) and washed with 15.5 mL of 1 wt % HCl aqueous solution to remove traces of NH2(CH2)3Cl.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1CCCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (17.1 mg, 53.5%), MS (ISP)m/z=457.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: [F:1][CH:2]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:18]([CH2:22][CH3:23])([CH2:19]2)[CH2:17][CH2:16][C:15](=[O:24])[CH:14]=3)=[C:11]([Cl:25])[C:10]=1[Cl:26])[C:3]([O:5]CC)=[O:4].C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][CH:2]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[C:18]([CH2:22][CH3:23])([CH2:19]2)[CH2:17][CH2:16][C:15](=[O:24])[CH:14]=3)=[C:11]([Cl:25])[C:10]=1[Cl:26])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)Oc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OC(F)C(=O)O)c(Cl)c1Cl)C2
Reaction time: 0.25 h

Procedure:
Ethyl fluoro[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (4.01 gm., 0.02 mole) is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (3.36 gm., 0.04 mole) in water (150 ml.). The mixture is heated and stirred on a steam bath for 15 minutes and then concentrated in vacuo to a volume of 50 ml. The residual solution is diluted with water (50 ml.) and acidified to Congo red test paper with 6 normal hydrochloric acid. The precipitate that forms is removed by filtration, washed with water and dried. The product is sufficiently pure for use but it may be further purified by recrystallization from a mixture of acetic acid and water to produce pure fluoro[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1.[Na].[CH3:25][SH:26]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH:16]([S:26][CH3:25])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: CC(OS(C)(=O)=O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CSC(C)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-3-mesyloxy-1-(triazol-1-yl)butan-2-ol (100 mg; 0.263 mmol) in dimethylsulfoxide (1 ml) was added 15 % aqueous methanethiol sodium salt at room temperature, and the mixture was stirred at 50 to 60° C. for 8 hours. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2-(2,4-dichlorophenyl)-3-methylthio-1-(triazol-1-yl)butan-2-ol (71 mg, 81 %) as crystals. m.p., 122-123° C. This compound was identical with Compound 4A obtained in Example 4.