Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)O[O:3]1.[CH3:6][C@H:7]1[C@H:28]2[O:29][C@@H:30]3[C@@:65]([CH3:68])([CH2:66][CH2:67][C@@H:27]2[O:26][C@@H:10]2[CH2:11][C@:12]4([CH3:25])[O:18][C@@H:17]5[C:19]([CH3:24])=[CH:20][C:21]([O:23][C@H:16]5[CH2:15][C@H:13]4[O:14][C@H:9]2[CH2:8]1)=[O:22])[O:64][C@@:33]1([CH3:69])[CH2:34][C@H:35]2[O:43][C@H:42]4[CH2:44][C@H:45]5[O:51][C@@:50]6([CH3:62])[C@@H:52]([OH:61])[CH2:53][C@@H:54]([CH2:56][C:57]([CH:59]=[O:60])=[CH2:58])[O:55][C@@H:49]6[CH2:48][C@@H:46]5[O:47][C@@H:41]4[CH:40]=[CH:39][CH2:38][C@:36]2([CH3:63])[O:37][C@@H:32]1[CH2:31]3>CC(C)=O>[CH3:6][C@H:7]1[CH:28]2[O:29][CH:30]3[C@@:65]([CH3:68])([CH2:66][CH2:67][CH:27]2[O:26][CH:10]2[CH2:11][C@:12]4([CH3:25])[O:18][CH:17]5[C:19]([CH3:24])=[CH:20][C:21]([O:23][CH:16]5[CH2:15][CH:13]4[O:14][CH:9]2[CH2:8]1)=[O:22])[O:64][C@@:33]1([CH3:69])[CH2:34][CH:35]2[O:43][CH:42]4[CH2:44][CH:45]5[O:51][C@@:50]6([CH3:62])[CH:52]([OH:61])[CH2:53][CH:54]([CH2:56][C:57]([CH:59]=[O:60])=[CH2:58])[O:55][CH:49]6[CH2:48][CH:46]5[O:47][CH:41]4[CH:40]4[O:3][CH:39]4[CH2:38][C@@:36]2([CH3:63])[O:37][CH:32]1[CH2:31]3
Reactant: CC1(C)OO1
Reactant: C=C(C=O)C[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]3C[C@@H]4O[C@@H]5C[C@]6(C)O[C@]7(C)CC[C@@H]8O[C@@H]9C[C@]%10(C)O[C@@H]%11C(C)=CC(=O)O[C@H]%11C[C@H]%10O[C@H]9C[C@@H](C)[C@H]8O[C@H]7C[C@H]6O[C@@]5(C)CC=C[C@H]4O[C@H]3C[C@H]2O1
Agent: C=C(C=O)C[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]3C[C@@H]4O[C@@H]5C[C@]6(C)O[C@]7(C)CC[C@@H]8O[C@@H]9C[C@]%10(C)O[C@@H]%11C(C)=CC(=O)O[C@H]%11C[C@H]%10O[C@H]9C[C@@H](C)[C@H]8O[C@H]7C[C@H]6O[C@@]5(C)C/C=C\[C@H]4O[C@H]3C[C@H]2O1
Solvent: CC(C)=O
Product: C=C(C=O)CC1CC(O)[C@]2(C)OC3CC4OC5C[C@]6(C)O[C@]7(C)CCC8OC9C[C@]%10(C)OC%11C(C)=CC(=O)OC%11CC%10OC9C[C@@H](C)C8OC7CC6O[C@]5(C)CC5OC5C4OC3CC2O1
Yield: 95 %

Procedure:
Epoxidation of the C-27, C-28 Double Bond of PbTx-2 To Provide PbTx-6. Dimethyldioxirane was generated in a distillation apparatus, connected to a dry ice condenser, according to the procedure described by Adam17 for a small-scale preparation. The receiving flask was charged with PbTx-2 (2.33 mg) in 5.0 mL of acetone and was cooled in an ice/salt bath. The reaction was monitored by HPLC. When all of the PbTx-2 was consumed, the acetone was evaporated in vacuo, and the residue taken up in 1.0 mL of methanol and purified by HPLC to provide 2.25 mg (95%) of PbTx-6. DCI MS (NH3): 911 (M+1), 928 (M+NH4), 893 (M−H2O). 1H and 13C NMR were identical to that reported by Shimizu.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].C(Cl)/C=C/C>>[CH3:10][O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:11]/[CH:12]=[CH:13]/[CH3:14]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: C/C=C/CCl
Agent: [H-]
Agent: [Na+]
Product: C/C=C/CCC(=O)CC(=O)OC

Procedure:
In accordance with the process of Reference 1, sodium hydride (1.20 g; 50 m mol), methyl acetoacetate (5.70 g; 50 m mol), n-butyl lithium (50 m mol) and trans-crotyl chloride (4.43 g; 50 m mol) were used to obtain 3.60 g of (E)-3-oxo-6-octenoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCCCCC>O1CCCC1>[OH:22][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(C2(O)CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (54 mL) at −78° C. was added n-butyllithium (19.1 mL of 1.6 M in hexanes, 30.6 mmol) dropwise while maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 min. Cyclohexanone (1.55 mL, 14.9 mmol) was added dropwise while maintaining the reaction temperature below −65° C. The mixture was stirred at −78° C. for 10 min then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and 1N HCl (25 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred with 1:1 dichloromethane/hexane (20 mL) to provide a white solid, which was filtered and discarded. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-5% methanol/dichloromethane) to provide an off-white solid. The solid was stirred with hexane, filtered, and dried to provide 4-(1-hydroxycyclohexyl)benzoic acid (375 mg, 11%). ESI-MS m/z calc. 220.1. Found 221.3 (M+1)+; Retention time: 1.18 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 1.81-1.46 (m, 9H), 1.35-1.17 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1

Procedure:
A solution of 1 g of β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl ]-4-fluorostyrene in 10 ml of toluene and 5 ml of ethanol is hydrogenated with 500 mg of 5 percent palladium-charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. The black suspension is subsequently filtered. Evaporation of the filtrate gives 1-[2-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]ethyl]-4 -fluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](N)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[OH-:25].[NH4+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([OH:25])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2]benzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol to give the end product as white prisms, mp 297°-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C@H:13]1[CH2:16][C@H:15]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][N:25]=[C:20]3[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[CH:11][C:2]=1[NH:12][C@H:13]1[CH2:16][C@H:15]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][N:25]=[C:20]3[C:19]([CH3:26])([CH3:27])[C:18]2=[O:28])[CH2:14]1
Reactant: Clc1ccc2cccnc2n1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ccc4cccnc4n3)C2)c2nccnc21
Temperature: 100 °C

Procedure:
2-chloro-1,8-naphthyridine (89 mg, 0.54 mmol), 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (100 mg, 0.431 mmol), and cesium carbonate (202 mg, 0.620 mmol) were suspended in dry dimethylformamide (0.86 mL) under nitrogen and heated to 100° C. for 18 h. The mixture was cooled and extracted with ethyl acetate and water. The phases were separated and the organic was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using the ISCO (0-100% EtOAc in hexane), gave the desired 5-(trans-3-((1,8-naphthyridin-2-yl)amino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (32 mg, 0.089 mmol, 21% yield) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ: ppm 1.45 (s, 6 H) 2.42 (ddd, J=13.88, 9.28, 3.29 Hz, 2 H) 3.44-3.62 (m, 2 H) 5.22-5.38 (m, 2 H) 6.71 (d, J=8.92 Hz, 1 H) 7.16 (dd, J=7.82, 4.46 Hz, 1 H) 7.79-7.98 (m, 2 H) 8.11 (q, J=3.12 Hz, 2 H) 8.84 (dd, J=4.38, 1.90 Hz, 1 H).
Reaction SMILES: [Si](Cl)(Cl)(Cl)Cl.[CH2:6]=[CH:7][CH3:8].[C:9]([OH:12])(=[O:11])[CH3:10]>C(OC(=O)C)(=O)C>[C:9]([O:12][CH2:6][CH:7]([O:12][C:9](=[O:11])[CH3:10])[CH3:8])(=[O:11])[CH3:10]
Reactant: C=CC
Reactant: CC(=O)O
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 160 °C

Procedure:
2 g silicon tetrachloride were dissolved together with 2 g cuprous chloride and 2 g cupric chloride in 500 ml glacial acetic acid and 50 ml acetic anhydride. This solution was saturated with propylene and with compressed air at 40 atmospheres, and then heated to 160°C. Distillation resulted in the preparation of 4.6 g propylene glycol diacetate.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46].O>CN(C)C=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3]
Reactant: CCN(CC)CCCCl
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Temperature: 65 °C
Reaction time: 7 h
Yield: 23.5 %

Procedure:
After dissolving 480 mg of 6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-ol sodium salt in 5 ml of dimethylformamide, 350 mg of potassium carbonate and 204 mg of 3-chloropropyldiethylamine were added and the mixture was heated and stirred at 65° C. for 7 hours. After standing to cool, water was added and extraction was performed with ethyl acetate and tetrahydrofuran, after which the solvent was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain 135 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:1][C:23](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chlorobenzonitrile (7.25 g, 47.5 mmol ), in anh. pyridine (38 mL, 475 mmol) and DCM (300 mL) cooled in an ice-H2O bath under Ar was added PhCOCl (5.8 mL, 50 mmol) dropwise. The reaction was allowed to slowly warm to rt within the cooling bath and then was stirred at rt overnight. The reaction mixture was washed (H2O, 2 M aq HCl (2×), H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.27 min (OpenLynx, polar—5 min).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[C:32](=[CH:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]>>[NH:28]1[C:32](=[CH:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(C=C2NC(=O)NC2=O)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C=C2NC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C27H20N4O5
Reaction SMILES: [OH:1][CH:2]([CH2:13][OH:14])[CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O1CCCC1.CCOCC>[Si:20]([O:14][CH2:13][CH:2]([OH:1])[CH2:3][CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOP(=O)(CCC(O)CO)OCC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of diethyl 3,4-dihydroxybutylphosphonate (8.5 g, 0.038 mol) in dry tetrahydrofuran (200 ml) was added imidazole (5.25 g, 0.077 mol). After stirring at ambient temperature for 2 minutes, t-butyldimethysilyl-chloride (5.8 g, 0.038 mol) was added. After 18 hours, the solution was filtered and the filtrate evaporated to give a colorless oil. The oil was dissolved in ether, and washed with water. The organic phase was dried (magnesium sulphate) and evaporated to give an oil which was purified by chromatography on silica gel (dichloromethane-methanol (98:2) as eluant). The title compound was obtained as an oil (8 g, 62%). IR:υmax (film), 3400, 2940, 2860, 1250, 1170, 960, 840, 780 cm-1. 1H NMR: δH (CDCl3) 0.00 (6H, s, SiMe2), 0.83 (9H, s, SiBut), 1.25 (6H, t, J=7Hz, (OCH2CH3)2), 1.5-2.0 (4H, m, CH2CH2P), 2.7 (1H, bs, D2O exchangeable, OH), 3.35-3.65 (3H, m, OCH2CH), 4.0 (4H, m, (OCH2CH3)2) Found: C, 48.66; H, 9.83%. C14H33O5SiP requires: C, 49.39; H, 9.77%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([Cl:38])[N:37]=2)[C:31]([O:33]C)=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([Cl:38])[N:37]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
To a solution of 66 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinate in 2.0 ml of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 68 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinic acid as a pale yellow resinous compound. ESI+: 600
Reaction SMILES: [CH:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:5](=[O:15])[C@H:4]1[NH:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[O:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C:31]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32]>C(#N)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C@H:3]([CH:1]=[CH:33][C:31](=[O:32])[C@@H:27]3[CH2:28][CH2:29][CH2:30][O:26]3)[C@H:4]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=O)cc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H]1CCCO1
Solvent: CC#N
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=CC(=O)[C@@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of (3S,4S)-4-formyl-1-(4-methoxyphenyl)-3-phenylacetamidoazetidin-2-one (10.39 g, 30.7 mmol) in acetonitrile (250 ml) was treated with (S)-tetrahydrofuran-2-ylcarbonylmethylenetriphenylphosphorane (11.50 g, 30.7mmol) and stirred at room temperature for 2 days. The bulk of the product was collected by filtration and washed with acetonitrile. The remainder of the product was purified by chromatography on silica gel eluting with ethyl acetate yielding a further 1.66 g. The title compound was isolated as a white solid (total 12.12 g, 91%); m.p. 159°-162° C.; [α]D -83.4° (c=1 CHCl3); (Found: C, 69.41; H, 6.28; N, 6.20%; M+, 434.1832. C25H26N2O5 requires: C, 69.11; H, 6.03; N, 6.45%; M 434.11842); ννmax (CHCl3) 3414, 1751, 1682, 1631, 1513 and 1250 cm-1 ; δH (CDCl3) 1.75-1.92 (3H, m), 2.18 (1H, m), 3.57 (2H, s), 3.76 (3H, s), 3.70-3.90 (2H, m), 4.39 (1H, m), 4.88 (1H, t, J 5.4 Hz), 5.49 (1H, dd, J 8.0, 5.4 Hz), 6.20 (1H, d, J 8.0 Hz), 6.60 (1H, d, J 16.1 Hz), 6.78-6.85 (3H, m) and 7.18-7.38 (7H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].O=S(Cl)[Cl:19]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6]([Cl:19])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(F)(F)F)cc1C(=O)O
Product: CCOc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 90 °C

Procedure:
A mixture of 2-ethoxy-5-(trifluoromethyl)benzoic acid (0.20 g, 0.84 mmol) and SOCl2 (5 mL) was warmed to 90° C. for 2 h and then was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 10 mL toluene and was concentrated again. This dilution/concentration was repeated two additional times to provide 2-ethoxy-5-(trifluoromethyl)benzoyl chloride, that was used directly below.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH3:50])[CH2:48][OH:49].Cl.NCC(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C@@H:47]([CH3:50])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C[C@H](N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH:44]=[CH:45][CH:46]=O)[C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)#[N:27].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:46][CH:45]=[CH:44][C:30]3[C:31]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)=[CH:32][CH:33]=[C:28]([C:26]#[N:27])[CH:29]=3)=[CH:17][C:16]=2[C:22]([F:25])([F:23])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
To a mixture of 4-[(N-(t-butoxycarbonyl)piperidin-4-yl)oxy]-3-trifluoromethylbenzenamine (4.9 g) and 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (4 g) in MeOH (80 mL) was added acetic acid (0.73 g). The resulting solution was stirred at ambient temperature for 15 minutes and then NaCNBH3 was added. The resulting solution was stirred at ambient temperature for 1 hour and concentrated. The residue was taken up in 100 mL of aqueous NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried, concentrated and purified on silica gel column (ethyl acetate/hexane, 3:7) to afford 5.7 g of 4-(N (t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C=CC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared analogously to step 4 of example B(29) where 4-(4-ethoxycarbonyl-but-3-enyl)-piperidine-1-carboxylic acid tert-butyl ester from step 2 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester of that example. 1H NMR (400 MHz, CDCl3): δ 0.99-1.12 (m, 2H), 1.23-1.40 (m, 8H), 1.45 (s, 9H), 1.56-1.66 (m, 4H), 2.27-2.32 (m, 2H), 2.61-2.70 (m, 2H), 4.04-4.16 (m, 4H). ESIMS (MH+): 314.