Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:6]1[C:7]1[NH:8][C:9]3[C:14]([C:15]=12)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:4].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:6]12[CH2:19][CH2:18][CH:16]([C:15]3[C:14]4[C:9]([NH:8][C:7]=31)=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:17][CH:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1c1[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC2CCC1c1[nH]c3ccccc3c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,4-ethanocarbazole-2-carboxylic acid methyl ester (13.0 g, 0.05 mole, described in Example 1), potassium carbonate (7.0 g, 0.05 mole), methanol (160 ml) and water (40 ml) was refluxed for 4 hr (oil bath at 90° C.) and stirred at room temperature for 18 hr. The reaction mixture was poured into water (500 ml) and washed with diethyl ether (2×). The aqueous phase was acidified with hydrochloric acid IN (100 ml) and extracted with diethyl ether (3×). Organic layers were washed with a saturated sodium chloride solution, dried and evaporated to dryness to afford the title compound (12 g). Crystallization afforded a total of 7.5 g of title compound: mp 212°-214° C.; NMR (DMSO-d6) δ 1.7 (m, 6H), 2.8 (m, 1H), 3.5 (m, 2H), 6.7-7.5 (m, 4H), 10.9 (s, 1H) and 11.8 (br, 1H); and Anal. Calcd for C15H15O2N: C, 74.66% H, 6.27% N, 5.81% and Found: C, 74.67% H, 6.48% N, 5.80%.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](I)=[C:40]([F:45])[CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([O:36][CH:34]2[CH2:33][N:32]([C:30]([N:26]3[CH2:27][CH2:28][CH2:29][N:23]([CH:19]4[CH2:22][CH2:21][CH2:20]4)[CH2:24][CH2:25]3)=[O:31])[CH2:35]2)=[C:40]([F:45])[CH:39]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(Cl)cc2F)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenantroline with 3,4,7,8-tetramethylphenantroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.19 mmol) and 4-chloro-2-fluoro-1-iodobenzene (77 mg, 0.3 mmol) gave the title compound as colourless oil after purification by preparative HPLC (60 mg, 61%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=1[CH3:20])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1Cl)[CH:26]=[O:27]>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:30]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=2[Cl:22])=[CH:15][C:14]=1[CH3:20])[CH3:8]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with finely powdered K2CO3 (31.8 g, 230 mmol) and anhydrous DMF (104 mL). Next, a solution of compound 10.3 (26.1 g, 115 mmol) and 3,4-dichlorobenzaldehyde (21.0 g, 120 mmol) in anhydrous DMF (52 mL) was added dropwise at 90° C., and the reaction was vigorously stirred at same temperature for 1 h. The reaction mixture was poured into 468 mL of ice-water and extracted with 3×200 mL of AcOEt. The combined organics were sequentially washed with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexane—20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (34.9 g). 1H NMR (300 MHz) (CDCl3) δ 9.85 (1H, s); 7.81 (1H, d, J=1.5 Hz); 7.50 (1H, dd, J=1.8, 8.1 Hz); 7.37-7.35 (2H, m); 6.80-6.74 (2H, m); 4.71 (2H, s); 4.30 (2H, q, J=7.2 Hz); 2.32 (3H, s); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:7]([O:4][C:3](=[O:5])[CH:2]([Br:1])[CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: CC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(Br)C(=O)OCc1ccccc1

Procedure:
20.0 g (0.13 moles) of 2-bromopropionic acid were stirred with 14.1 g (0.13 moles) of benzyl alcohol in dry methylene chloride at 5°-10° C., before 0.16 g (1.3e-3 moles) of 4-dimethylaminopyridine (DMAP) were added. The temperature was raised to ~15° C. before a solution of dicyclohexylcarbodiimide (DCC) (26.7 g, 0.13 moles) in dry methylene chloride was added dropwise. The solution was added at a rate as to not increase the reaction temperature above 35° C. After the imide addition was complete, the reaction proceeded at 25° C. for several hours or until infrared spectroscopy analysis indicated the absence of a carboxylic acid stretch at 1730 cm-1. Upon completion, the reaction mixture was filtered under vacuum to remove the dicyclohexyl urea (DCU) byproduct and the filtrate was extracted once with water, once with 5% acetic acid solution (to remove DMAP) and again with water. The organic layer was dried over anhydrous magnesium sulfate before being filtered and concentrated under reduced pressure. Yield was 25 g (72%) of a mixture of Benzyl-2-bromopropionate and Benzyl-2-chloropropionate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:16]([OH:18])=O)[CH2:12][CH:11]2[C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19]C(N)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:12][CH:11]2[C:13](=[O:14])[NH:19][C:16]3=[O:18])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)C1CC1(C(=O)O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)C2(c3cccc([N+](=O)[O-])c3)CC12
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of 9.8 g of 1-(3-nitrophenyl)-1,2-cyclopropanedicarboxylic acid and 4.9 g of urea in 250 ml of xylene (mixture of isomers) is stirred for about 16 hours at a bath temperature of about 150° C. The xylene is then evaporated off in vacuo and the residue is partitioned between ethyl acetate and water. The organic phases are combined, dried over MgSO4, filtered, and concentrated in vacuo. Recrystallisation from ethyl acetate/petroleum ether gives the title compound (e) in the form of pale yellow crystals with m.p. 173°-174° C. and Rf=0.3 on thin-layer silica gel plates in the system hexane/ethyl acetate (4:6).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.Br[CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1ccc(O)cc1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Yield: 73.5 %

Procedure:
2.82 g of 4-hydroxy-N-(2,3-dichlorophenyl)-benzamide and 1.67 g of bromoacetic acid were dissolved in 10 ml of dioxane. To this solution, a mixture of 0.97 g of sodium hydroxide and 2 ml of water was dropwise added over a period of 10 minutes at a temperature of 20° C. under stirring. After the dropwise addition, the reaction solution was stirred at a temperature of 80° C. for 2 hours. After completion of the reaction, the reaction solution was poured into 50 ml of water, and acidified with hydrochloric acid. Then, the crude product obtained by collecting precipitates by filtration, was recrystallized from toluene/methanol to obtain 2.5 g of desired 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetic acid. Yield: 70.6% Melting point: 198°-199.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclopentenylpropanoic acid (56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford (S)-2-(tert-butoxycarbonylamino)-3-cyclopentylpropanoic acid (55 g, 97% yield) as viscous oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]([C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31](OC)=[O:32])=[C:28]=[O:29].C(N1CCOCC1)C>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[C@H:30]([CH:35]([CH3:37])[CH3:36])[NH:27][C:28]1=[O:29])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of 0.517 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in 5 ml of dichloromethane was treated with 0.302 g of methyl (S)-(+)-2-isocyanato-3-methylbutyrate and 0.3 ml of N-ethylmorpholine. The mixture was stirred at room temperature for 4 hours and then the solution was washed with 5% aqueous citric acid solution, saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in 5 ml of toluene containing 0.2 ml of triethylamine. The mixture was heated at reflux for 24 hours. The solution was cooled, diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium chloride solution, dried over anhydrous magnesium sulphate, and evaporated. The residue was triturated with ether and there was obtained 0.468 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH3:49])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 81 %

Procedure:
In analogy to Example 5, 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (R)-2-tert-butoxycarbonylaminopropionic acid and, after workup and purification, 324 mg (81%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13](Cl)([Cl:15])[Cl:14].[OH-].[Na+].O>CN1CCCC1=O>[Cl:8][C:7]1[C:2]([CH:13]([Cl:15])[Cl:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cnc(C(Cl)Cl)c(Cl)c1

Procedure:
2,3-Dichloro-5-(trifluoromethyl)pyridine (43.2 g, 0.20 mole) was dissolved in 140 g (1.17 mole) of chloroform and 105 g of N-methylpyrrolidone. Sodium hydroxide (40 g of 50 percent aqueous solution, 0.5 mole) was added with stirring and the mixture was allowed to stir for 20 hours at room temperature. Another 10 g of 50 percent aqueous sodium hydroxide was added and stirring was continued. After 27 total hours a large excess of water was added. The resulting aqueous layer was removed and the organic layer was concentrated on a rotary evaporator under reduced pressure to obtain an oil containing the title compound. The oil was distilled in a fractionating column and the product fractions washed with dilute aqueous sodium carbonate to obtain 18.8 g of the title compound (35.5 percent of theory) having 97 percent purity by gas chromatography. The product, which was identified by its mass spectrum (parent peak at 263 mass units) and gas chromatographic parameters (compared with an authentic standard), had a boiling point of 108°-114° C. at 19 mm Hg pressure. Approximately 17.5 g of unreacted 2,3-dichloro-5-(trifluoromethyl)pyridine was also recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]/[C:10](=[N:13]/[H])/[NH:11][OH:12])=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:13]=[C:35]([CH2:34][N:17]3[CH2:18][CH2:19][CH2:20][C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]3=[O:15])[O:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(/CCc1ccc(Cl)cc1)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1N(Cc2nc(CCc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
(Z)-3-(4-Chlorophenyl)-N-hydroxypropanimidamide (0.070 g, 0.352 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.109 g, 0.352 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.135 g, 0.705 mmol) were stirred together in dichloromethane (0.5 mL) at room temperature for 2 hours, then heated to 85° C. overnight. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.39-7.04 (m, 14H), 4.83 (s, 2H), 3.54 (t, J=6.5, 2H), 3.11-2.99 (m, 4H), 2.74-2.61 (m, 2H), 1.99-1.76 (m, 2H); MS (ESI+) m/z 472.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
L-alanine methyl ester hydrochloride (15.0 g, 107 mmol) was dissolved in N,N′-dimethylformamide (150 mL), added potassium carbonate (32.5 g, 235 mmol) and benzyl bromide (18.4 g, 107 mmol) and the mixture was stirred at 80° C. overnight. Then, the mixture was reverted to room temperature, the reaction solution was filtered through a pad of celite, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (12.7 g, 61%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:18][CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg]Br.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[O:22][CH:19]1[CH2:18][CH2:17][N:16]([C:3]2([CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: C[Mg]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
1,1-Dimethylethyl 4′-cyano-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxylate (100 mg) was dissolved in THF (6 ml). Methyl magnesium bromide (3M in ether, 220 μl) was added and the mixture was stirred at RT for 2 h. Further methyl magnesium bromide (220 μl) was added and the solution was stirred for a further 60 h. Potassium carbonate solution (saturated aqueous) was added and the mixture was extracted with DCM. The organic phase was dried, filtered and evaporated to give the subtitle compound (100 mg; MS [M+H]+ (APCI+) 443/445).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@@H:8]1[OH:32])(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCCC>[OH:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][C@@H:8]1[OH:32]
Reactant: CC(C)[Si](OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O
Reaction time: 3 h
Yield: 344 %

Procedure:
A reactor was charged with (1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol (2.94 kg total, ˜1.6 kg assumed pure material, 3.02 mol). The reactor was charged with THF (6 L) and agitation started. While maintaining the temperature less than 25° C., tetrabutylammonium fluoride (1M solution in THF, 3.02 L, 3.0 mol) was added. The reaction mixture was allowed to stir at 20° C. to 22° C., for 3 hours. TLC (50% ethyl acetate/heptane, UV visualization) confirmed a complete conversion of the starting material to the product. The reaction mixture was concentrated under reduced pressure to ˜2 L volume and transferred to a second reactor. The concentrate was diluted with methylene chloride (16 L), washed with saturated aqueous ammonium chloride (8 L), and DI water (8 L). The organic phase was dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give an amber oil (3.88 kg) which was purified by silica gel chromatography. Two columns were performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (5 kg) in 10% ethyl acetate/heptane. About 1.9 kg of the oil was adsorbed onto silica gel (1.5 kg) and loaded on the column and the polarity was gradually increased from 10% to 50% ethyl acetate/heptane. Pure fractions were combined and concentrated under reduced pressure to afford the title compound (800 g) as a white solid. 1H NMR (300 MHz, CDCl3, δ): 7.57-7.53 (m, 5H), 7.32-7.18 (m, 10H), 4.26-4.23 (m, 1H), 3.65-3.46 (m, 2H), 3.36-3.29 (m, 1H), 2.17-2.07 (m, 2H), 1.65-1.62 (d, 1H), 1.51-1.39 (m, 2H), 1.37-1.26 (m, 1H) and 1.2-1.17-1.11 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>COCCOC>[F:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:44])[F:43])[CH:23]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 56.3 %

Procedure:
A solution of thiophene-2-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (263 mg, 0.63 mmol) in DME (5 ml)/2M Na2CO3 (1.10 ml, 2.22 mmol) was with 2-trifluoromethoxyphenylboronic acid (196 mg, 0.95 mmol) and Pd[PPh3]4 (146 mg, 0.13 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (176 mg, 56%). MS m/e 497.41 (M+H+)
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:2][O:4][C:5]([C:6](=[C:23]1[CH2:22][CH2:21][CH2:20][N:18]1[CH3:19])[C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1)=[O:17]
Reactant: c1ccncc1
Reactant: CCOC(=O)Cc1ccc(OC)c(OC)c1
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=C1CCCN1C)c1ccc(OC)c(OC)c1

Procedure:
Add a solution of 0.46 g of sodium in 5 ml of methanol dropwise to a mixture of 5.8 g of the title compound of Example 11 and 4.5 g of homoveratric acid ethyl ester in 15 ml of pyridine. Stir the resulting reaction mixture for 2 hours at 60°, and then distil pyridine and alcohol off under a vacuum before extracting the oily residue first with water and subsequently with petroleum ether. Chromatograph thus-extracted residue on a silica gel column with chloroform/methanol (19:1) to obtain eluate with an RF value 0.76. Concentrate the eluate to obtain a yield (10.5% of theory) of the title compound in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=[O:22]>C(O)C.O.O>[C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
3-(4-formyl-phenyl)-acrylic acid tert-butyl ester (150 mg, 0.64 mmol) and KOH (72 mg, 1.28 mmol)) were dissolved in ethanol/water (1:1, 5 ml) and 3,4-difluoroacetophenone (83.2 μl, 0.64 mmol) was added to the resulting solution. The resulting mixture was stirred at room temperature overnight and then diluted with H2O. The precipitate was filtered and dried under vacuo to give 210 mg of 3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid tert-butyl ester.