Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1>>[ClH:3].[ClH:3].[Cl:3][C:6]1([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: OC1(c2ccncc2)CN2CCC1CC2
Product: Cl
Product: ClC1(c2ccncc2)CN2CCC1CC2
Yield: 3.4 %

Procedure:
By the procedure described in Example 5, thionyl chloride (2.38 ml, 32.7 mmol) and 3-hydroxy-3-(4-pyridinyl)-1-azabicyclo[2.2.2]octane (3.34 g, 15.4 mmol, prepared as in Example 10a) gave 0.11 g of 3-chloro-3-(4-pyridinyl)-1-azabicyclo[2.2.2]octane dihydrochloride; m.p. 165°-170° C.; Found: C, 46.78; H, 5.97; N, 8.77. C12H17N2Cl3.0.75H2O requires C, 46.62; H, 6.03; N, 9.06; δ(360 MHz, D2O) 8.882 (2H, d, J= 7.0 Hz, py-H), 8.231 (2H, d, J=7.9 Hz, py-H), 4.38 (2H, m, H2 -2), 3.70-3.15 (4H, m, H2 -6 and H2 -7), 2.75-1.60 (5H, m, H-4, H2 -5 and H2 -8); m/e 222 (M+), and 1.29 g of 3-(4-pyridinyl)-1-azabicyclo[2.2.2]oct-2-ene dihydrochloride; m.p. 245°-250° C.; Found: C, 55.40; H, 6.19; N, 10.68. C12H16N2Cl2.0.05H2O requires C, 55.41; H, 6.24; N, 10.77; δ(360 MHz, D2O) 8.814 (2H, d, J=6.9 Hz, py-H), 8.171 (2H, d, J=6.9 Hz, py-H), 7.529 (1H, d, J=1.4 Hz, H-2), 3.73 and 3.27 (5H, m, H-4, H2 -6 and H2 -7), 2.25 and 1.93 (4H, m, H2 -5 and H2 -8); m/e 186 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)(Cl)Cl.CC1C=CN=C(N)C=1C.CCN(C(C)C)C(C)C.[P:45]([O-:62])([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][P:45](=[O:62])([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:13]=2)=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1O
Agent: Cc1ccnc(N)c1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
(E)-N-(3-Chloro-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylamide (compound 55, 1.608 g, 5.31 mmol) was dissolved in dry CH3CN (80 ml) and CCl4 (5.13 ml, 53.1 mmol) and the resulting solution was cooled at 0° C. Dimethyl amino pyridine (65 mg, 0.53 mmol), DIPEA (2.88 ml, 22.3 mmol) and then dibenzyl phosphite (3.52 ml, 15.93 mmol) were added and the mixture was stirred at RT for 1 h. The reaction was quenched with 0.5M KH2PO4 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to dryness. The crude was purified by column chromatography (eluent DCM/MeOH from 100:1 to 99:1) to give phosphoric acid dibenzyl ester 5-[(E)-2-(3-chloro-phenylcarbamoyl)-vinyl]-2-methoxy-phenyl ester (1.87 g).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[C:8]2([O:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]1=O)[C:3]#[N:4].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][C:2]1([CH3:29])[CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][C:11]([S:15]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)(=[O:16])=[O:17])=[CH:10][C:9]=3[C:8]3([O:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:7]2=[N:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCCC3)cc1C21OCCCO1
Temperature: 135 °C
Yield: 45.1 %

Procedure:
A mixture of 2,2-dimethyl-3-[2′-oxo-5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]propanenitrile (0.69 g, 1.64 mmol) and wet Raney Nickel (0.70 g) in 2M EtOH.NH3 (50 mL) and THF (20 mL) was hydrogenated in a Parr hydrogenation bottle (500 mL) at 541 b/in2 hydrogen for 67 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel, diluted with 2M EtOH.NH3 (50 mL) and THF (20 mL) and heated at 135° C. for 22 hr. The reaction was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/.05) to give the title compound as a white solid (0.300 g, 45% yield). NMR: consistent. MS: (API-ES+) m/z 406 [M+H].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.Cl>O1CCCC1>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][C:10]([CH3:18])([CH3:9])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:22][CH:21]=1
Reactant: CC(C)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
At −78° C., 34.7 ml (69.4 mmol) of a 2 M lithium diisopropylamide solution are slowly added dropwise to a solution of 10.0 g (69.34 mmol) of tert-butyl 2-methylpropionate (Example I-1) in 100 ml of tetrahydrofuran. After the addition has ended, the mixture is stirred at −78° C. for 1 h, and a solution of 15.76 g (63.04 mmol) of 4-bromobenzyl bromide in 10 ml of tetrahydrofuran is then added and the mixture is stirred at −78° C. for 1 h. The reaction is then warmed to room temperature and poured into 100 ml of 1 N hydrochloric acid, the phases are separated and the aqueous phase is extracted 3× with diethyl ether. The combined organic phases are washed with NaHCO3 solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Distillative purification of the residue under oil pump vacuum gives 16.75 g (85%) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Br)(OC(C)(C)C)=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[CH2:19]([NH:23][CH2:17][C:9]1[NH:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)n1c(CBr)nc2ccccc21
Reactant: CCCCN
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a stirred solution of 1-BOC-2-bromomethylbenzimidazole (2.00 g, 6.4 rnmol) in dry THF (20 mL) was added n-butylamine (1.2 g, 15.4 mmol). After stirring at RT overnight, the mixture was concentrated. The residue was taken up in H2O and extracted with CH2Cl2. The organic extracts were dried over MgSO4 and concentrated to give a brown residue, which was dissolved in CH2Cl2 (15 mL) and treated with TFA (5 mL). The resulting mixture was stirred at RT overnight then was concentrated. The residue was taken up in H2O, and the solution was neutralized with 2.5 N NaOH. CH2Cl2 extraction, drying (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2Cl2) gave the title compound as a yellow oil (0.91 g, 70%): 1H NMR (250 MHz, CDCl3) δ 0.79 (t, J=7.2 Hz, 3H), 1.23 (m, 2H), 1.54 (m, 2H), 3.35 (t, J=7.2 Hz, 2H), 4.55 (s, 2H), 7.25 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCO
Reactant: O=C1CCC(O)N1
Product: CCCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 7.5 g of 5-hydroxy-pyrrolidin-2-one in 10 cm3 of n-octanol and 4 g of Amberlite IR 120 H is agitated at 60° C. for 4 hours. After filtering, and concentrating to dryness, 5.5 g of the expected product is obtained, m.p. 36°-38° C., crystallized from hexane. By re-crystallizing from hexane, m.p.=38°-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C[Si](C)(C)Cl.[C:19](=O)(O)[O-].[Na+].CN(C)C.[CH2:28]([OH:31])[CH2:29]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]2[O:31][CH2:28][CH2:29][O:13]2)[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=Cc1cc(Cl)cc(C(=O)O)c1O
Reactant: O=C([O-])O
Reactant: OCCO
Agent: CN(C)C
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: COC(=O)c1cc(Cl)cc(C2OCCO2)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 73.2 g of 5-chloro-3-formyl-2-hydroxybenzoic acid, 350 ml of ethylene glycol and 129 ml of trimethylchlorosilane is stirred at room temperature for 2 hours. The reaction mixture is poured into a mixture of an aqueous saturated sodium bicarbonate solution and trimethylamine, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent to give 86 g of methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate as yellow powder.
Reaction SMILES: C[O-].[Na+].[CH:4](=[O:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(P([CH:20]([CH3:23])[C:21]#[N:22])(CC)=O)C.O>CO.C(O)(=O)C>[CH3:23][C:20](=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([CH:4]=[O:13])=[CH:6][CH:7]=1)[C:21]#[N:22]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCP(=O)(CC)C(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C#N)=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.5 %

Procedure:
360 g of a 30% solution of sodium methylate in methanol are added dropwise to a suspension of 134 g of terephthalaldehyde in 500 ml of methanol at 20°-25° C. 191 g of 2-(diethylphosphoryl)-propionitrile [prepared by the method of M. L. Raggio and D. S. Watt, J. Org. Chem. 41, 1873 (1976)] are now slowly added dropwise to the resulting reaction solution at 20°-25° C. The reaction mixture is stirred at room temperature for 6 hours and then poured onto 1,000 ml of water, and the aqueous suspension is adjusted to a pH value of 7 with acetic acid. The product which has precipitated is filtered off, dried and then chromatographed on silica gel. 35 g (20.5% of theory) of 2-methyl-3-(4-formylphenyl)-2-propenonitrile of the formula ##STR32## and then obtained in the form of colourless crystals having a melting point of 63°-64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0° C. was added methanesulfonyl chloride (20 ml, 258 mmol) dropwise. The mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2×100 ml). The organic layers were dried with MgSO4 and evaporated in vacuo. The residue was triturated and washed with methanol to give 1-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals.
Reaction SMILES: O[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: OCCSc1ccc(O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc(SCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 5.0 g 4-(2-hydroxy-ethylsulfanyl)-phenol (29 mmol) in 100 ml CH2,Cl2 were added at 0° C. 2.6 ml pyridine (32.3 mmol) and 2.34 ml SOCl2 (32.3 mmol), dissolved in 10 ml CH2Cl2. The reaction mixture was stirred for 1 h at r.t. and then quenched by the addition of water. The organic phase was separated and washed twice with sat. NaHCO3-solution. The combined aqueous phases were extracted with CH2Cl2 twice and the combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give 4.6 g product (24.3 mmol, 83%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 3-hydroxybenzoic acid as brown solid (41%). MS 424 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:15][CH3:16])=[O:4]
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](C)CCCc1ccccc1
Yield: 91 %

Procedure:
To a solution consisting of (S)-(+)-2-methyl-5-phenylpentanoic acid (20mb(i), 2.3 g, 12 mmol) in ethanol (200 mL) was added 4 drops of concentrated sulfuric acid. The stirring reaction mixture was brought to reflux overnight and was subsequently cooled and concentrated under vacuum. The residue was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to afford the title compound (2.4 g, 91%) as a clear oil; TLC Rf 0.66 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic; MS (ESI+) m/z 221.2 (M+H)+; 1H-NMR (CDCl3) δ 7.29-7.25 (m, 2H), 7.21-7.13 (m, 3H), 4.12 (q, J=6.96 Hz, 2H), 2.64-2.57 (m, 2H), 2.48-2.39 (m, 1H), 1.75-1.54 (m, 3H), 1.52-1.41 (m, 1H), 1.24 (t, J=7.14 Hz, 3H) 1.16-1.11 (m, 3H); [α]Tλ=α/cl, [α]21.9D=+0.101/(0.01506 g/1.5 ml)(0.5)=+20.12° (c=1, CHCl3).
Reaction SMILES: C([Li])CCC.[N:6]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][CH:28]2[C:32](=O)[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[O:29]2)=[CH:25][CH:24]=1.C1C[O:45]CC1>>[Cl:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][C:28]2([OH:45])[CH:32]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)=[CH:16][CH:17]=3)[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[O:29]2)=[CH:25][CH:24]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)OC(Cc1ccc(Cl)cc1)C2=O
Agent: [Li]CCCC
Product: COc1ccc2c(c1)OC(O)(Cc1ccc(Cl)cc1)C2c1ccc(OCCN2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (5.27 ml, 7.80 mM) in THF was added dropwise to a solution of 4-[2-piperidinoethoxy]phenyl bromide (1.45 g, 7.80 mmol) in THF (5 ml) at -78° C. After stirring for 30 minutes at -78° C., 2-(p-chlorobenzyl)-6-methoxy-3(2H)- benzofuranone (1.50 g, 5.20 mmol) in THF was added dropwise to the mixture at -78° C. The reaction mixture was stirred at -78° C. for 1 hour. It was warmed to room temperature. After stirring for 18 hours, it was quenched with saturated ammonium chloride and THF was evaporated off. The residue was dissolved in ethyl acetate (30 ml), washed with sodium chloride (2×20 ml), dried (anhydrous magnesium sulphate) and the solvent evaporated off to yield an oil which was purified by flash chromatography (eluent, dichloromethane:hexane:triethylamine=1:1:0.2), yielding a light brown oil of the tertiary alcohol, 2-(p-chlorobenzyl)-3-[p-(2-piperidinoethoxy)phenyl]- 6-methoxybenzofuranol (Rf =0.23) which gave a characteristic reddish stain with ammonium molybdate-ceric sulphate in 2M sulphuric acid spray. A solution of methanol (0.40 ml) saturated with dry hydrogen chloride gas was added to the tertiary alcohol dissolved in sodium-dried ether (40 ml). The reaction mixture was stirred at room temperature for 1/2 hour. A white precipitate was formed which was filtered and recrystallised from ethanol to give the hydrochloride salt of the title compound as a white crystalline solid. Yield (74 %); m.p. 133°-136° C.; 1H-NMR (CDCl3)δ 1:58-3.03 (bm, 10H, N(CH2CH2)2CH2), 3.42 (t, 2H, J 6.0 Hz, OCH2CH2N), 3.85 (s, 3H, OCH3), 4.10 (s, 2H, CH2 at C-2), 4.44 (t, 2H, J 6.0 Hz, OCH2CH2N), 6.81-7.44 (m, 11H, ArH); m/z (%) 477 (M+ -HCl, 8), 475 (M+ -HCl, 3), 364 (13), 98 (100). (Found: C, 64.89, H, 6.20, N, 2.49, Cl, 13.38. C29H30O3ClN.HCl.3/2H2O required C, 64.56, H, 6.35, N, 2.60, Cl, 13.14).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1OCC1CCOCC1
Temperature: 75 °C
Yield: 85.9 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (5.0 g, 32 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (8.6 g, 32 mmol) and K2CO3 (9.5 g, 68.8 mmol) in DMF (50 mL) was heated at 75° C. overnight. After cooled to room temperature, the mixture was poured into water. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (7.0 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39]>>[OH:40][CH:37]([CH2:38][OH:39])[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: NCC(O)CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)CO)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]4-carboxylic acid, and (2RS)-3-amino-1,2-propanediol, the title compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=426.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: [OH-]
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1g, 4.149 mmol) in THF (25 ml), 0.5 M solution of 9-BBN in THF (9.8 ml, 4.979 mmol) was added at 0° C. and stirred for 2 hrs at room temperature. The reaction mixture was cooled to 0° C., and then 2N NaOH (2.43 ml, 4.979 mmol) and 30% H2O2 (1.6 ml, 14.93 mmol) were added. The reaction mixture was stirred at room temperature for 4 hr and later it was poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, filtered and concentrated under vacuum. Purification by column chromatography offered 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (6 g, 56%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2].Cl[CH2:17][C:18]([CH3:20])=[CH2:19]>C(Cl)(Cl)Cl.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CCc1cc2c(O)ccc(C)c2[nH]c1=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C=C(C)COc1ccc(C)c2[nH]c(=O)c(CC)cc12
Yield: 75 %

Procedure:
Using 3-ethyl-5-hydroxy-8-methylcarbostyril (0.91 g, 4.87 mmol) and 3-chloro-2-methyl-1-propene (0.485 g, 5.36 mmol), the procedure of Reference Example 31 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 0.94 g of the title compound as pale brown crystals (75.1%).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:20])[C:13](=O)[C:14](OCC)=[O:15]>C(O)C(F)(F)F>[CH:12]([C:13]1[C:14](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:20])[CH3:11]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCOC(=O)C(=O)C(C)C
Solvent: OCC(F)(F)F
Product: CC(C)C1=N[C@H](c2ccccc2)COC1=O
Yield: 35.6 %

Procedure:
(R)-2-phenylglycinol (4) (2.00 g, 14.6 mmol, 1.0 equiv.) and ethyl 3-methyl-2-oxobutyrate (2.20 mL, 14.6 mmol. 1.0 equiv.) were refluxed in trifluoroethanol (30 mL) over activated 4 molecular sieves (7.0 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (4:1) to furnish the title compound as a colourless oil (1.13 g, 36%); v(max)(film) 2965 (C—H), 1740 (C═O), 1638 (C═N) cm−1; δH (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.90-4.83 (1H, m, PhCH), 4.55 (1H, dd, J 4.4 Hz, T 11.5 Hz, 6β-H), 4.13 (1H, dd/10.9 Hz, T 11.4 Hz, 6α-H), 3.32 (1H, m, CH(CH3)2), 1.25 (3H, d, J 5.0 Hz, CH(CH3)2×3), 1.22 (3H, d, /5.0 Hz, CH(CH3)2×3); δc (62.5 MHz, CDCl3) 167.7, 155.7, 137.5, 129.3, 128.6, 127.4, 71.7, 59.7, 32.7, 20.7, 19.9: m/z (CL, NH3), 220 (100%), 218 (MH+, 17%), 217 (27%), and 216 (25%); HRMS for C13H16NO2 requires 218.1177 found 218.1181. [α]D20 −207.5 (c 1.17 CHCl3).