Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of ethyl 4-bromo-2-chlorobenzoate (1.00 g, 3.79 mmol), tributyl(vinyl)tin (2.41 g, 7.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (439 mg, 0.38 mmol) in DMF (15 mL) was stirred at 100° C. for 1 hr. After cooling, the mixture was diluted with water (150 mL), and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=20:1) to give the title compound (820 mg, 100%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3(OCC[O:29]3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:26][CH2:27][C:28](=[O:29])[CH2:33][CH2:34]2)[CH2:21][CH2:20]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
The compound (5) (26.35 g), formic acid (10 ml) and toluene (100 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 8 hours, and cooled slowly to room temperature. Water (200 ml) and toluene (200 ml) were added and mixed thereto. Subsequently, the mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 22.39 g of 4′-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-bicyclohexyl-4-one (6). The yield based on the compound (5) was 93.7%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]2[S:16][C:17]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:19]=2)=[O:12])=[CH:20][CH:21]=1
Reactant: O=C(NCc1cccs1)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 62.8 %

Procedure:
Chlorosulfonic acid (20.1 ml, 198 mmol) in CH2Cl2 (80 ml) was added dropwise to a solution of (63a) (10 g, 40 mmol) in CH2Cl2 (500 ml) at −80° C. The mixture was allowed to reach room temperature in 5 h. The reaction mixture was poured on ice and quickly extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was evaporated to dryness which afforded 8.8 g (63%) of desired sulfonyl chloride (63b); mp 133-35° C., 1H NMR (DMSO-d6) δ 9.21 (t, J=6.4 Hz, 1H), 7.87 (d, J=8.67 Hz, 2H), 7.53 (d, J=8.67 Hz, 2H), 6.91 (d, J=3.39 Hz, 1H), 6.77 (d, J=3.39 Hz, 1H), 4.53 (d, J=3.77 Hz, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7](I)[CH:6]=[N:5]1.[C:10]([C:12]1[CH:13]=[C:14]([C:18]2[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)#[CH:11]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:24][C:19]1[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]#[C:11][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][F:1])[CH:8]=3)[CH:13]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: FCCn1cc(I)cn1
Reactant: C#Cc1cccc(-c2cccnc2F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: FCCn1cc(C#Cc2cccc(-c3cccnc3F)c2)cn1
Temperature: 65 °C
Yield: 75.6 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole (148 mg, 0.62 mmol) in DMF (5.0 mL) is added dichlorobis(triphenylphosphine)palladium (16 mg, 0.022 mmol), copper iodide (3 mg, 0.015 mmol), TEA (0.53 mL, 3.8 mmol) and 3-(3-ethynylphenyl)-2-fluoropyridine (150 mg, 0.76 mmol). The reaction mixture is heated at 65° C. for 3 h, cooled and quenched with H2O. The aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 30/70) to afford the title compound (145 mg, 76%) as an oil. MS (+) ES: 310 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CO>[CH2:1]([NH:17][CH:19]([CH3:20])[C:18]([O:22][CH3:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCCCCCNC(C)C(=O)OC
Reaction time: 8 h

Procedure:
66.4 g of hexadecylamine are dissolved in 250 ml of methanol. 27 ml of methyl acrylate are added and the mixture is left to stand overnight. After removal of the solvent by distillation the residue is recrystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:21])=[CH:9][CH:10]=1.CC1C=CC(S(O[CH2:34][C:35]([C:38]#[N:39])([CH3:37])[CH3:36])(=O)=O)=CC=1.[CH3:40][C:41]1[N:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([C:44]3[CH:45]=[N:46][C:41]([CH3:40])=[CH:42][CH:43]=3)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:21][CH2:37][C:35]([CH3:34])([CH3:36])[C:38]#[N:39])=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C#N)cc1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(OCC(C)(C)C#N)ccc2O3)cn1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA13 above, but using (S)-2-amino-2′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (prepared as described in Method BB40 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid), 2-cyano-2-methylpropyl 4-methylbenzenesulfonate, and (6-methylpyridin-3-yl)boronic acid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.Br[CH2:39][C:40]1[C:48]2[N:47]=[C:46]([C:49]([O:51][CH3:52])=[O:50])[N:45](COCC[Si](C)(C)C)[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]2[O:1][CH2:39][C:40]2[C:48]3[NH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[CH:13][CH:12]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COC(=O)c1nc2c(CBr)cccc2n1COCC[Si](C)(C)C
Product: COC(=O)c1nc2cccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c2[nH]1

Procedure:
Analogously to Method D, 1.58 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 1.43 g of methyl 4-bromomethyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole-2-carboxylate are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=29.5 (II).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#N)=[C:4]([Cl:11])[CH:3]=1.[OH2:12].[OH-:13].[K+]>C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]([OH:13])=[O:12])=[C:4]([Cl:11])[CH:3]=1
Reactant: O
Reactant: N#CCc1ccc(Br)cc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(Br)cc1Cl
Temperature: 75 °C
Reaction time: 13 h

Procedure:
To 4-bromo-2-chlorobenzyl cyanide (383 g) of Reference Example 14 were added water (908 mL), ethanol (6812 mL) and 85% aqueous potassium hydroxide solution (549 g), and the mixture was stirred at an inside temperature of 75° C. for 13 hr. The mixture was concentrated, and diisopropyl ether (4500 mL) and water were added. The aqueous layer was neutralized with 1M hydrochloric acid, and partitioned and extracted with ethyl acetate. The organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residual crude crystals were recrystallized from a mixed solvent of diisopropyl ether and hexane to give the title compound (240 g) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:21]=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:24][C:25]=3[O:26][CH3:27])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc(-c2ccccc2)cc1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cc(-c3ccccc3)ccc2OC)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-4-methoxy-biphenyl as in Example 1 d. 1H-NMR (400 MHz, d8-DMSO) δ 8.85 (s, 1H), 8.55 (br, 1H), 7.70 (d, 1H), 7.60 (d, 2H), 7.46 (t, 2H), 7.38 (dd, 1H), 7.33 (t, 1H), 7.16 (d, 1H), 7.02 (dd, 1H), 6.98 (d, 1H), 6.72 (br, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 426.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12]C(C#N)=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([OH:22])(=[O:21])[CH3:20].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:20]([C:19]([OH:22])=[O:21])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To 92 mg of 3-(3-fluorophenyl)-1H-6-indazolecarbonitrile were sequentially added 1 ml of glacial acetic acid, 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 6 hours. After standing to cool, 35 ml of ethyl acetate was added to the reaction mixture. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 94 mg of the title compound as bright yellow crystals.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=2[N+:25]([O-:27])=[O:26])=[CH:11][CH:10]=1>CC(O)=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([I:8])=[C:19]([F:24])[C:18]=2[N+:25]([O-:27])=[O:26])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(NCc2ccc(-c3ccccc3)cc2)cc(F)c(I)c1F
Temperature: 70 °C

Procedure:
NIS (7.9 g, 35.1 mmol) was added to a solution of N-(biphenyl-4-ylmethyl)-3,5-difluoro-2-nitroaniline (10.86 g, 31.9 mmol) in AcOH (150 mL). After heating at 70° C. for 2 h, the reaction mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was separated, washed with brine, dried (Na2SO3) and concentrated. The resulting solid was recrystallized from DCM/hexanes afforded the desired product as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2cccc(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
A mixture of intermediate (9) (1.32 g) and phosphorous oxychloride (5 ml) was refluxed for 2 hours, cooled, poured onto ice and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried, concentrated, yielding 2-methyl-4-chloro-8-(2′,4′-dichlorophenyl)quinoline (intermediate 1) (1.31 mg. 300 MHz 1H NMR (CDCl3): δ 2.58 (s, 3H), 7.34 (s, 2H), 7.39 (s,1H), 7.53 (s, 1H), 7.63-7.65 (m, 2H), 8.26 (dd,1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:29][C@@H:28]3[CH3:41])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.O>C1COCC1.CO>[CH2:34]([N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:42])[C@@H:28]([CH3:41])[CH2:29]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)O)CC3)c2)[C@@H](C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (365 mg, Example 122) in THF (4 mL) was added 1N NaOH solution (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3 mL). The resulting solution was concentrated under vacuum to give crude product, which was subjected to reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% H2O to 100% MeOH) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid (228 mg; 66%). 1H NMR (300 MHz, CD3OD) δ 7.49 (m, 2H), 7.38 (m, 6H), 7.28 (m, 1H), 7.18 (dd, J=8.0, 8.0 Hz, 1H), 6.73 (m, 2H), 6.67 (s, 1H), 5.26 (s, 1H), 4.48 (m, 1H), 4.27 (d, J=13.0 Hz, 1H), 3.66 (m, 2H), 3.13 (m, 1H), 3.01 (m, 2H), 2.85 (m, 2H), 2.68 (m, 1H), 2.49 (m, 2H), 2.13 (dd, J=10.5, 10.5 Hz, 1H), 2.00 (m, 1H), 1.82 (m, 1H), 1.65 (m, 2H), 1.28 (d, J=6.5 Hz, 3H), 1.17 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([S:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][C@H:12]1[CH2:36][NH2:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:40]=1[CH:41]=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([SH:16])[CH2:13][C@H:12]1[CH2:36][NH:37][CH2:41][C:40]1[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:39]=1[F:38])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1cc(F)ccc1F
Product: O=C(OCc1ccccc1)N1C[C@H](S)C[C@H]1CNCc1cc(F)ccc1F

Procedure:
(2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester and 2,5-difluorobenzaldehyde and subsequent cleavage of the trityl protecting group analogously to reductive amination and deprotection gave (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid benzyl ester as colorless oil, MS: 393 (MH+).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4](OCC)=[O:5])[CH2:2]1.[NH3:12]>>[NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4]([NH2:12])=[O:5])[CH2:2]1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: N
Product: NC(=O)[C@@H]1CCCNC1
Reaction time: 72 h

Procedure:
To 14.7 g (93.5 mmol) of (R)-ethyl nipecotate in a 300 ml round-bottomed flask were added 200 ml of concentrated aqueous ammonia at room temperature, and the mixture was allowed to stand for 3 days at room temperature. The reaction mixture was distilled off at a water bath temperature of lower than 40° C. to obtain (R)-nipecotamide as a pale yellow oil. To this were added 100 ml of methylene chloride and 50 ml of ethanol at room temperature, and 15.6 ml (1.2 eg.) of triethylamine were added while cooling with ice. To this reaction mixture were gradually added dropwise 11.1 ml (1 eg.) of benzyl bromide under cooling with ice. After dropwise addition, the mixture was stirred for 10 minutes under cooling with ice and further for 4 hours after returned to room temperature, which was allowed to stand overnight. The reaction mixture was distilled off under reduced pressure and the residue obtained was dissolved into 200 ml of methylene chloride, which was washed with 1N sodium hydroxide and saturated aqueous solution of sodium chloride in turn. The aqueous layer was extracted with methylene chloride (50 ml×3) and, after washed with saturated aqueous solution of sodium chloride, these were combined with previous organic layer and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure and the residue thus obtained was recrystallized to obtain 8.61 g (yield 42 %) of title compound.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CC[O:23][CH2:22]C1.ClC(OCC(C)C)=O.[CH3:34][O:35][C:36](=[O:44])[CH2:37][CH:38]([NH2:43])[CH2:39][CH2:40]OC.CN(C1C=CC=CN=1)C>CN(C=O)C>[CH3:34][O:35][C:36](=[O:44])[CH2:37][CH:38]([NH:43][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH:39]([O:23][CH3:22])[CH3:40]
Reactant: COCCC(N)CC(=O)OC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)CCC(=O)Nc1ccc(C=NN)cc1)C(C)OC
Reaction time: 0.08 h
Yield: 40 %

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (5.0 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.7 g, 18.5 mmol) and isobutyl chloroformate (2.8 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Methyl-5-methoxy-3-aminovalerate (3.0 g, 18.5 mmol) was added followed by dimethylaminopyridine. After 1 h, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 2.8 g of a white solid: 1H NMR (d6 -DMSO) δ1.74 (m, 2H), 2.4 (m, 4H), 2.6 (m, 2H), 3.16 (s, 3H), 3.33 (m, 2H), 3.56 (s, 3H), 4.12 (m, 1H), 7.78 (s, 4H), 7.81 (d, 1H, J=8.5 Hz), 9.02 (bs, 2H), 9.15 (bs, 2H), 10.40 (s, 1H); MS (FAB) m/z 379.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:2]1([NH:1][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 9.3 g (0.10 Mole) of aniline (IIIa) and 8.3 g (0.10 Mole) pyridine in 100 mL CH2Cl2 at 0° C. under an argon atmosphere was added a solution of 15.5 g (0.10 Mole) phenylacetyl chloride (IIa) in 25 mL CH2Cl2 over a 30 minute period. The solution was allowed to warm to 25° C. over 1 hour and was quenched into 200 mL H2O. The aqueous layer was washed with two 100 mL portions of CH2Cl2 and the combined organic layers were washed with two 100 mL portions of 10% HCl solution The organic extract was dried over MgSO4, filtered, concentrated, and crystallized from CH2Cl2 /hexane to give 20.07 g (95%) of colorless needles. mp. 115°-116° C. δ1H-NMR (CDCl3) ppm 7.0-7.6 (m,11 H); 3.67 (S,2 H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)[CH3:2].[BH4-].[Na+].C(O)(=O)C.O>O1CCCC1>[CH2:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CNC(C)=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Reaction time: 6 h

Procedure:
Ethyl trans-{4-[(acetylamino)methyl]cyclohexyl}acetate (1.19 g, 4.93 mmol) was dissolved in tetrahydrofuran (25 mL), the solution was added with sodium borohydride (932 mg, 24.66 mmol), the mixture was added dropwise with a solution of acetic acid (1.48 g, 24.66 mmol) in tetrahydrofuran (25 mL) over 1 hour under reflux by heating, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was added dropwise with water with stirring under ice cooling, and the reaction was thereby quenched. The reaction mixture was made alkaline with 2 M aqueous sodium hydroxide, and extracted with ethyl acetate, and the organic layer was successively washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting crude product of ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate was dissolved in ethanol (20 mL), the solution was added with 4 M hydrochloric acid in ethyl acetate (6 mL), and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was successively washed with 2 M sodium hydroxide, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the objective ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate as pale brown oil (1.12 g, 99%).