Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])=[CH:4][C:3]=1[CH3:14].[C:15](=O)(OCC)[O:16]CC.C[O-].[Na+].[NH4+].[Cl-]>O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][C@H:10]([CH2:11][OH:12])[O:13][C:15]2=[O:16])=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc(NC[C@H](O)CO)ccc1Br
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1cc(N2C[C@H](CO)OC2=O)ccc1Br
Temperature: 130 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of (S)-3-(4-bromo-3-methyl-phenylamino)-propane-1,2-diol (202 mg, 0.777 mmol), diethyl carbonate (3 ml), sodium methoxide (28% in MeOH, 0.160 ml) and MeOH (4 ml) was stirred at 130° C. overnight. The reaction mixture was treated with saturated NH4Cl and H2O and extracted with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give (R)-3-(4-bromo-3-methyl-phenyl)-5-hydroxymethyl-oxazolidin-2-one (170 mg, 77%).
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: CC(C)(CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12

Procedure:
The titled compound was prepared from the product of example 5, step (e) (50 mg) and 2-amino-2-methyl-1-propanol (66 μl) using the method of example 5, step (f) and purified by preparative HPLC to yield a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.CC(O)=[O:39].O>C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:39]
Reactant: N#Cc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1ccc2c(c1)CCc1cc(C=O)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of the intermediate from step 3 (2.5 g, 9.5 mmol) in dry CH2Cl2 (320 mL), cooled at −78° C. and under N2 atmosphere, add DIBAL 10M in toluene (28.4 mmol). Allow the mixture to warm to room temperature and stir overnight. Cool the mixture to 0° C. and add AcOH/H2O. Stir at room temperature for 1 hour. Extract the aqueous layer with CH2Cl2 (×2). Combine the organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography (eluent: EtOAc/hexane 3/1) to obtain the title compound (1.75 g, 69%). 1H-NMR (MeOD, 300 MHz): 9.91 (s, 1H), 7.81-7.73 (m, 4H), 7.37-7.26 (m, 2H), 3.21 (m, 4). 13C-NMR (MeOD, 300 MHz): 193.2, 162.6, 160.3, 134.4, 133.8, 133.2, 131.9, 131.3, 130.6, 128.8, 123.3, 122.4, 32.9, 32.8.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([NH:14][S:15]([CH2:18][CH:19]2[CH2:22][N:21]([CH:23]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:20]2)(=[O:17])=[O:16])[CH:8]=1)C.O1CCCC1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(OCC)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:23]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[N:21]2[CH2:22][CH:19]([CH2:18][S:15]([NH:14][C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([F:13])[CH:10]=3)[C:6]([OH:38])=[O:5])(=[O:16])=[O:17])[CH2:20]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc(F)cc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: O=P([O-])([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
0.222 g of lithium hydroxide is added, in two parts, to a solution of 2.5 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid ethyl ester in a mixture comprising 34 cm3 of tetrahydrofuran and 9 cm3 of water, stirred under an argon atmosphere. The reaction medium is stirred at a temperature in the region of 20° C. for 24 hours. 100 cm3 of a saturated aqueous solution of sodium hydrogen phosphate are then added so as to bring the pH to 5. The aqueous phase is extracted four times with 200 cm3 of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered through sintered glass and then concentrated to dryness under reduced pressure, to give a foam which is taken up twice with 150 cm3 of ethyl ether. After concentration under reduced pressure, 2.3 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH2:30][CH3:31])=[C:28]([CH3:32])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:33])[C:5]=1[CH2:34][CH3:35].[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH:47]=O)[CH3:46])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH3:47])[CH:46]=[CH:8][C:7]1[C:6]([CH3:33])=[C:5]([CH2:34][CH3:35])[C:4]([O:3][CH3:2])=[C:29]([CH2:30][CH3:31])[C:28]=1[CH3:32])[CH3:37]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCc1c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(CC)c1OC
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(CC)c(OC)c(CC)c1C

Procedure:
4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce the 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)acid, m.p: 153°-154° C.
Reaction SMILES: [CH2:1]([O:17][C:18]([CH:21]1[CH2:23][O:22]1)([CH3:20])[CH3:19])[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].[OH-].[K+].CS(C)=[O:28]>O>[CH2:1]([O:17][C:18]([CH3:19])([CH3:20])[CH:21]([OH:28])[CH2:23][OH:22])[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: CCCCCCCCCCCCCCCCOC(C)(C)C1CO1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(C)(C)C(O)CO
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 35 g of [1-(hexadecyloxy)-1-methylethyl]oxirane, 30.07 g of potassium hydroxide, 70 ml of water and 450 ml of dimethyl sulfoxide was stirred at 110° C. for 8 hours, then cooled, poured into water and extracted with ether. The ether extract was dried and the solvent removed. The residue was chromatographed via HPLC, eluting with hexane:ethyl acetate (4:1). The lower Rf component was the desired compound, giving 18.2 g of an oil.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCCl>[CH3:31][N:9]([CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:12][CH:11]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(NCCc2ccccc2)cc1
Agent: C=O
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Product: CN(CCc1ccccc1)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A mixture of 4-phenethylamino-N-quinolin-3-yl-benzamide (0.213 g, 0.57 mmol), paraformaldehyde (0.17 g, 5.8 mmol) and tetramethylammonium triacetoxyborohydride (0.37 g, 1.42 mmol) in 1,2-dichloroethane (˜10 mL) was heated at reflux for 6 hours. The resultant solution was washed with saturated aqueous sodium bicarbonate and applied to a flash silica gel column. The product was eluted with ethyl acetate (40%) in hexanes to give the product, 0.2 g (92%). MS: m/z 382 (MH+). 1H NMR (DMSO-d6): 2.90 (t, 2 H), 2.93 (s, 3 H), 3.66 (t, 2 H), 6.73 (d, 2 H), 7.21-7.35 (m, 5 H), 7.53 (d of t, 1 H), 7.63 (d of t, 1 H), 7.80-7.87 (m, 3 H), 8.05 (m, 1 H), 8.85 (d, 1H) and 8.91 (d, 1 H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.CN(C=O)C.O>[CH2:10]([O:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C#N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)COCc1ccccc1
Temperature: -10 °C
Yield: 95 %

Procedure:
A solution of 60% sodium hydride (367.1 mg, 15.3 mmol) was washed with hexane (3×2 mL) and suspended in DMF (2 mL). The suspension was cooled to -10° C. and then a mixture of 3-hydroxy-2,2-dimethylpropanenitrile (1.4 g, 13.9 mmol) and DMF (8 mL) was added. The mixture was cooled 2.5 hour with stirring stirred at -10° to -5° C. and then benzyl bromide (1.7 mL, 13.9 mmol) was added. The mixture was cooled 2 hours with stirring at -5° C., diluted with water (10 mL) and extracted with diethyl ether (3×10 mL). The combined extracts were washed with water (1×10 mL) and brine (1×10 mL), dried (MgSO4) and concentrated to give 3-benzyloxy-2,2-dimethylpropanenitrile (2.5 g, 13.2 mmol).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:14][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (413 mg, 2.85 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (171 mg of 60% dispersion in oil, 4.27 mmol). The mixture was stirred for 40 min at room temperature. Methyl iodide (0.36 mL, 5.78 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (25 mL) and the mixture was extracted with ethyl acetate (3×25 mL). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2) gave 1-methyl-1H-indole-4-carbaldehyde (452 mg g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.08 (d, J=3.2 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[CH3:25][CH:24]([CH3:26])[C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)=[O:27]
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Triethylamine (976 mg, 9.66 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (1.00 g, 4.83 mmol) in dichloromethane (20 mL) at 0° C. and stirred for 30 min. Isobutyryl chloride (617 mg, 5.79 mmol) was then added and the mixture was warmed to ambient temperature and stirred for 4 h. the reaction mixture was quenched with ice-water and the organic layer separated. The aqueous layer was extracted with dichloromethane (5×5 mL) and the combined organic layers were washed water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one (1.20 g, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:48][CH3:49])[C:14]([NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:21][C@H:20]([O:32][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:19][CH2:18]2)=[O:15])[C@@H:6]1[OH:50]>C(O)(C(F)(F)F)=O.C1COCC1.O>[O:24]=[C:23]1[N:22]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:21][C@H:20]([O:32][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:19][CH2:18][C@@H:17]1[NH:16][C:14](=[O:15])[C@H:13]([O:48][CH3:49])[C@H:7]([OH:8])[C@@H:6]([OH:50])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:1])([CH3:51])[CH3:52]
Reactant: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@@H]2OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]2O)C(=O)N(Cc2cccnc2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C)C(=O)N(Cc2cccnc2)C1
Yield: 69 %

Procedure:
To a solution of TFA/THF/H2O (3/3/2) (30 mL) at 0° C. is added tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-yl ester (0.3 g, 0.42 mmol). After 30 min the reaction is evaporated under high vacuum, toluene is added (20 mL) and evaporated under high vacuum to remove remaining TFA. The residue is dissolved in CH2Cl2 at 0° C. and neutralized by adding NH4OH dropwise. The solution is concentrated and chromatographed on silica (98% CH2Cl2/2% CH3OH) to give 0.2 g (70.7%) of tetradecanoic acid (3R,6S)-7-oxo-1-pyridin-3-ylmethyl-6-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoylamino)-azepan-3-yl ester as a with solid. 1H NMR 300 MHz δ 8.62 (s, 2H), 8.17 (d, 1H), 7.67 (d, 1H), 7.33 (m, 1H), 5.83 (d, 1H), 5.42(dd, 1H), 4.69 (m, 1H), 4.54 (m, 1H), 4.33 (d, 1H), 4.32 (t, 1H), 3.83 (dd, 2H), 3.67 (d, 1H), 3.25 (s, 3H), 3.17 (m, 1H), 2.94 (d, 1H), 2.29 (t, 2H), 2.13 (m, 2H), 2.00 (m, 1H), 1.60 (m, 3H), 1.29 (m, 24H), 1.04 (s, 9H), 0.89 (t, 3H); MS (ESI) 690.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:5]=[C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:10]2=[O:26])[S:7][CH:8]=1)=[O:3].C(Cl)Cl>C(C(O)=O)(F)(F)F>[CH3:1][S:2]([C:4]1[N:5]=[C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]2=[O:26])[S:7][CH:8]=1)=[O:3]
Reactant: CS(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl {3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in CF3CO2H (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[CH:36]=[C:37]([O:47][CH3:48])[C:38]2[C:43]([CH:44]=1)=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][CH:39]=2>>[CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:36]=[C:37]([O:47][CH3:48])[C:38]3[C:43](=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][CH:39]=3)[CH:44]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCl)cc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCSCc3ccccc3)cc2)cc2c(OC)cccc12

Procedure:
(ee) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 123d)] with 3-chloromethyl-1,5-dimethoxy-naphthalene [Example 123r)] there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-(4,8-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow, viscous oil; MS: 658 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:18])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]([CH2:15][OH:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].CO[C:21](OC)([CH3:23])[CH3:22]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:17]=[C:6]([C:7]([N:9]2[C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:15][O:16][C:21]2([CH3:23])[CH3:22])=[O:8])[CH:5]=[N:4][C:3]=1[Cl:18]
Reactant: COC(C)(C)OC
Reactant: CC(C)C[C@H](CO)NC(=O)c1cnc(Cl)c(Br)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(Br)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
5-Bromo-6-chloro-N—((R)-1-hydroxymethyl-3-methyl-butyl)-nicotinamide (2.6 g, 8.0 mmol) was dissolved in 2,2-dimethoxypropane (25 mL, 200 mmol). To the solution was added camphorsulfonic acid (19 mg, 0.08 mmol) and the reaction mixture was stirred for 24 h at 60° C. After cooling drops of triethylamine were added and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 2.0 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=[O:9].[OH-].[K+]>CO>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CCCCC1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1CCCCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-methylcyclohexanecarboxylate (50 g, 0.295 mmole) was added to a solution of potassium hydroxide (27 g, 0.48 mole) in anhydrous methanol (300 ml). The mixture was stirred overnight at room temperature and then evaporated to dryness under reduced pressure. The residue was redissolved in water and the solution extracted with ether (3×200 ml), then acidified (pH<2), and re-extracted with ether (3×200 ml). The final, combined organic extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure to yield 2-methylcyclohexanecarboxylic acid. The crude product was converted to the acid chloride by treatment with excess thionyl chloride (100 ml) at room temperature for 30 minutes. The thionyl chloride was evaporated under reduced pressure and the residue distilled in vacuo to give 2-methylcyclohexanecarboxyl chloride (33 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]=[CH2:30])=[CH:23][CH:22]=2)([CH3:20])[CH2:12][CH2:13][C:14](OCC=C)=[O:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O1CCCC1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=2)([CH3:20])[CH2:12][CH2:13][CH2:14][OH:15])=[CH:22][CH:23]=1)[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)CCC(C)(c1ccc(OCC=C)cc1)c1ccc(OCC=C)cc1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(C(C)(CCCO)c2ccc(OCC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A 5-L flask equipped with a stirrer, thermometer, and nitrogen purging line was charged with 655 g of allyl 4,4-bis(4-allyloxyphenyl)pentanoate and 1,310 g of tetrahydrofuran in a nitrogen atmosphere. Under ice cooling, 605 g of 70 wt % toluene solution of sodium bis(2-methoxyethoxy)aluminumhydride was added dropwise to the solution, followed by stirring at room temperature for 3 hours. Under ice cooling, 1,526 g of 10 wt % hydrochloric acid aqueous solution was added dropwise to quench the reaction. To the reaction solution were added 250 g of ethyl acetate and 750 g of toluene. An organic layer was taken out and washed three times with 500 g of water. The solvent was distilled off from the organic layer, and the residue was dissolved in 1,000 g of toluene, which was sequentially washed with five 300-g portions of 4 wt % sodium hydroxide aqueous solution, 330 g of 2 wt % hydrochloric acid aqueous solution, and four 300-g portions of water. Thereafter, the solvent was distilled off from the organic layer, obtaining 555 g of 4,4-bis(4-allyloxyphenyl)pentanol in crude form.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of compound 2 (27.00 g, 0.118 mol) and hydrobromic acid (48% w/v, 350 ml) in glacial acetic acid (600 ml) was heated under reflux for 6 h. The cooled solution was poured into an ice/water mixture (11) and the resulting white precipitate was filtered off and washed with water until acid-free. Recrystallization, from glacial acetic acid afforded white crystals which were dried over potassium hydroxide in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]Br.C([O-])(O)=[O:15].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:15]
Reactant: FC(F)(F)c1cccc(Br)c1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Product: OCc1c(Br)cccc1C(F)(F)F
Yield: 98 %

Procedure:
To 1-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene (CXXVIII) (7.51 g, 23.62 mmol) was added an aqueous saturated solution of NaHCO3 (400 mL). The reaction mixture was vigorously stirred and refluxed overnight. The reaction mixture consisted of an upper aqueous layer and a bottom oily layer, which solidified in an ice bath. The water layer was decanted and the solid was dissolved in EtOAc, dried over anhydrous MgSO4, filtrated and evaporated to dryness to give (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) as an orange oil (5.49 g, 23.16 mmol, 98%). 1H NMR (DMSO-d6) δ ppm 4.67 (d, J=4 Hz, 2H), 5.23 (t, J=5 Hz, 1H), 7.43 (dd, J=8 Hz, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H); 19F NMR (DMSO-d6) δ ppm −56.33 (s, 3F); ESIMS found for C8H6BrF3O m/z 237.3 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])N(OC)C)=[N:16][CH:15]=1.[BH4-].[Na+]>C1COCC1.ClCCl>[CH3:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:25])=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)N(C)OC)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)nc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Diisobutylaluminum hydride (1.5 M solution in toluene, 9.82 mL) was added dropwise to a solution of 6-(methoxy-methyl-carbamoyl)-nicotinic acid methyl ester (1.1 g, 4.91 mmol) in THF (50 mL) at −78° C. over 10 minutes. The reaction mixture was stirred for 2 hours at −78° C., quenched with 5% HCl/ethanol and warmed to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was taken up in saturated K2CO3 and extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MeOH (15.0 mL) was added to the crude reaction mixture and cooled to 0° C. Sodium borohydride (0.280 g, 7.20 mmol) was added in two portions to the reaction mixture and stirred at 0° C. for 30 minutes. Additional sodium borohydride (0.136 g, 3.6 mmol) was added to the reaction mixture, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (75.0 mL), washed with water and saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield 6-hydroxymethyl-nicotinic acid methyl ester (0.400 g, 49% yield) as a solid.