Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]=[C:18]=[O:19].FC1C=CC=C(N=C=O)C=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([NH:17][C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[F:9])=[O:19])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(F)c(N=C=O)c1
Agent: O=C=Nc1cccc(F)c1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Br)cn2)c1

Procedure:
The desired product was prepared by substituting 2-amino-5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 324.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[N:58]([CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])=[O:65])=[C:59]=[O:60]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:59](=[O:60])[NH:58][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:70])([CH3:72])[CH3:71])=[O:65])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: C[Si](C)(C)CCOC(=O)CCCN=C=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)NCCCC(=O)OCC[Si](C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 2 h

Procedure:
A solution of the FR-900506 substance (310 mg), 2-trimethylsilylethyl 4-isocyanatobutyrate (350 mg) and triethylamine (6 drops) in anhydrous benzene (4 ml) was heated at 50° C. with stirring for 2 hours. The reaction mixture was allowed to stand at room temperature overnight. The mixture was concentrated to dryness under reduced processure to leave a residue, which was chromatographed on silica gel in chloroform. Elution was carried out with chloroform to give 17-allyl-12-[2-[3-methoxy-4-{3-(2-trimethylsilylethoxycarbonyl)propylcarbamoyloxy}cyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone (99 mg). This product was treated with tetra(n-butyl)ammonium fluoride (0.12 m mole) in tetrahydrofuran (2.5 ml) at room temperature for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to leave a residue, which was purified with preparative thin layer chromatography on silica gel. Elution with a mixture of chloroform and methanol (5:1) gave 17-allyl-12-[2-{4-(3-carboxypropylcarbamoyloxy)-3-methoxycyclohexyl}-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (18.1 mg).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.ClCCCl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=CC1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: c1ccc2c(c1)nnn2-c1ccnc(NC2CCC(CN3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanecarbaldehyde (39 mg), morpholine (14 μL) and acetic acid (2 drops) in DCE (2 mL) was stirred at RT for 2 hours; sodium triacetoxyborohydride was then added. The resulting mixture was stirred for 3 hours at RT. Water was added; the organic layer was separated and washed 3 times with water. The aqueous layer was re-extracted with DCM. The combined organic extracts were dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure and the residue was purified via preparative TLC to afford 13.2 mg of (4-benzotriazol-1-yl-pyrimidin-2-yl)-(4-morpholin-4-ylmethyl-cyclohexyl)-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (1 H, d, J=8.31 Hz), 8.36-8.46 (1 H, bd), 8.12 (1 H, d, J=8.31 Hz), 7.55-7.69 (1 H, m), 7.40-7.52 (2H, m), 5.22-5.64 (1 H, m), 3.49-3.96 (5 H, m), 2.12-2.56 (6 H, m), 1.46-2.04 (5 H, m), 1.03-1.46 (4 H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([OH:24])[CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[CH3:5].Br[C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[O:24][C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1)[CH3:5]
Reactant: CS(=O)(=O)c1cnc(Br)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91 %

Procedure:
3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (340 mg, 1.03 mmol) synthesized in Example (107c) was dissolved in acetonitrile (10 mL), and 2-bromo-5-(methylsulfonyl)pyrazine (300 mg, 1.27 mmol) synthesized in Example (107d) and cesium carbonate (850 mg, 2.61 mmol) were added at room temperature, followed by stirring at room temperature for 4.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate=100%) to afford the desired compound (456 mg, yield 91%) as a white solid.
Reaction SMILES: BrCCCC1C=CC=[C:7]2[C:8]([NH:10][C:11](=O)C=12)=O.[CH3:16][C:17]1[N:18]=[CH:19][O:20][C:21]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26].[N+:27](C=C(SC)SC)([O-:29])=[O:28]>>[CH3:8][NH2:10].[N+:27]([CH:7]=[C:8]([NH:10][CH3:11])[NH:26][CH2:25][CH2:24][S:23][CH2:22][C:21]1[O:20][CH:19]=[N:18][C:17]=1[CH3:16])([O-:29])=[O:28]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cc1ncoc1CSCCN
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Product: CN
Product: CNC(=C[N+](=O)[O-])NCCSCc1ocnc1C

Procedure:
Phthalimidoethanethiol (2 g) was added portionwise with stirring to a solution of sodium ethoxide (prepared from 0.23 g of sodium) in ethanol (20 ml) at 0° under a nitrogen atmosphere. After stirring at 0° for a further 21/2 hours, the resulting yellow solution was cooled with an ice-salt bath and a solution of 4-methyl-5-chloromethyloxazole (0.86 g) in ethanol (5 ml) was added dropwise over 10 minutes. After addition the mixture was stirred at room temperature overnight, then acidified with ethanolic hydrogen chloride and evaporated to dryness. Addition of water precipitated unreacted phthalimidoethanethiol (0.6 g) which was removed by filtration. The filtrate was concentrated and basified with aqueous sodium bicarbonate solution to furnish a white precipitate which, on recrystallisation from aqueous ethanol, gave 4-methyl-5-[(2-phthalimidoethyl)thiomethyl]oxazole (0.75 g). A stirred mixture of this phthalimido derivative (0.62 g) in aqueous hydrobromic acid (40 ml. 18%) was heated under reflux overnight. After cooling to 0°, the resulting clear solution was filtered and the filtrate evaporated to dryness. Recrystallisation of the residue from ethanol gave 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole dihydrobromide (0.52 g). (ii) Reacting 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole with 1-nitro-2,2-bis-methylthioethylene and then with methylamine by the procedure of Example 8 gives the title product.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([OH:24])=O)=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.[F:30][C:31]([F:50])([F:49])[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=3[CH:41]=[N:40]2)=[N:36][CH:37]=1>CC(N(C)C)=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([NH:48][C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[N:40][N:39]5[CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:50])([F:49])[F:30])=[CH:37][N:36]=4)=[O:24])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1
Reactant: Nc1cccc2c1cnn2Cc1ccc(C(F)(F)F)cn1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4ccc(C(F)(F)F)cn4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium chloride (0.0653 g, 0.188 mmol) in dry DMA (2.0 mL) at 0° C. was added POCl3 (0.0345 mL, 0.376 mmol) and the mixture was stirred at 0° C. for 30 minutes. 1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g, 0.188 mmol) was added as a DMA solution (1.0 mL) and the mixture was gradually warmed to ambient temperature and stirred overnight. The mixture was concentrated under vacuum and 2M LiOH (2.5 mL) was added. The mixture was stirred for 10 minutes. The mixture was diluted with CHCl3 (20 mL) and with saturated aqueous NaHCO3 and the layers were mixed and separated. The aqueous phase was further extracted with CHCl3 and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by preparative TLC (15% MeOH/CH2C12 adding 1% 7N NH3/MeOH) to provide 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid (0.028 g). The solid was dissolved in MeOH (2.0 mL) and HCl (1.88 mL, 3.76 mmol, 2.0M in Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and finally with hexanes and dried under vacuum to provide the title compound (0.032 g, 24%). MS (ES+APCI) m/z=579 (M+H-3HCl).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:49])([CH3:48])[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)(=O)=[O:39]>>[CH3:35][Si:36]([CH3:49])([CH3:48])[N:37]=[S:38]([Cl:1])([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)c1ccc(F)cc1

Procedure:
The reactants used in the general procedure were hexachloroethane (0.0953 mol, 23.02 g), triphenylphosphine (0.0963 mol, 25.51 g), triethylamine (0.0991 mol, 12.5 ml), and a mixture of N-mono- and N,N-bis(trimethylsilyl sulfonamides (3c) and (5c) containing about 89.5% monosilylsulfonamide (3c) (0.0881 mol, 21.76 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[F:57][C:58]1[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:59]=1[CH2:60][CH:61]1[CH2:66][N:65]([CH3:67])[CH2:64][CH:63]([NH2:68])[CH2:62]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:68][CH:63]3[CH2:62][CH:61]([CH2:60][C:59]4[C:69]([F:73])=[CH:70][CH:71]=[CH:72][C:58]=4[F:57])[CH2:66][N:65]([CH3:67])[CH2:64]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1
Reactant: CN1CC(N)CC(Cc2c(F)cccc2F)C1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(Cc2c(F)cccc2F)CC(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g, 2.07 mmol) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of 5-(2,6-difluorobenzyl)-1-methylpiperidin-3-amine (511 mg, 2.13 mmol) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was progressed to the next step without purification.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14]1.N12CCCN=C1CCCCC2.Cl.CN(C=[O:38])C>C(N(CC)CC)C.C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[C:2]([OH:38])([CH3:12])[O:20][C:19](=[O:21])[C:18]=2[C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(O)OC(=O)C(c2ccsc2)=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3.08 g of 2-bromo-4′-chloropropiophenone, 1.79 g of 3-thiopheneacetic acid, acetonitrile and 10 ml of DMF was added 1.53 g of triethylamine, and the mixture was stirred for 2 hours at room temperature. The resultant mixture was cooled to 0° C., and 4.60 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise into this, and the mixture was stirred for 3 hours at room temperature. Then, the reaction mixture was stirred for 11 hours at room temperature while blowing air into the reaction mixture. To the reaction mixture was added 200 ml of 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 3.98 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-furanone.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Reaction time: 18 h
Yield: 71.5 %

Procedure:
A solution of benzoyl chloride (2.30 ml, 20.0 mmol) in tetrahydrofuran (25 ml) was added dropwise to a solution of 4-aminophenol (2.18 g, 20.0 mmol) and triethylamine (10 ml) in tetrahydrofuran (75 ml) at ambient temperature and the reaction allowed to stir for a further 18 hours. The reaction was poured into water and the solid material which formed was collected by suction filtration. Recrystallisation from ethyl acetate/isohexane (1:1), followed by solvent evaporation in vacuo, yielded N-benzoyl 4-hydroxyaniline (3.05 g, 72% yield) as a white solid:
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:14])[CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>ClCCl>[Br:1][CH:5]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:4](=[O:3])[CH3:14]
Reactant: CC(=O)Cc1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)C(Br)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Bromine (5.28 g) in dichloromethane (80 ml) was added dropwise at 25° C. over 1 hour to 4-(2-oxopropyl) benzonitrile in dichloromethane (85 ml). The reaction mixture was stirred for 1/2 hour after the addition was complete. The mixture was washed with brine (50 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a pale red oil (7.55 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([CH2:48][O:49][CH2:50][C@H:51](O)[CH2:52][O:53]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>N1C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:48][O:49][CH2:50][C@H:51]2[CH2:52][O:53]2)[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H]3CO3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in example 1) (h)-(l), (R)-3-[(3S,4R,5R)-4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol was treated with di-tert-butyl-dicarbonate in dioxane/water in the presence of sodium hydrogencarbonate to yield the (3S,4R,5R))-3-[(2R)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester. Subsequent mono-tosylation of the aforementioned diol by toluene-4-sulfochloride in pyridine led to the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which after treatment with NaOH in DMSO yielded (3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester. Further reaction of the epoxide with sodium methylate in a mixture of N,N-dimethylformamide and methanol gave the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxymethyl]-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which was finally deprotected by treatment with hydrochloric acid in methanol to yield the (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol as a colorless foam; MS: 660 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2s1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2s1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-benzothiazolyl)amino) ethoxy]benzaldehyde (1.9 g) and 2,4-thiazolidinedione (0.8 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered and the filtered solid was dried to give the title compound (mp 219° C.).
Reaction SMILES: O.[OH-].[K+].Br[C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[N:11][OH:12].COCCO>[Cu].ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:6]3[S:7][CH:8]=[CH:9][C:5]=3[O:12][N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=NO)c2sccc2Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: COCCO
Product: COc1ccc(-c2noc3ccsc23)cc1
Temperature: 60 °C
Yield: 64 %

Procedure:
Add to a solution of water (20 mL) and potassium hydroxide (7.2 g, 0.128 mol), (3-bromothiophen-2-yl)-(4-methoxyphenyl)-methanone oxime (19.6 g, 0.0628 mol) and 2-methoxyethanol (200 mL). Stir the solution and then treat under nitrogen with copper powder (1.0 g, 0.0157 g-atom 0.25 equiv.). Heat the stirred mixture to 60° C. for four hours, and then pour into a mixture of water (800 mL) and dichloromethane (450 mL). Add hydrochloric acid (10 mL, 6N), filter the mixture, and wash the copper with dichloromethane and water. Separate the filtrate, and wash the organic phase twice with water, dry (Na2SO4), filter and evaporate. Dissolve the residue in dichloromethane and chromatograph the compound over alumina, eluted with 4:1 heptane:dichloromethane, and then with 3:1 heptane:dichloromethane. Evaporate the fractions, triturate the residue with heptane, and collect the solid and dry at 60° C. to give the title compound (9.3 g, 64% yield), m.p. 93-94° C.