Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([C@@H:21]([CH2:33][CH:34]=[CH2:35])[C:22](N1[C@@H](C(C)C)COC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:14]([C@H:21]([CH2:33][CH:34]=[CH2:35])[C:22]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: C=CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
5.63 ml (9.01 mmoles) of butyllithium (as a 1.6M hexane solution) were added, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.24 ml (12.0 mmoles) of benzyl alcohol in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred for 10 minutes, and then a solution of 1.81 g (6.01 mmoles) of 3-[2(R)-benzyl-4-pentenoyl]-4(S)-isopropyl-2-oxazolidinone (prepared by a procedure similar to that described in Preparation 17) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was then stirred for 30 minutes, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 10:1 by volume mixture of hexane and ethyl acetate as eluent), to give 1.58 g (yield 94%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH2:32]OS(C)(=O)=O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-:57].[F-].[K+]>C1COCC1>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH2:32][F:57])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COS(C)(=O)=O)C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: C1CCOC1
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CF)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A mixture of 165 (774 mg, 1.359 mmol), TBAF 1M in THF (2038 μl, 2.038 mmol) and potassium fluoride (79 mg, 1.359 mmol) in dry THF (25 ml) is stirred under nitrogen at r.t. for 2 hours, then at reflux for 1 hour 30 minutes. The mixture is partitioned between AcOEt and water, then the aqueous phase is extracted with AcOEt; the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give an orange oil which is purified by silica gel chromatography (eluent: DCM/MeOH 98/2) to give the title compound (185 mg, 27.6% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[S:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Sc1cc(C(=O)CCCCCl)ccc1O2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Sc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Temperature: 110 °C

Procedure:
A mixture of 35 g (0.08 mole) of 2,8-bis(5-chlorovaleryl)phenoxathiin, 2 g potassium iodide, 100 ml piperidine and 100 ml tetrahydrofuran is heated for 24 hours with stirring in a Parr bomb at 110° C. After cooling the mixture is filtered and washed with tetrahydrofuran, and the filtrate is evaporated to dryness. The residue is cooled and diluted with water. The mixture is extracted twice with ether, the ether extracts combined and filtered. The filtrate is evaporated to dryness, cooled and diluted with pentane followed by filtering off of the solid, washing with pentane and drying. The residue is recrystallized from isopropanol to yield 2,8-bis(5-piperidinovaleryl)phenoxathiin, M.P. 128.5°-129.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17]([CH:20]=O)[NH:16][C:15]=1[CH3:22])=[O:13])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1>C(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:28]2\[C:29](=[O:34])[NH:30][C:31]3[C:27]\2=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)[NH:16][C:15]=1[CH3:22])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of {3-[(5-Formyl-2,4-dimethyl-1H-pyrrole-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.200 g, 0.62 mmol) and 5-Fluoro-1,3-dihydro-indol-2-one (0.011 g, 0.62 mmol), pyrrolidine (0.003 ml) in ethanol (2 ml) was heated at 78° C. for 3 hours. The reaction was cooled to 0° C. and the resulting precipitate filtered, washed with cold ethanol. The product was suspended in ethanol (4 ml) and stirred at 72° C. for 30 minutes. The reaction was filtered, the precipitate dried in a vacuum oven at 40° C. to yield the desired compound as a solid (0.265 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 13.8 (s, 1H); 11.00 (s, 1H); 7.80 (m, 2H); 7.70 (m, 1H); 7.0 (m, 1H); 6.9 (m, 2H); 3.30 (q, 2H); 3.10 (q, 2H); 2.50 (dd, 6H) 1.60 (m, 2H)); 1.40 (s, 9H). LCMS: method D, RT=2.86 min, [M+Na+=479], and [M−Boc+Na+=379].
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].O=[CH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CO.C(OCC)C>[CH2:14]([N:13]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]-ethyl]dodecanamine (2.0 g, 4.2 mmol) in methanol (50 ml) was treated with sodium cyanoborohydride (0.55 g, 8.4 mmol) and ethyl 4-oxobutyrate (1.04 g, 8.4 mmol). The resulting mixture was stirred at 22° C. for 16 h, diluted with diethyl ether (350 ml), washed with water (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/AcOEt 9:1 to 6:1) to afford the title compound (1.8 g, 73%) as a liquid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1[CH:9]=[C:8]2[CH:10](O)[C:11]3[C:16]([O:17][C:7]2=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.O>C(O)(=O)C>[C:1]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:7]2[C:8]1=[CH:9][CH:4]=[CH:5][CH:6]=2)#[N:2]
Reactant: [C-]#N
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
17.5 g (0.268 mol) of potassium cyanide are added in portions to a solution, heated at 50° C., of 24.2g (0.122 mol) of xanthydrol in 420 ml of acetic acid. The reaction mixture is subsequently stirred at 60° C. for 2 hours and then cooled, poured onto 400 ml of water and extracted with ethyl acetate/hexane=1:1. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the mobile phase system hexane/ethyl acetate=19:1 and crystallization of the pure fractions from ether/petroleum ether gives 20.2 g (80%) of 9-cyano-xanthene, melting point 101° C. (compound (102), Table 1). The compounds (111), (112), (113), (114), (115), (116) and (117) are prepared analogously to Example 2 from the corresponding substituted xanthydrols and thioxanthydrols, such as, for example, 4-cyclohexyl-xanthydrol, 2-tert-butyl-xanthydrol, 2-nonyl-xanthydrol, 2-(α,α-dimethylbenzyl)-4-methyl-xanthydrol, 2-n-propoxy-xanthydrol, 2,4-diethylthioxanthydrol or 2-dodecyl-thioxanthydrol.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:6][C:16](=[O:17])[CH2:15][Cl:14])[CH3:5]
Reactant: CC(O)/C=C/I
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(/C=C/I)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
57.1 g (0.25 mol) of (2RS,3E)-4-iodo-3-buten-2-ol (86 percent, produced according to Example 2) was dissolved in 400 ml of toluene under argon, cooled to 0° C. and mixed with 2.4 g (20 mmol) of 4-(dimethylamino)pyridine. Then the mixture was cooled to -5° C., mixed with 11.07 g of triethylamine and cooled again to -10° C. After drop-by-drop addition of a first portion of 12.4 g of chloroacetyl chloride within 15 minutes (exothermic reaction) and another 0.5 hour of stirring, the same amounts of triethylamine and chloroacetyl chloride were instilled in succession. Again after 0.5 hour finally a third portion each was instilled, thus, altogether there were 33.21 g of triethylamine and 37.2 g chloroacetyl chloride added. Triethylammonium chloride precipitated during the addition of chloroacetyl chloride. After the final addition the mixture was stirred 1.5 hours more at -5° C. and then heated to room temperature. After another 3 hours the triethylammonium chloride was filtered off and washed with toluene. The filtrate was washed twice with 80 ml of 0.1M hydrochloric acid each. The aqueous phase was reextracted once with 50 ml of toluene. The combined organic phases were dried on magnesium sulfate, filtered and concentrated by evaporation on a rotary evaporator. The yield was 72.4 g (crude product, still contains some toluene). Further data on the product is:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:22]([OH:24])=[O:23])[C:16]=4[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[C:37](=[O:49])([O:45][CH:46](Cl)[CH3:47])[O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([O:38][C:37]([O:45][CH:46]([O:23][C:22]([C:17]2[C:16]3[CH:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]4[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]4)[N:13]([CH2:12][C:9]4[CH:8]=[C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)[O:11][N:10]=4)[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:24])[CH3:47])=[O:49])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: CC(C)N1CCC(NC(=O)c2cc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: CC(OC(=O)OC1CCCCC1)OC(=O)c1cccc2c1cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
can be prepared from 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-4-carboxylic acid and cyclohexyl 1-chloroethyl carbonate by the procedure described by K. Kubo et al., J. Med. Chem. 1993, 36, 2343-2349.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[S:12][CH2:13][CH2:14][C:15]([OH:17])=O.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:11]1[C:5]2[CH:6]=[C:7]([NH:10][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=[CH:9][C:4]=2[NH:3][C:15](=[O:17])[CH2:14][CH2:13][S:12]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(N)c(C(SCCC(=O)O)c2ccccc2Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)SCCC(=O)N2
Reaction time: 1.5 h

Procedure:
A solution of 138.2 g of 3-[(2,5-diaminophenyl)(2-chlorophenyl)methylthio]propionic acid dihydrochloride in 8.6 l of dry methylene chloride is treated at -5° with 94 ml of triethylamine. Subsequently, there are successively added thereto at 0° to 2° 129.1 ml of ethyl chloroformate and 188 ml of triethylamine. The cooling means is then removed and the mixture is stirred for a further 90 minutes. The mixture is evaporated and the residue is chromatographed on 1.44 kg of silica gel. Elution is carried out with chloroform in order to remove impurities and then with chloroform/ethanol (89.5:1.5). There is obtained ethyl 6-(2-chlorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine-8-carbamate of melting point 229°-231°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20]([CH2:22][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:24]Cl)=[O:21])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][N:23]([CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[S:24][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:28])[CH3:31]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCOC(=O)CN(CC(=O)OCC)SCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CN(CC(=O)OCC)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 30 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 5.1 g (0.02 mole) of bis(ethoxycarbonylmethyl)aminosulfenyl chloride obtained in Example 1 or 2, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 30 hours at 30° to 35° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product. Yield: 7.5 g (85.2%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](Cl)=[O:20])=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:20])=[CH:11]1
Reactant: OCCN1CCCCC1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(OCCN1CCCCC1)c1c[nH]c2ccccc12

Procedure:
1-Piperidineethanol was reacted with 1H-indole-3-carboxylic acid chloride using the method described in Example 1 a to afford 2-(1-piperidyl)ethyl 1H-indole-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[C:5](=[O:10])[N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccnc1O
Product: CCOC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Sodium hydride (4.08 g of a 60% dispersion in mineral oil, 0.10 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (50 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (13.0 g, 0.093 mole) was added in small portions over a 45-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. Ethyl bromoacetate (0.75 mL, 0.097 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford 15.7 g (75% yield) of the title compound as yellow solid. Rf=0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:20][CH:21]=[CH2:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[O:31]1[CH2:22][CH:21]1[CH2:20][CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: C=CCC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
A mixture of 12.92 g (43.6 mmole) of t-butyl 2-(1-naphthylmethyl)-4-pentenoate (prepared as described in Preparation 10), 11.29 g (65.4 mmole) of m-chloroperbenzoic acid and 100 ml of methylene chloride was stirred at room temperature for 24 hours. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 5: 95 by volume mixture of methanol and methylene chloride), to afford 4.57 g (33.6%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([C@@H:33]([CH3:35])[CH2:34][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1[C@@H](C)CNC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 8, intermediate a), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (R)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a yellow solid (100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[N:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:10]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19]
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 21 %

Procedure:
A mixture of 6.0 g (0.0195 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 6 ml of 1-piperazinecarboxylic acid, ethyl ester in 2 ml of toluene was heated in an oil bath at 135° for 3 hr, allowed to cool, diluted with ethyl acetate and toluene, washed with water, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 700 g of silica gel first with 2 l of ethyl acetate and then with 2 l each of the following solutions of methanol in ethyl acetate: 2%, 5%, 10%, and 20%. The eluant containing product, Rf (silica--ethyl acetate)=0.16, was concentrated to dryness. The residue was taken up in ether, filtered to remove dark flocculent material, and then treated with 1.2 ml of 85% phosphoric acid in 30 ml of ethanol. The gum which settled was washed with ether and acetone and then dissolved in 2-propanol and water. The pH of the solution was adjusted to 8 with ammonium hydroxide. The solution was then heated on the steambath, diluted with water to the cloud point and chilled to afford 1.7 g (21%) of the title compound, mp. 59°-60°.
Reaction SMILES: C[O-].[K+].[F:4][C:5]1[C:6]([O:34][C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)=[N:7][C:8]([O:23][C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:9]([F:22])[C:10]=1[O:11][C:12]1N(C)N=C(C(F)(F)F)C=1.O>CO>[CH3:40][N:39]1[C:35]([O:34][C:6]2[C:5]([F:4])=[C:10]([O:11][CH3:12])[C:9]([F:22])=[C:8]([O:23][C:24]3[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[N:7]=2)=[CH:36][C:37]([C:41]([F:44])([F:42])[F:43])=[N:38]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1nc(Oc2cc(C(F)(F)F)nn2C)c(F)c(Oc2cc(C(F)(F)F)nn2C)c1F
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(F)c(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A 25% solution of potassium methylate in dry methanol (4.4 ml, 15 mmol) is added to a solution of 3,5-difluoro-2,4,6-tris (1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (9.1 g, 15 mmol; see (a) above) in dry methanol (50 ml). After 30 min at ambient temperature the reaction is stopped by adding 2 ml of water. The solvent is removed under reduced pressure and pentane/ethyl acetate (1/1 by volume) is added to the residue. After filtration through a bed of silica gel the filtrate is washed with a 2 N sodium hydroxide solution. After drying and filtration of the organic layer, the solvents are removed and the residue is washed with diisopropyl ether. One obtains colorless crystals (5.3 g 75% yield), m.p. 83° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:37][N:36]=[N:35][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.160 g, 0.362 mmol) was reacted with NaN3 (0.118 g, 1.808 mmol) and NH4Cl (0.097 g, 1.808 mmol) in DMF (5 ml) to give the product (0.136 g, 0.280 mmol, 77%) as a white solid, mp 190-192° C. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 4.10 (s, 2H), 5.43 (s, 2H), 5.49 (s, 2H), 6.99 (d, J=7.0 Hz, 2H), 7.09-7.13 (m, 3H), 7.20-7.30 (m, 8H), 7.40 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.9 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H); IR (solid) 3030, 2905, 2850, 1605, 1520, 1480, 1440, 1360, 1270, and 1250 cm−1; [ESI(−)], m/z 484 (M−H)−; Anal. Calcd. for C31H27N5O: C, 76.88; H, 5.60; N, 14.42; Found: C, 76.71; H, 5.57; N, 14.37.