Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)Cc3ccccc3)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N,N-dimethylacetamide (15 mL) was added 2-phenylacetyl chloride (0.32 g, 2.0 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.33 g, yield 46%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[C:9]1([C:15](Br)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C(C)=CC=CC=1C.ClC1C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][CH:4]([O:8][C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(O)CCCl
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: Clc1ccccc1
Product: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30.0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95° C. for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, ν max. 1600, 1030, and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[C:18](B(O)O)=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2>C1COCC1>[S:14]1[C:18]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cc2ccccc2s1
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20 g), benzo[b]thiophene-2-boronic acid (16 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10 g), and Pd(tBu3P)2 (0.417 g). The solution was immediately heated to 60° C. and aged for 1.5 h. (Note: The HPLC assay at this point routinely indicated complete consumption of 5-bromo-2,4-dimethoxybenzaldehyde, <0.5 area % of benzo[b]thiophene-2-boronic acid along with 0.5 area % of an unknown (0.55 RRT). These impurities are removed during crystallization.) Upon completion, as determined by HPLC, the reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was batch concentrated and solvent switched to 33 wt % 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde in THF in preparation for crystallization. (Note: The internal temperature during batch concentration should be kept above 45° C. to prevent premature crystallization.) The resulting THF solution of 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde was then charged with heptane (20 mL) and slowly cooled to ambient temperature. Crystallization was then completed with the slow addition of heptane (175 mL) and cooling to 4° C. After aging for 1 h, the batch was filtered and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40° C., 20 inHg) affording 23.74 g (97% yield) of desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde as a light orange crystalline solid, m.p. 134–136° C. HPLC assay of this solid indicated >99.9 LCAP. 1H-NMR identical as above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[CH2:11][CH:10]([C:12](OCC)=[O:13])[CH2:9][C:8]1=[O:17].[BH4-].[Na+].[BH4-].C(O)(=O)C>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:8]1=[O:17]
Reactant: CCOC(=O)C1CC(=O)N(Cc2ccc(OC)c(OC)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2CC(CO)CC2=O)cc1OC
Reaction time: 0.33 h

Procedure:
8.0 g of 1-(3,4-dimethoxybenzyl)-4-ethoxycarbonyl-pyrrolidin-2-one were dissolved in 100 ml of methanol. Over a period of 20 minutes, at 0°-10° C., a solution of 2.8 g of sodium borohydride in 30 ml of water was added dropwise, while mechanically stirring, and the mixture was stirred for 5 hours more at 0°-10° C. The excess borohydride was then carefully decomposed by the addition of glacial acetic acid up to a pH of 5 and until the development of gas had ceased, and the methanol was distilled off in vacuo. Some water was added, and the reaction product was taken up in methylene chloride. The methylene chloride phase was then washed with water, dried and evaporated. The residue was chromatographed on silica gel (eluant: methylene chloride/methanol 98:2). Finally, 4.8 g (62% of theory) of the title compound were obtained from the eluate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CC[CH2:17][C:16]1=O.O.ICC>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([CH2:16][CH3:17])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCI
Solvent: c1ccccc1
Solvent: O
Product: CCC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 100 °C

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25.1 mmol), pyrollidone (5 mL) and p-toluenesulfonic acid (25 mg) in benzene (100 mL) was heated at reflux for 16 h with azeotropic distillation of water. The resulting enamine solution was cooled to rt and concentrated. The crude enamine was dissolved in acetonitrile (50 mL); iodoethane (4.67 g, 30.1 mmol.) was added and the mixture was heated at 100° C. for 0.5 h, cooled to rt and concentrated. The mixture was dissolved in ethyl acetate (200 mL), washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The extract was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by silica gel chromatography (80% hexanes/20% ethyl acetate) to afford 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (680 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:13]2)[O:9][N:8]=1.O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:13]2)[O:9][N:8]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: COCCO
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 684 mg (8.99 mmol) of ethylene glycol monomethyl ether in 8.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.90 ml (0.90 mmol; 1 M solution in n-hexane) of phosphazene P4 base. Subsequently, 200 mg (0.450 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was admixed with water, filtered and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 89.8 mg (41% of theory).
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38][C:37](F)=[CH:36]C=2)[CH2:23][CH2:22]1.C1(/C=C/B2OC(C)(C)C(C)(C)O2)CC1>>[CH:38]1(/[CH:39]=[CH:34]/[C:28]2[C:29]([NH2:33])=[N:30][CH:31]=[N:32][C:27]=2[N:24]2[CH2:23][CH2:22][CH:21]([C:6]3[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:41])[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:19])([F:18])[F:20])[CH:11]=4)[N:7]=3)[CH2:26][CH2:25]2)[CH2:37][CH2:36]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Agent: CC1(C)OB(/C=C/C2CC2)OC1(C)C
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2/C=C/C2CC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine using (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4-fluorophenyl boronic acid. LC-MS: (M+1=544, obsd.=544).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:16])[CH2:14]C)=[CH:7][C:5]=2[N:6]=1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:16])[CH2:14][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC[C@H](O)COc1ccc2sc(C)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Reaction time: 8 h

Procedure:
A solution of (2S)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed- to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=O)[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]=3[CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:34].[OH-].[NH4+]>C(O)C>[C:23]([CH2:22][C:20]1[N:19]([CH:28]2[CH2:30][CH2:29]2)[C:18]2[CH:31]=[C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[C:15]([F:32])=[CH:16][C:17]=2[N:21]=1)(=[O:25])[NH2:34]
Reactant: CCOC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(N)=O)n3C2CC2)CC1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
Ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate (4.5 g, 10 mmol) is dissolved in ethanol (100 ml) and treated with ammonium chloride (5.35 g, 100 mmol) and 25 percent ammonium hydroxide solution (50 ml). The suspension obtained is stirred at 50° for 18 hours and thereafter evaporated under reduced pressure. The residue is suspended in ethyl acetate (150 ml) and the insoluble ammonium chloride is filtered off. The filtrate is concentrated to a volume of 50 ml and then chromatographed on silica gel (eluent: ethyl acetate/methanol 9:1). The product is recrystallized from ethyl acetate/n-hexane. There are obtained 2.22 g (53%) of tert-butyl 4-[2-(carbamoylmethyl)-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate with a m.p. of 219°-220°.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(C)(C)C>C(O)C>[CH3:9][C:10]1[CH:5]=[CH:6][CH:7]=[C:10]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)(C)c1ccncc1
Solvent: CCO
Product: Cc1cccc2cccnc12

Procedure:
The reactor effluent vapor was directed through a condenser and the recovered liquid was weighed at convenient times. Typically, the liquid obtained from the first 20 minutes of the run was discarded. Three one-hour test periods were then taken with the mid-point of each period representing 0.8, 1.8 and 2.8 hours-on-stream (HOS). The reaction crudes were homogenized with ethanol before adding 4-tert-butylpyridine as a standard. The samples were then analyzed by GC using standard techniques. The reported 8-methylquinoline selectivity and yield are based on the moles of ortho-toluidine. The purity of the 8-methylquinoline is based on the 8-methylquinoline/2,8-dimethylquinoline (2,8 -Me2Q) weight ratio.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=2)[CH2:4][CH2:3]1.FC1C=C([Mg]Br)C=C(F)C=1F.C1(=O)CCC(=O)CC1.[Cl:36][C:37](Cl)([Cl:41])[C:38](Cl)=O>O>[F:16][C:10]1[CH:9]=[C:8]([CH:5]2[CH2:6][CH2:7][C:2]3([C:37]([Cl:41])([Cl:36])[CH2:38][CH2:1]3)[CH2:3][CH2:4]2)[CH:13]=[C:12]([F:14])[C:11]=1[F:15]
Reactant: C=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Fc1cc([Mg]Br)cc(F)c1F
Agent: O=C1CCC(=O)CC1
Solvent: O
Product: Fc1cc(C2CCC3(CC2)CCC3(Cl)Cl)cc(F)c1F

Procedure:
0.1 mol of 4-methylene-1-(3,4,5-trifluorophenyl)-cyclohexane (obtainable by reacting 3,4,5-trifluorophenylmagnesium bromide with the monoethylene ketal of cyclohexane-1,4-dione followed by elimination of water, hydrogenation and ketal cleavage) and 0.1 mol of trichloroacetyl chloride are reacted in accordance with Example 1B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cccc(F)c2F)CCN(C(=O)OC(C)(C)C)C1
Yield: 55.3 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(2,3-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (8.12 g, 27.1 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 1.63 g, 40.7 mmol), iodomethane (3.38 mL, 54.3 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (4.7 g, 55%). MS m/z (rel. intensity, 70 eV) 240 (bp), 237 (72), 183 (81), 171 (82), 57 (87).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:17][CH2:18][CH3:19])=[C:9]([CH:16]=1)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>Cl.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:17][CH2:18][CH3:19])=[C:9]([CH:16]=1)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCCc1ccc(OCOC)cc1OCC(=O)OC
Agent: Cl
Solvent: CO
Product: CCCc1ccc(O)cc1OCC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of methyl 2-(5-methoxymethoxy-2-propylphenoxy)acetate (1.60 g) and 10% hydrogen chloride-methanol (50 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give methyl 2-(5-hydroxy-2-propylphenoxy)acetate as a colorless oil (1.17 g, 87%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([F:28])[F:27])=[CH:22][N:21]=2)[CH:16]=1)=[O:14])(C)(C)C.O>O1CCCC1>[F:28][CH:26]([F:27])[C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([C:13]([OH:14])=[O:12])=[CH:16]2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccn(-c2ccc(C(F)F)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2ccc(C(F)F)cn2)c1
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (13.6 ml) was added at room temperature to a solution of 1-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid tert-butyl ester (1.01 g) in tetrahydrofuran (3.4 ml) and stirred at the same temperature for an hour. After completion of the reaction, water was added to the reaction solution and the precipitated solid was collected by filtration to give the titled compound (790 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]([CH3:24])=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:13]=2)[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:15]([CH3:24])=[C:14]([S:25](=[O:27])(=[O:26])[NH2:28])[CH:13]=2)[CH:6]=1)[O:11][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of compound 14 (202 mg, 0.5 mmol) in DMF (20 mL) were added Cs2CO3 (325 mg, 1 mmol) and methyl 4-bromobutanoate (99 mg, 0.55 mmol). The reaction mixture was stirred for 4 h at 40° C., then water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 15 (176 mg, 70%).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC=CC=1.[OH-].[Na+]>CN1CCCC1=O>[C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C1CCCCCCC1
Reaction time: 2 h
Yield: 71.1 %

Procedure:
10.6 g of stabilized IBX prepared as in Example 10 are suspended in 60 ml of N-methylpyrrolidone at 20° C., and 2 g of cyclooctanol are added dropwise while maintaining the temperature at from 20° C. to 25° C. After 2 hours, agitation, the medium is poured into a mixture of 130 ml of water and 80 ml of toluene; the pH of the aqueous phase is brought to approximately 7 by the addition of aqueous NaOH and the organic phase, after separation of the insoluble material formed and of the aqueous phase, is concentrated to give 1.4 g of pure cyclooctanone (NMR and GPC)
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[OH:28])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: C[C@@H](N)[C@@H](O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccc(Cl)cc1

Procedure:
2-(Benzo[1,2,5]-thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.17 min. MS (ESI−): mass calcd. for C22H18Cl2N4O4S2, 536.01; m/z found, 535/537 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.64 (s, 1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.72 (d, J=2.0, 1H), 7.38-7.33 (m, 2H), 7.33-7.28 (m, 2H), 7.24 (d, J=8.5, 1H), 6.95 (dd, J=8.4, 2.0, 1H), 6.22 (br d, J=8.1, 1H), 4.97 (d, J=2.9, 1H), 4.42 (ddq, J=8.3, 7.0, 2.9, 1H), 1.04 (d, J=6.9, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[N:25]1[N:26]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[N:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:5]2[CH2:4][CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[N:26]3[N:27]=[CH:28][CH:29]=[N:25]3)[CH2:6]2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: COc1ccc(COC2CC(N)C(NC(=O)OC(C)(C)C)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COC2CC(NC(=O)OC(C)(C)C)C(NC(=O)c3ccccc3-n3nccn3)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl N-{2-amino-4-[(4-methoxyphenyl)methoxy]cyclopentyl}-carbamate (1.71 g, 5.08 mmol) in dry DMF (17 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 1.06 g, 5.59 mmol), HATU (2.90 g, 7.62 mmol) and triethylamine (2.13 ml, 15.25 mmol). The reaction was stirred at room temperature for 72 hours then partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.