Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)[C:29]#[N:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[C@H:38]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[C:26]([F:25])[CH:27]=1)#[N:30]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Yield: 54.6 %

Procedure:
Crude title compound was obtained as an oil in a similar manner to that described in Example 1(iii) above using 643.3 mg (1.80 mmol) of (2R,3R)-2-(2,3-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 7(vi) above], 361.8 mg (1.80 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]-benzonitrile [prepared as described in Example 1(ii) above] and 376.3 mg (1.98 mmol) of p-toluenesulfonic acid monohydrate. The oil was purified by chromatography on a silica gel (50 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 533.7 mg (yield 55%) of the title compound as a colorless non-crystalline solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH:21]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 35 mL of dimethylformamide was cooled to 0° C. and 7 mL of phosphorus oxychloride was added with stirring. The solution was allowed to warm to ambient temperature, and then a solution of 10.0 grams (0.0625 mole) of 2-phenylthiophene in 10 mL of dimethylformamide was added in one portion. The reaction mixture was heated to 80° C. where it stirred for 24 hours and then poured into 250 mL of an aqueous 10% sodium hydroxide solution containing 50 grams of ice. The resulting slurry was extracted with diethyl ether, and the extract was washed in succession with water, an aqueous solution saturated with sodium chloride, and water. The organic layer was concentrated under reduced pressure to a solid residue which was dried under high vacuum to yield 6.8 grams of 5-formyl-2-phenylthiophene.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([OH:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.[H-].[Na+].O>O1CCOCC1>[O:15]1[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][O:19][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=3)=[CH:11][C:12]=2[O:13][CH2:14]1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cncc(OCc2ccc3c(c2)OCO3)n1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and piperonyl alcohol (335 mg, 2.20 mmol) in dioxane (5 mL) was added NaH (55% in mineral oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred overnight. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying, Na2CO3, filtration and concentration in vacuo furnished an oil (0.54 g) that was used directly in the next step. HRMS m/z calcd for C12H9ClN2O3 (M)+ 264.0302, found 264.0303.
Reaction SMILES: C1([C:7]2[S:8](=[O:16])[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=2)C=CC=CC=1.C1(Br)C=CC=CC=1>>[N:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]=2[S:8](=[O:16])[CH:7]=1
Reactant: O=S1C(c2ccccc2)=Nc2cccnc21
Solvent: Brc1ccccc1
Product: O=S1C=Nc2cccnc21

Procedure:
In Scheme 6, Step A, a phenyl thiazolo-pyridinone of formula (22) is coupled with a phenyl bromide of formula (25a) or (25b) to give a thiazolo-pyridinone of formula (19) or formula (I). The reaction takes place in an inert solvent such as THF, or preferably dioxane with an inorganic base added, such as cesium carbonate. A copper catalyst is used, such as copper (I) iodide in the presence of sym-dimethylethylene diamine. The reaction is heated at a temperature of about 70° C. to the reflux temperature of the solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=O.C([OH:24])C.O1CCCC1>Cl.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]=1[CH:14]=[O:24]
Reactant: CCO
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)c1c[nH]c2ncccc12
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(F)c(-c2[nH]c3ncccc3c2C=O)c1

Procedure:
Compound 295 (130 mg, 0.46 mmol) was suspended in 6 M hydrochloric acid (10.0 mL) and ethanol (5.0 mL) unser an atmosphere of nitrogen. Tetrahydrofuran (5.0 mL) was added to completely dissolve the compound. Iron (229 mg) was added to the mixture and the reaction was heated to reflux for 2.5 hours. The reaction was cooled and concentrated under reduced pressure. The solid was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic portions were dried with anhydrous magnesium sulfate and adsorbed onto silica and purified by silica gel flash chromatography using 3% methanol:dichloromethane. The appropriate fractions were combined and concentrated to provide compound 296 as a pure white solid characterized by MS and 1H-NMR (33.9 mg, LRMS (ESI) [M+H+]+=256.1, [M−H+]−=254.1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[OH:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Reaction time: 3 h

Procedure:
A solution of 8.2 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester in 150 ml of methanol is mixed with 20 ml of 2 N sodium hydroxide solution and the mixture is boiled for 3 hours under reflux. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 100 ml of 2 N hydrochloric acid and 3 times 100 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate, treated with active charcoal and evaporated in vacuo. The evaporation residue, when crystallised from ethanol-petroleum ether, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in the form of yellow platelets of melting point 185°-7° C.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]2[CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][CH:12]1[N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH:9]2[CH:13]1[CH2:14][CH2:15][NH:8]2
Reactant: CCOC(=O)N1CC2C(CCN2Cc2ccccc2)C1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2NCCC2C1C

Procedure:
13 g (44.9 mmol) of ethyl 2-benzyl-6-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 150 ml of ethanol are hydrogenated on 2 g of palladium/active carbon (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off, and the filtrate is concentrated and distilled.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:16]1[CH:17]=[C:18]([Br:27])[C:19]2[O:23][C:22]([CH3:24])=[C:21]([CH3:25])[C:20]=2[CH:26]=1)[CH2:9][CH2:10]OS(C)(=O)=O)(=O)=O.C([N:30]([CH2:33][CH3:34])CC)C.C(Br)[C:36]1[CH:41]=[CH:40]C=[CH:38][CH:37]=1>O1CCCC1>[CH2:33]([N:30]1[CH2:10][CH2:9][CH:8]([C:16]2[CH:17]=[C:18]([Br:27])[C:19]3[O:23][C:22]([CH3:24])=[C:21]([CH3:25])[C:20]=3[CH:26]=2)[CH2:7][CH2:6]1)[C:34]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc2c(Br)cc(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)cc2c1C
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: Cc1oc2c(Br)cc(C3CCN(Cc4ccccc4)CC3)cc2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: (a) 3.08 g (0.01 mol) of 4-(2,3-dimethyl-7-bromo-5-benzofuranyl)-piperidine (c.f. Example 21) are dissolved in 100 ml of tetrahydrofuran, and 1.4 ml of triethylamine and then 1.30 ml (0.0105 mol) of benzyl bromide are added to the solution. A white precipitate thereby forms. The reaction mixture is stirred at room temperature for 31/2 hours. The solvent and excess triethylamine are then removed under a waterpump vacuum and the residue is added to water. The mixture is extracted 3 times with ether and the combined ether solutions are washed once with 2 N sodium hydroxide solution and then twice with water and once with saturated sodium chloride solution. The combined ether solutions are then dried over sodium sulfate and evaporated completely under a waterpump vacuum. 1-Benzyl-4-(2,3-dimethyl-7-bromo-5-benzofuranyl)-piperidine which melts at 86°-91°, is thereby obtained. In the thin layer chromatogram on silica gel using chloroform/5% methanol as the running agent, this product has an Rf value of 0.4. A sample recrystallised from ether/hexane has a melting point of 88°-91°. The product is of sufficient purity for further use.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:5](=[O:18])[CH:6]=[C:7]([N+:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[O:8][CH:9]=1.FC(F)(F)C(O)=[O:22].[Cl:26]C1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl-:26].[CH3:2][O:3][C:4]1[C:5](=[O:18])[CH:6]=[C:7]([N+:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:22])=[CH:14][CH:15]=2)[O:8][CH:9]=1
Reactant: COc1coc(-[n+]2ccc(SC)cc2)cc1=O
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Solvent: ClCCl
Product: COc1coc(-[n+]2ccc(S(C)=O)cc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of this pyridinium chloride (1 mmol) in dichloromethane (5 ml) at 0° C. was added sufficient trifluoroacetic acid to give a clear solution. A solution of m-chloroperoxybenzoic acid (1 mmol) in dichloromethane (2 ml) was added over about 1 minute and the mixture was allowed to warm to room temperature. After 30 minutes, further m-chloroperoxybenzoic acid (1 mmol) in dichloromethane (2 ml) was added. After a further 15 minutes the solvent was removed by evaporation under reduced pressure and the residue was triturated with ethyl acetate to give 1-(5-methoxypyran-4-on-2-yl)4-methylsulphinylpyridinium chloride as a crude gum (which was used in this form for the reaction of Example 32); (DMSO-d6) 3.00(s,3H); 3.65(s,3H); 6.0(s,2H); 6.70(s,1H); 8.15(s,1H); 8.55(d,2H); 9.42(d,2H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].O.[OH-].[Li+].C(OC(C)=O)(C)C>C1COCC1.O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester (27 mg, 51 umol) was dissolved in THF (0.2 ml). A solution of lithium hydroxide monohydrate (3 mg, 72 umol) in water (0.2 ml) was added and the mixture was stirred at ambient temperature for 14 h. Ice water/0.1 N aqueous HCl solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound compound (26 mg, 51 umol; quant.) as a yellow oil which was used in the next step without further purification. MS (ESI): m/z=514.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[C:22]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCCCCC
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (92 mg, 80%); 1H NMR δ (CDCl3): 8.47 (d, J=8.51 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.22 Hz, 1H), 2.53 (t, J=7.08 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); LCMS m/z: 229.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
1.90 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 15 ml of 1-methyl-2-pyrrolidone; 0.841 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected and recrystallized from ethyl acetate to yield 1.28 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: CC(=O)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 1-(3-bromo-4-hydroxy-phenyl)-ethanone (example B.a4) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5F)c4)c3c2)o1
Yield: 88 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 88%) was obtained as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:36])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[F:36][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexane carboxylate (150 mg) was dissolved in a mixed solvent of methanol (750 μL) and tetrahydrofuran (750 μL), and a 1 M aqueous sodium hydroxide solution (899 mL) was added thereto, followed by stirring at room temperature for 2 hours. After the completion of the reaction, 1 M hydrochloric acid was added thereto under ice-cooling until the reaction solution became weakly acidic, followed by stirring at 0° C. for 1 hour. The resulting solid was collected by filtration and washed with hexane to obtain trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexanecarboxylic acid (74 mg) as a white powder.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([CH2:22][CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:11]([F:21])[CH:10]=1)=[O:7])[CH3:4].[CH3:24][O:25][C:26](=[O:37])[CH:27](Br)[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:37])[CH:27]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:22][CH3:23])=[CH:10][C:11]=2[F:21])[CH2:20][CH2:19]1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Reactant: COC(=O)C(Br)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3ccc(C#N)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.4 %

Procedure:
A mixture of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide dihydrochloride (0.06 g, 0.16 mmol), bromo-(4-cyano-phenyl)-acetic acid methyl ester (0.05 g, 0.20 mmol), and anhydrous K2CO3 (0.08 g, 0.55 mmol) in DMF (5 mL) was stirred at rt for 20 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×30 mL). The combined organic phases were washed with water, dried (Na2SO4), and concentrated. The residue was purified (SiO2; acetone/DCM) to give the title compound (0.06 g, 79%). MS: mass calcd. for C26H31FN4O3, 466.24. m/z found, 467.4 [M+H]+. 1H NMR (CDCl3): 7.68-7.60 (m, 4H), 7.45 (dd, J=14.0, 2.4, 1H), 7.27 (br s, 1H), 7.13-7.08 (m, 1H), 6.85 (t, J=9.0, 1H), 4.14 (s, 1H), 3.72 (s, 3H), 3.10-3.03 (m, 4H), 2.69-2.56 (m, 4H), 2.04-1.95 (m, 1H), 1.74-1.62 (m, 2H), 1.59-1.48 (m, 2H), 0.92 (t, J=7.4, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[ClH:19].[CH3:1][C:2]1[C:6]([C:7]([Cl:19])=[O:8])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nn(-c2cccnc2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(-c2cccnc2)cc1C(=O)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.250 g (1.23 mmol) of 3-methyl-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid were initially charged in approx. 12 ml of dichloromethane, and admixed under argon with 2 drops of dimethylformamide. 0.453 g (3.56 mmol) of oxalyl chloride were added dropwise and, after the end of the addition, the mixture was stirred at room temperature for 1 h. The solution was concentrated and the residue was admixed with approx. 10 ml of toluene and concentrated. This gave a colourless solid which was converted further immediately.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:30])[C@H:12]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2]>C(O)C>[C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:30])[C@H:12]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NS(=O)(=O)c1ccc(N)cc1
Yield: 75.1 %

Procedure:
In ethanol (100 ml) was dissolved (2S,3S)-2-acetoxy-3-[[N-(4-nitrobenzenesulfonyl)-(L)-leucyl]amino]tetrahydrofuran (1.0 g) followed by addition of palladum-on-carbon (5%, 0.5 g) and the catalytic hydrogenation was carried out at ambient temperature and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide (2S,3S)-2-acetoxy-3-[[N-(4-aminobenzenesulfonyl)-(L)-leucyl]amino]tetrahydrofuran (chemical formula below) (0.7 g, 74%). As recrystallized from ethyl acetate-methonol-ether, colorless needles, m.p. 189°-190° C., optical rotation [α]D -59.2° (C=0.27, dimethyl sulfoxide) ##STR69##
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
nBuLi 1.6 M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-methylbenzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (20-45 μm) (eluent: DCM/EtOAc 96/4). The pure fractions were collected and the solvent was evaporated, yielding 13 g (38.3%) of 3-(3-chlorophenyl)-α-(4-methylphenyl)-2,1-benzisoxazole-5-methanol (intermediate 18).