Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C@@H:39]([OH:44])[CH2:40][N:41]([CH3:43])[CH3:42])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][N:41]([CH3:42])[CH2:40][C@H:39]([OH:44])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:34]1
Reactant: CN(C)C[C@H](O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@H](O)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), (S)-1-(3-amino-pyrazol-1-yl)-3-dimethylamino-propan-2-ol (158 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((S)-3-dimethylamino-2-hydroxy-propyl)-1H-pyrazol-3-yl]-amide as an off white powder (63.2 mg, 43.6%). HRMS (ES m/z Calcd. for C31H36Cl2F2N6O2+H [(M+H)+]: 633.2318. found: 633.2313.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(CC(=O)O)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(F)c1

Procedure:
(3-Fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) is dissolved in MeOH (100 mL). To it is added concentrated H2SO4 (5 mL) and the solution is warmed to reflux for 2 h. At that point, the solution is evaporated to dryness and taken up in EtOAc. The solution is washed with saturated aqueous NaHCO3, dried (Na2SO4) and evaporated to give (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (cas# 588-14-7) as a yellow oil. MS (ESI) m/z 199.3 (M+H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([OH:16])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[Cl:1][S:2]([C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:16])=[O:15])=[CH:10][CH:11]=1)(=[O:5])=[O:3]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 41 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To neat chlorosulfonic acid (5.3 ml, 80 mmol) at 0-5° C. temperature slowly cinnamic acid (41) (1.47 g, 10 mmol) was added. As the reaction proceeded hydrogen chloride gas evolved. The reaction mixture was stirred successively at 0° C. for 1 hour, at ambient temperature for 2 hours and at 40-42° C. for 2 hours. The dark, viscous syrup was poured onto ice, the precipitated solid was filtered and washed with water. The title compound (0.5 g, 20%) as a white solid was obtained. 1H NMR (DMSO-d6, HMDSO), δ: 6.55 (1H, d, J=16 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])C.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH3:19][N:10]1[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=2[C:8]2[CH2:7][CH:6]([C:4]([NH:23][CH2:21][CH3:22])=[O:5])[CH2:20][C:9]1=2
Reactant: CCN
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Solvent: CCO
Product: CCNC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 90 °C
Reaction time: 120 h
Yield: 47.7 %

Procedure:
In a 50 ml sealed tube was dissolved 1,2,3,4-tetrahydro-4-methyl-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (2.8 g, 0.01 mole)in 25 ml of ethanol. To this was added an aqueous solution of ethylamine (70% solution, 5 ml, 0.075 mole). After stirring at 90° C. for five days, the mixture was concentrated to a brown solid, (~3 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined to yield 1.3 g of a white solid, m.p. 162°-3° C. A sample of this material (0.5 g) was recrystallized from ethyl acetate/ether (1:10) to give the product as white crystals, 0.4 g, m.p. 163°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Br)C.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].Cl>C1COCC1.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[Cl:13])[OH:17]
Reactant: O=Cc1ccccc1Cl
Reactant: Clc1ccccc1I
Agent: CC[Mg]Br
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1ccccc1Cl
Temperature: -12.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, 1-chloro-2-iodobenzene (40 ml, 0.33 mol) was dissolved in THF (360 ml) and cooled to −10 to −15° C. Within 30 min, a 1M solution of ethyl magnesium bromide (344 ml, 0.34 mol) in TBME was added at this temperature. The mixture was stirred at −10 to −15° C. and the reaction was followed by HPLC. After the reaction was complete (15 to 30 min), a solution of 2-chloro benzaldehyde (40.7 ml, 0.36 mol) in TBME (160 ml) was added at −10 to −15° C. within 30 min and the reaction was followed by HPLC. After complete reaction (15 to 30 min), the mixture was hydrolized with dilute HCl until all solids were dissolved at a final temperature of 20 to 25° C. The organic phase was washed with water (2×40 ml) and evaporated to dryness at a temperature of 45 to 50° C. The residue was co-evaporated twice with heptane (80 ml each) and crystallized from hot n-heptane (280 ml at 95 to 100° C.). The product was isolated by filtration after stirring for 1 h at 0 to 5° C. and washed with cold n-heptane (40 ml at 0 to 5° C.). The product was dried under vacuum at 50° C. to constant weight. Yield: 73.4 g (88%). Assay (HPLC): 100% pure vs. standard.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>CS(C)=O.C(OCC)(=O)C>[N:1]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:5])([F:15])[F:16])=[CH:14][CH:13]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide (2.30 g, 35.4 mmol) was added to a solution of 4-(trifluoromethyl)benzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethyl sulfoxide (15 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the title compound. The crude product was used in the next step without further characterization.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:16]([Br:17])=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[C:7]([Cl:18])[CH:6]=1)[CH:2]=[CH2:3].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)[CH3:20].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:4][C:5]1[C:16]([Br:17])=[CH:15][C:8]([C:9]([C:24]2[CH:25]=[CH:26][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:10])=[C:7]([Cl:18])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(C(=O)N(C)OC)cc1Br
Reactant: CCc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cc(Cl)c(C(=O)c2ccc(CC)cc2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
To solution of Weinreb amide 22 (4.5 g, 13.4 mmol) in THF (100 mL) was added 4-ethylphenylmagnesium bromide (0.5 M in THF, 50.8 mL, 26.9 mmol) at 0° C. The reaction mixture was warmed up to r.t. slowly and stirred at r.t. for 15 hours. To the reaction mixture was added aqueous saturated NH4Cl solution (100 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane (100 mL) and stirred at r.t. for 30 min. The solid was precipitated, filtered, washed with hexane (50 mL) and dried under high vacuum to obtain the title product (4.30 g, 73%).
Reaction SMILES: O[CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:5]=2[CH:4]1[CH2:16][CH2:17][CH3:18].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:33]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:19][CH2:2][CH:3]2[O:7][C:6]3[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:5]=3[CH:4]2[CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=1)[CH2:27][CH2:28][C:29](=[O:30])[O:31][CH3:32]
Reactant: CCCC1c2c(ccc(C(C)=O)c2O)OC1CO
Reactant: COC(=O)CCC(=O)c1ccc(S)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 15 (1.4 g, 5.59 mmoles, 1 equivalent) and methyl 4-mercapto-γ-oxobenzenebutanoate (1.4 g) was taken up in 30 ml THF. This mixture was added dropwise to a 0° solution of 1.2 equivalent DEAD, (1.1 ml) and 1.2 equivalent (1.76 g) in 40 ml THF. The reaction mixture was stirred cold 30 minutes, then warmed to room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, purified on a column of silica gel using 10/1 toluene/ethyl acetate to afford the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])(=[O:3])[CH3:2].CC(=CC)C.P([O-])([O-])(O)=[O:21].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]([OH:21])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCOc1ccccc1C=O
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)OCOc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
21.79 g (112.2 mmol) of 2-acetoxymethoxy-benzaldehyde and 100 ml (900 mmol) of 2-methyl-2-butene are diluted in 400 ml of tert-butanol. A solution containing 41 g (337 mmol) of sodium hydrogen phosphate and 35 g (393 mmol) of sodium chlorite in 100 ml of water is added dropwise to the reaction mixture, which is stirred for 2 hours at room temperature. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The white solid obtained is precipitated in heptane at 0° C. The precipitate is filtered, then rinsed with heptane and dried. 14.8 g of 2-acetoxymethoxy-benzoic acid is obtained in the form of white powder at a yield of 63%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Nc1c(F)cccc1F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.9 %

Procedure:
2,6-Diacetylpyridine (4.04 g, 24.7 mmol) and 2,6-difluoroaniline (3.2 g, 24.7 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 5 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. From the resulting mixture of 2,6-diacetylpyridine, monoimine, and diimine. Most of the 2,6-diacetylpyridine was removed by sublimation in vacuo at 80-90° C. The residue contained based on 1H-NMR data 0.35 mmol 2,6-diacetylpyridine , 1.28 mmol diimine and 5.46 mmol monoimine. This mixture was reacted with 162 mg (1.28 mmol) FeCl2 in 10 ml THF to remove the diimine. After stirring for 16 h at room temperature, the solvent was removed in vacuo. Toluene (50 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed in vacuo. Crystallisation from ethanol yielded 1.35 g of 2-[1-(2,6-difluorophenylimino)ethyl]-6-acetylpyridine (18) (19.8%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[S:16]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[O:15][C:21]([C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)=[N:23][N:24]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: NNC(=O)c1ccsc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccsc2)o1
Yield: 38 %

Procedure:
As described for example 121, 5-methyl-3-phenylisoxazole-4-carboxylic acid (357 mg, 1.76 mmol) using thiophene-3-carboxylic acid hydrazide instead of thiophene-2-carboxylic acid hydrazide was converted to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 207 mg, 38%) which was obtained as a yellow semisolid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [Cu][C:2]#[N:3].[CH2:4]1[O:22][C:7]2([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)[O:6][CH2:5]1>CN(C=O)C.O>[CH2:4]1[O:22][C:7]2([CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]([C:2]#[N:3])=[CH:19][CH:20]=3)=[O:14])[CH2:11][CH2:12]2)[O:6][CH2:5]1
Reactant: O=C(c1ccc(Br)nc1)N1CCC2(CC1)OCCO2
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cn1
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A stirred suspension of copper (I) cyanide (0.66 g, 7.4 mmol) and 1-(6-bromo-3-pyridyl)carbonyl-4-piperidone ethylene ketal (2.2 g, 6.7 mmol, prepared as in Example V from 6-bromo-3-pyridinecarboxylic acid) in DMF (30 ml) was heated at 150° C. for 3 h. The mixture was cooled, diluted with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated. Purification by flash chromatography on silica, eluting with 20% ethyl acetate/hexane, gave a white crystalline solid (0.96 g, 52%), m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][NH:22][C:23]1([CH3:30])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:22]([CH3:21])[C:23]3([CH3:30])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CNC1(C)CCS(=O)(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)C1(C)CCS(=O)(=O)C1
Reaction time: 23 h
Yield: 27.7 %

Procedure:
A mixture of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (210 mg, 0.71 mmol), methyl-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)amine (116 mg, 0.71 mmol), sodium triacetoxyborohydride (301 mg, 1.42 mmol) and 4 Å powdered molecular sieves (280 mg) in DCE (15 mL) was stirred for 23 h. The reaction mixture was filtered through Celite® and the filtrate loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a pale yellow solid (87 mg, 28%). LCMS (method H): RT 2.01 min [M+H]+ 443.2
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:14])=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:2].Cl.[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.CCN=C=NCCCN(C)C>O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[N:14]=[C:16]1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCNc1ccc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A mixture of 1.0 g of N1-ethyl-4-trifluoromethylbenzene-1,2-diamine, 1.05 g of isonicotinoyl chloride hydrochloride and 15 ml of pyridine was stirred for 4 hours at 60° C. Then, 0.94 g of WSC was added, and the mixture was stirred for 8 hours at 80° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, then, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 1-ethyl-2-(pyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 221).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25](O)=[O:26])[CH:23]=1>>[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:26])[CH:23]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(C(=O)OC)c3)CC2)ccc1Cl
Yield: 92 %

Procedure:
The title compound (80 mg, 92%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with isophthalic acid monomethyl ester. MS: 431.6 (MH+).
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](N(CC)CC)[CH3:12].C(OC(Cl)=O)C>ClCCl>[CH2:11]([O:10][PH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[CH3:12]
Reactant: O=[PH](O)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCO[PH](=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13.34 g of benzylphosphinic acid are dissolved in 150 ml of dichloromethane, the solution is cooled to 5°, and 8.64 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 5° again, and 9.3 g of chloroformic acid ethyl ester are added dropwise within a period of 30 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. The mixture is allowed to warm to room temperature and is then stirred at room temperature for 3 hours, taken up in dichloromethane and washed with water, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding benzylphosphinic acid ethyl ester having a boiling point of 96°-100° (5×10-6 bar).
Reaction SMILES: Cl.[F:2][C:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([F:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[N:20]1([C:29]2[O:30][C:31]([CH2:41][CH2:42][C:43](O)=[O:44])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[N:33]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:20]1([C:29]2[O:30][C:31]([CH2:41][CH2:42][C:43]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([P:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:19])([F:2])[F:11])=[CH:5][CH:6]=3)=[O:44])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[N:33]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(NC(=O)CCc2oc(-n3cnc4ccccc43)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of the obtained hydrochloride (100 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (30 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (22 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (29 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (1 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-{4-[(diethylphosphono)(difluoro)methyl]phenyl}propionamide (51.4 mg, yield 50%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 155–156° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][Si](C(C)C)(C(C)C)C(C)C)=[C:21]([CH:37]([C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[O:38][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=2)[O:7][C@@H:6]1[CH2:57][O:58][C:59](=[O:61])[CH3:60])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[C:21]([CH:37]([C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[OH:38])[CH:20]=2)[O:7][C@@H:6]1[CH2:57][O:58][C:59](=[O:61])[CH3:60])(=[O:3])[CH3:2]
Reactant: CCc1ccc(C(O[Si](C(C)C)(C(C)C)C(C)C)c2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2CO)cc1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Step 4) To a solution of compound 149 (870 mg, 0.98 mmol) in tetrahydrofuran (10.0 mL) was slowly added tetrabutylammonium fluoride solution (5.0 mL, 1.0M in tetrahydrofuran) at 0° C. and the reaction mixture was stirred for 2 h. The resulting mixture was quenched with sat. NH4Cl solution, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-((4-ethylphenyl)(hydroxy)methyl)-4-(hydroxymethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (150, 500 mg, 89%) as a pale yellow solid.