Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:35]([O:37]C)=[O:36])[CH2:13][CH2:14][P:15]([CH:18]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:22]([F:34])[CH:21]=1)[OH:19])(=[O:17])[OH:16])=O)C1C=CC=CC=1>Cl>[NH2:11][CH:12]([CH2:13][CH2:14][P:15]([CH:18]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:22]([F:34])[CH:21]=1)[OH:19])([OH:17])=[O:16])[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)COc1c(F)cc(C(O)P(=O)(O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1F
Agent: Cl
Product: NC(CCP(=O)(O)C(O)c1cc(F)c(OCC(=O)O)c(F)c1)C(=O)O
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of ((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)((4-(2-ethoxy-2-oxoethoxy)-3,5-difluorophenyl)(hydroxy)methyl)phosphinic acid (552 mg, 0.99 mmol) in 6 N HCl (6M) was refluxed during 3 h. Then, the mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was diluted in EtOAc (50 mL) and extracted with 1 N HCl (2×80 mL). The combined aqueous layers were washed twice with EtOAc and the solvent was evaporated to afford 238 mg (0.62 mmol) of crude product which was purified by cation (and anion) exchange resin chromatography. Cation exchange resin chromatography: 238 mg of crude compound were deposited on a Dowex AG 50W-X4, H+, 50-100 mesh. The compound was eluted with water and 85 mg of desired product were collected. Anion exchange resin chromatography: 85 mg of compound were deposited on a Dowex AG 50W-X4, AcO−, 200-400 mesh. The compound was eluted with boiled water and formic acid. 27 mg (yield 7% on 2 steps) of pure product derivative 28 were collected (2 M HCOOH). 1H NMR (250 MHz; D2O) δ (ppm): 1.87 (m, 2H); 2.17 (m, 2H); 4.13 (m, 1H); 4.87 (s, 2H); 4.94 (d, JHP=9.4 Hz, 1H); 7.13 (d, J=9.1 Hz, 2H). 13C NMR (63 MHz; D2O) δ (ppm): 21.7 (d, JCP=91.0 Hz); 22.8; 53.1 (d, JCP=14.8 Hz); 69.8; 71.3 (d, JCP=109.5 Hz); 110.8 (dd, JCF=23.3 Hz and 4.0 Hz); 133.2 (t, JCF=14.0 Hz); 134.0 (t, JCF=8.1 Hz); 154.7 (dd, JCF=246.6 Hz and 5.4 Hz); 171.4; 172.9. 31P NMR (200 MHz; D2O) δ (ppm): 41.5 (s). 19F NMR (376 MHz: D2O) δ (ppm): −129.0 (s) MS (ESI) m/z: 384 [M+H+]. HPLC: tR=10.1 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=C)=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[O-:38]I(=O)(=O)=O.[Na+].O>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[O:38])=[CH:28][CH:27]=2)(=[O:24])=[O:25])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(C=O)cc2)ncnc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
318 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide, 5.3 mg of osmium tetroxide and 270 mg of sodium(meta)periodate were added in succession to a mixture of 1.5 ml of water and 4 ml of dioxane at room temperature. After stirring at room temperature for 1 hour, the dioxane was distilled under reduced pressure. Thereafter, the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate was washed twice with water and once with NaCl solution (saturated), dried and distilled under reduced pressure. The residue was chromatographed over 30 g of SiO2 with CH2Cl2 /ethyl acetate and yielded 150 mg of rac-p-[[5-(o-methoxybenzyl)-6-[2-[(tetra-hydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]sulfamoyl]-benzaldehyde as white foam. MS: 527 (M); 443 ##STR12## (--OCH3 +SO2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([O:19][CH3:20])=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15]Cl)=[C:10]([Br:21])[CH:9]=2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Br:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:18]([O:19][CH3:20])=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CCc1ccccc1O
Reactant: COc1cc(OCCCCl)c(Br)cc1-c1ccc(F)cc1
Product: CCOC(=O)CCc1ccccc1OCCCOc1cc(OC)c(-c2ccc(F)cc2)cc1Br
Yield: 76 %

Procedure:
The title intermediate was prepared from 3-(4-(4-fluorophenyl)-2-bromo-5-methoxyphenoxy)propyl chloride and ethyl 3-(2-hydroxyphenyl)propionate in 76% yield by the procedure of Preparation 36. NMR
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>>[C:23]([CH:22]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1)([OH:25])=[O:24]
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)c1ccccc1
Yield: 33 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-phenylglycine to provide the title compound in 33% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]1[O:7][C:8]2[CH:9]=[CH:10][C:2]([C:1]([C:10]3[CH:9]=[CH:8][C:4]([OH:5])=[CH:3][CH:2]=3)=[O:11])=[CH:3][C:4]=2[O:5]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(O)cc1)c1ccc2c(c1)OCO2
Yield: 48.7 %

Procedure:
4-Tri-n-butyltin-1-methoxymethylphenol (1.282 g) obtained in Example 22 and commercially available piperonyloyl chloride (664 mg) were dissolved in chloroform (5 ml), commercially available bis(triphenylphosphine)palladium(II) chloride (8 mg) was added, and the admixture was refluxed with heat overnight. The reaction mixture was partitioned in the same manner as described in Example 23, and the resulting ether layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue (1.030 g) was dissolved in tetrahydrofuran (2 ml), water (5 ml) and 6 N aqueous hydrochloric acid (12 ml) were added, and the admixture was refluxed with heat 10.5 hours. The reaction mixture was treated in the same manner as described in Example 123 to obtain 212 mg of the title compound (yield: 29%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NCCC1C=CC(O)=C([OH:22])C=1.CN(C1C=CC=CN=1)C>O1CCCC1.CCCCCC.C1C=CC=CC=1>[CH:10]1([NH:9][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: CN(C)c1ccccn1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
DHA is first converted to DHA anhydride in the presence of dicyclohexyl carbodiimide. This is then reacted with dopamine in the presence of dimethylaminopyridine as the acid acceptor in tetrahydrofuran. In a typical experiment 300 mg of DHA (0.009 M) was dissolved in a mixture of 3 ml hexane and 4 ml benzene and stirred under nitrogen. Next, a solution of 0.00615 M of dicyclohexyl carbodiimide in 4 ml benzene (0.1267 g) was stirred together with the DHA for 3 hr at room temperature. A white precipitate of dicyclohexyl urea formed as the reaction proceeded. The dicyclohexyl urea was filtered off to give a clear solution of the anhydride in benzene. This was concentrated down to 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydrofuran (dry). The freshly prepared anhydride was then added to a solution of dopamine hydrobromide (0.1053 g) (or 0.005 M) in the presence of 0.009 M of diethylaminopyridine (0.098 g). The initially cloudy mixture after stirring for 30 min at room temperature gave a mixture of a clear liquid and a brown precipitate. At the end of the reaction, 0.2 ml of water was added to the mixture, and stirring was continued for an additional 30 min to completely hydrolyze any remaining unreacted anhydride. The liquid phase was isolated and evaporated to dryness to yield a brown viscous solid. This was then dissolved in 70% ethanol in water (25 ml), and the solution was then passed through a mixed-bed ion exchange resin containing a strong acidic resin based on polystyrene sulfonic acid and a strong basic resin based on quanternary ammonium substituents such as tetramethyl amonimum hydroxide (RG501, Fisher Scientific, Cambridge, Mass.) using 90% ethanol in water as the eluent. This resin removes from the mixture unreacted dopamine, dimethylaminopyridine, as well as the liberated DHA molecule. The effluent from the column (a pale yellow solution) was then evaporated in a rotary evaporator to give a solid. The product was recrystallized from aqueous ethanol (yield=75%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].C[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:17]=[CH:15][N:16]=[C:6]([OH:8])[CH:5]=1
Reactant: N=CN
Reactant: COCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1cc(O)ncn1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To a solution of methyl 4-methoxy-3-oxobutanoate (3.54 mL, 26.5 mmol) in methanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) and sodium methoxide (13 mL, 58.4 mmol). The mixture was then heated to reflux for 18 hours and cooled to ambient temperature, then concentrated. The residue was taken up in water and the pH adjusted to 7 with 1N HCl. The aqueous mixture was extracted with chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol, 37.1% yield). MS (LC/MS) R.T.=0.19; [M+H]+=141.20.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[C:6](=[O:21])[C:5]1=[O:22].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[C:6](=[O:21])[C:5]1=[O:22])=[N+:24]=[N-:25]
Reactant: COc1ccc(CN2CCN(CCBr)C(=O)C2=O)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCN=[N+]=[N-])C(=O)C2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A mixture of 4.5 g of 1-(2-bromoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 1.03 g of sodium azide and 45 ml of N,N-dimethylformamide was stirred at 80° C. for 1 hour and then distilled under reduced pressure to remove the solvent. To the resulting residue were added 60 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with two 30-ml portions of ethyl acetate. The combined organic layer was washed with 20 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, 5 ml of diisopropyl ether and 5 ml of diethyl ether were added to the resulting residue and the crystals were collected by filtration to obtain 3.7 g of 1-(2-azidoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: Br/[CH:2]=[C:3]1/[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[O:6][CH2:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]/1=2.[N:19]1([CH2:25][CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][C:34](C4(O)CCCB4O)=[CH:35][C:30]=3[NH:29][C:28]2=[O:43])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2=[C:5]([CH:14]=1)[O:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:3]/2=[CH:2]\[C:34]1[CH:33]=[CH:32][C:31]2[N:27]([CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:28](=[O:43])[NH:29][C:30]=2[CH:35]=1
Reactant: Fc1ccc2c(c1)OCc1ncccc1/C2=C\Br
Reactant: O=c1[nH]c2cc(C3(O)CCCB3O)ccc2n1CCN1CCOCC1
Product: O=c1[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4ncccc43)ccc2n1CCN1CCOCC1
Yield: 38.6 %

Procedure:
Following procedures essentially as described in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene (192 mg, 0.63 mmol) and 1-(2-morpholinyl-ethyl)-5-(dihyroxyborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (219 mg, 0.75 mmol). Partition the reaction mixture between ethyl acetate (50 mL) and 1N aqueous hydrochloric acid solution (50 mL). Separate the layers and extract the aqueous layer with methylene chloride (2×50 mL). Combine the organic layers and extract with 1N aqueous hydrochloric acid solution (50 mL). Adjust the pH of the combined aqueous layers to 8.0 with 5N aqueous sodium hydroxide solution, and extract the product with ethyl acetate (3×50 mL). Purify the crude product by flash chromatography (25% ethanol/ethyl acetate) to provide 115 mg (39%) of purified product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5].[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:20])=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5]
Reactant: COCC(C)(C)n1c(C)c(C=O)c2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCC(C)(C)n1c(C)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.2 mmol) in acetone (2 mL) and water (2 mL) was added potassium permanganate (95 mg, 0.6 mmol). The resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was lyophilized directly to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carboxylic acid (50 mg, 94%) as a brown solid. LCMS (M+H+) m/z: calcd. 261.14. found 261.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C([NH2:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:15][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NC=O
Product: O=C1NC(=O)c2cc(Cl)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
The suspension of 4-chlorophthalic anhydride (3 g) in formamide (15 ml) was heated with stirring to 150° C. for 1 h. The resulting yellowish solution was cooled to rt and the product was fractionally precipitated by addition of water to yield 4-chlorophthalimide (1.91 g) as colourless crystals.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:14][C:15]1[C:19](C#N)=[C:18]([CH2:22][CH3:23])[NH:17][N:16]=1>C(O)(=O)C>[CH2:22]([C:18]1[C:19]([C:15]#[N:14])=[C:13]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:16]2[N:17]=1)[CH3:23]
Reactant: CCc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCc1nn2c(-c3ccccc3)ccnc2c1C#N

Procedure:
A mixture of 0.71 g. of 3-dimethylaminoacrylophenone, 15 ml. of glacial acetic acid and 0.55 g. of 3-amino-5-ethylpyrazole-4-carbonitrile is refluxed for 16 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 132°-134° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9]O>C(Cl)Cl>[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9][Br:2]
Reactant: Cc1cc(CO)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cc(CBr)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Yield: 90 %

Procedure:
A solution of PBr3 (401 mg, 1.48 mmol) in 10 ml of CH2Cl2 was added dropwise, under nitrogen, to a stirred solution of the above alcohol (Example 16, 850 mg) in 20 ml CH2C12 at 0° C. The reaction mixture was left to stand at room temperature over night and then diluted with CH2Cl2. The organic phase was washed with water, dried over MgSO4 and concentrated. The residue was purified by column chromathography (silica gel, 9:1 petroleum-ether/EtOAc) to give 465 mg of 3,5-dimethyl-4-(4-hydroxy-3-isopropyl-phenoxy)benzylbromide
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(Br)s2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1(C(=O)O)CCCC1)c1ccc(Br)s1

Procedure:
Prepared analogously to Example 1e from methyl 1-[(5-bromo-thiophene-2-carbonyl)-amino]-cyclopentane-1-carboxylate in methanol with 1-normal sodium hydroxide solution.
Reaction SMILES: [N:1]([C@H:4]([C@@H:31]([OH:44])[CH2:32][C@H:33]([C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:34]([CH3:36])[CH3:35])[CH2:5][C@@H:6]([CH:28]([CH3:30])[CH3:29])[CH:7](OC(=O)C(C)C)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21])[CH:9]=1)=[N+]=[N-]>CO.[Pd]>[CH2:39]([NH:38][C:37](=[O:43])[C@H:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][C@H:31]([OH:44])[C@@H:4]([NH2:1])[CH2:5][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21])[CH:9]=1)[CH:28]([CH3:29])[CH3:30])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(OC(=O)C(C)C)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(CCOCOC)c1)C(C)C)C(C)C

Procedure:
50 mg of {4(S)-Azido-7(S)-butylcarbamoyl-5(S)-hydroxy-2(S)-isopropyl-8-methyl-1 (R,S)-[4- methoxy-3-(2-methoxymethoxyethyl)-phenyl]-nonyl}-isobutyrate are hydrogenated in 10 ml of methanol in the presence of 50 mg of 10% Pd/C at room temperature and normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by FC (2 g of silica gel, dichloromethane/methanol 9:1). The title compound is obtained: Rf (dichloromethane/methanol 9:1)=0.19; HPLC Rt =13.42 minutes; FAB-MS (M+H)+ =509.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[Br:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[Br:20][C:21]1[N:22]=[CH:23][N:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:25]=1
Reactant: Brc1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.7) (0.50 g, 1.53 mmol) and commercially available 4-bromo-imidazole (0.34 g, 2.31 mmol) according to the general procedure IVb. Obtained as a white solid (0.38 g, 57%). MS (ISP) 439.0 [(M+H)+]; mp 225.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:10]([NH:32][C@H:33]([C:38]([OH:40])=O)[CH2:34][CH:35]([CH3:37])[CH3:36])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](O[N:58]2N=[N:65][C:60]3C=CC=C[C:59]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:59]([CH2:60][NH:65][C:38](=[O:40])[C@H:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[NH:32][C:10]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1)#[N:58]
Reactant: CC(C)C[C@H](Nc1nn(C(=O)OC(C)(C)C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nn(C(=O)OC(C)(C)C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N

Procedure:
To N-(1-(tert-butoxycarbonyl)-4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucine (864 mg, 1.55 mmol), PyBOP (890 mg, 1.71 mmol), aminoacetonitrile hydrochloride (315 mg, 3.41 mmol) in dry DMF (40 mL) under dry nitrogen was added triethylamine (0.76 mL, 5.43 mmol) dropwise and the reaction was stirred for 4½ hours. Aqueous sat. NaHCO3 was added and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6) to afford N1-(cyanomethyl)-N2-(1-(tert-butoxycarbonyl)-4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucinamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cccc(C#N)c1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cccc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 3-methyl-2-nitrobenzonitrile from Example 1c (5.72 g) and tert-butoxy-bis(dimethylamino)methane (9.5 ml) in dimethylformamide (30 ml) was heated to 90° with stirring for 1.5 hours. After cooling to ambient temperature the mixture was partitioned between ethyl acetate and water. The layers were separated with the aqueous phase further extracted using two portions of ethyl acetate. The combined ethyl acetate layer was washed with water then brine. The solution was dried over MgSO4 and filtered through a small pad of silica gel. After concentrating the material a very dark brown solid was obtained. Recrystallization from ethyl acetate/hexane gave the title product (6.99 g, 91%) as dark brown crystals.