Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([C:9]1[C:13]2[N:14]=[C:15]([C:19]3[C:20]([O:26][CH2:27][CH2:28][CH3:29])=[N:21][CH:22]=[C:23](I)[CH:24]=3)[NH:16][C:17](=[O:18])[C:12]=2[N:11]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:10]=1)[CH3:8].C(#N)C>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:7]([C:9]1[C:13]2[N:14]=[C:15]([C:19]3[C:20]([O:26][CH2:27][CH2:28][CH3:29])=[N:21][CH:22]=[C:23]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:24]=3)[NH:16][C:17](=[O:18])[C:12]=2[N:11]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:10]=1)[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCCOc1ncc(I)cc1-c1nc2c(CC)nn(CCN3CCOCC3)c2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)nn(CCN3CCOCC3)c2c(=O)[nH]1
Reaction time: 10 h
Yield: 16.1 %

Procedure:
Trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added to a solution of the title compound of example 5 (1.0 g, 1.86 mmol) in triethylamine (20 mL). Acetonitrile (1 mL), bis(triphenylphosphine)palladium (II) chloride (33 mg, 2.5 mol %), and copper (I) iodide (9 mg, 2.5 mol %) were added and the resultant mixture stirred at room temperature for 1 h after which further trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added and the mixture stirred for 10 h. After removal of the solvent in vacuo, the residue was partitioned between ethyl acetate (25 mL) and water (20 mL), the aqueous phase separated and extracted with further ethyl acetate (3×25 mL). Combined organics were washed with brine (25 mL), dried over MgSO4, and concentrated to an oil which was crystallised from diisopropyl ether to afford the title compound as a white solid (156 mg, 0.30 mmol). The addition of pentane to the concentrated mother liquors afforded a second crop (509 mg, 1.0 mmol).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cn(C)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)c1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A mixture of 130b (100 mg, 0.18 mmol) and lithium hydroxide hydrate (189 mg, 4.5 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 min. The mixture was evaporated under reduced pressure and the residue was added water (5 mL). It was then extracted with dichloromethane (3×10 mL). The combined extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 130 (41.1 mg, 44.4%) as white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56-8.53 (m, 2H), 7.90 (d, J=2.0 Hz, 1H), 7.78 (dd, J=2.0, 12.5 Hz, 1H), 7.61 (s, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.41-7.39 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 5.04-5.02 (m, 1H), 4.41-4.39 (m, 2H), 3.59 (s, 3H), 3.58 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C1CCC(C=Cc2cc(F)c(F)c(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Yield: 97.8 %

Procedure:
4-(2'-(3",4",5"-Trifluorophenyl)ethenyl)cyclohexanone (71 g) was dissolved in ethanol (500 ml), followed by adding Pd/C (5%) (2.0 g), hydrogenating the compound in a hydrogen gas atmosphere with stirring till the hydrogen absorption was completed, filtering off the catalyst after completion of the reaction, and concentrating the solvent under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexanone (70 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=O)[N:4]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[N:4]=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1cc(C)[nH]c(=O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Cc1cc(C)nc(Cl)n1
Yield: 56.1 %

Procedure:
A suspension of 4,6-dimethyl-1H-pyrimidin-2-one hydrochloride (3.0 g, 18.75 mmol) in dry POCl3 (25 mL, 272 mmol) was refluxed for 18 hours. The reaction mixture was evaporated to dryness and the residue dissolved in dichloromethane. The solution was washed with sodium bicarbonate solution until the pH of the aqueous washings were neutral, then with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-chloro-4,6-dimethyl-pyrimidine (1.5 g, 56%) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCc1ccc(C(C)(C)C)cc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butyl)benzaldehyde (0.208 mL, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.93 and 0.63. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.63) was isolated by flash chromatography (30% EtOAc in hexanes). 0.496 g (73%) of the pure titled compound was obtained as a white foam: mp 57-62° C. APCI-MS m/z 548.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.Cl[C:40]([C:42]([O:45][C:46](=[O:48])[CH3:47])([CH3:44])[CH3:43])=[O:41].Cl>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH:11][C:40](=[O:41])[C:42]([O:45][C:46](=[O:48])[CH3:47])([CH3:44])[CH3:43])(=[O:9])=[O:10])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)(C)C(=O)NS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonamide (0.10 g, 0.21 mmol) in dichloromethane (2 mL) was added triethylamine (0.033 mL, 0.23 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol) and acetic acid 1-chlorocarbonyl-1-methyl-ethyl ester (0.037 mL, 0.25 mmol). The resulting reaction mixture was stirred at ambient temperature overnight, treated with 0.2 N hydrochloric acid extracted with dichloromethane dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude title compound (0.140 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([CH3:17])=[C:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:18][CH2:17]/[C:9](/[C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1)=[C:10](/[F:16])\[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(F)=C(C)C1(C(=O)OCC)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C(\CBr)C1(C(=O)OCC)CC1
Yield: 49.8 %

Procedure:
To a solution of ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (152.78 g, 0.625 mol) in chloroform (1500 ml) were added N-bromosuccinimide (111.33 g, 0.625 mol) and a catalytic amount of 2,2'-azobis-(isobutyronitrile) and then the resultant mixture was heated under reflux for 16 hours. Then, the liquid reaction mixture was cooled and concentrated under reduced pressure. After adding benzene (300 ml), insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=4:1) to obtain 100.5 g (49.7%) of the title compound as a yellow oily substance. On the other hand, 75 g (37.1%) of (Z)-ethyl 4-bromo-3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (the geometrical isomer of the title compound) was obtained as a yellow oily substance with the use of another eluent (n-hexane:ethyl acetate=2:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#N)=[C:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:11]([CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C[OH:30]>>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:30])=[C:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:11]([CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(OCc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
To a 0° C. solution of 2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridine-3-carbonitrile (Cpd I, 1.0 g, 2.8 mmol) in MeOH (5 mL) was added NaBH4 (81 mg, 2.1 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated under vacuum to give [2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridin-3-yl]methanol (Cpd J, 147 mg, 14%) as a solid.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 4-(3-chlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 4 & 5, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 90% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: Brc1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2cccc3c2CCNC3)nc1

Procedure:
In close analogy to the procedure described above, 5-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][OH:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].N[C@H](CO)CC(=[O:15])N.N1CCC[C@H]1CO.N[C@H](CO)CCC(=O)N.N[C@H](CO)C.N[C@@H](CO)CCCCN.N[C@H](CO)CCCCN.N[C@@H](CO)CC(=O)O.N[C@H](CO)CCCN.N[C@H](C(N[C@H](CO)CCC(=O)O)=O)CC(=O)O>>[NH2:1][C@H:2]([C:8]([OH:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: NC(=O)C[C@H](N)CO
Reactant: N[C@H](CO)CCC(=O)O
Agent: C[C@H](N)CO
Agent: NC(=O)CC[C@H](N)CO
Agent: NCCCC[C@@H](N)CO
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A10 -ol, Glu-ol, Asn-ol, Pro-ol, Gln-ol, Ala-ol, D-Lys-ol, Lys-ol, D-Asp-ol, Orn-ol or is Asp-Glu-ol.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14].[C:29](=[O:31])=[O:30]>CCOCC>[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19]([C:29]([OH:31])=[O:30])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14]
Reactant: O=C=O
Reactant: COC(C)c1cc(Br)ccc1-c1ccccc1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: COC(C)c1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
A solution of tert-butyllithium in pentane (1.5M, 8.05 mL, 12.1 mmol) was added into anhydrous Et2O (40 mL) cooled at −78° C. under nitrogen atmosphere. Then a solution of 1-(4-bromo-2′-methylbiphenyl-2-yl)ethyl methyl ether (1.84 g, 6.03 mmol) in anhydrous Et2O (10 mL) was added dropwise over 10 minutes. The resulting mixture was stirred at −78° C. for 25 minutes, and then a large excess of dry ice was added and the cooling bath was removed. The reaction mixture was stirred until the temperature came back at RT, then diluted with water (20 ml) and a 5N aqueous solution of NaOH (0.5 mL). The layers were separated and the aqueous layer was washed with Et2O (20 ml). The organic layers were extracted with a 0.1N aqueous solution of NaOH (20 mL). The combined aqueous layers were acidified with a 5N aqueous solution of HCl (until pH˜1) and extracted with MTBE (2×50 mL). The organic layers were washed with brine (30 mL), combined, dried (Na2SO4) and concentrated under vacuum to give a pale yellow solid. After crystallization from a mixture of Et2O and heptane, the title compound was obtained as a white powder. HPLC (Method A) Rt 4.2 min (Purity: 98.2%). LC/MS (Method B): 269.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (s, 1H), 8.09 (d, J=1.8 Hz, 0.4H), 8.07 (d, J=1.8 Hz, 0.6H), 7.89 (dd, J=7.9, 1.8 Hz, 1H), 7.36-7.24 (m, 3H), 7.22 (d, J=7.9 Hz, 0.4H), 7.20 (d, J=7.9 Hz, 0.6H), 7.13 (d, J=6.9 Hz, 0.4H), 7.07 (d, J=6.9 Hz, 0.6H), 4.12 (q, J=6.4 Hz, 0.4H), 3.92 (q, J=6.4 Hz, 0.6H), 3.05 (s, 1.2H), 3.04 (s, 1.8H), 2.03 (s, 1.8H), 1.98 (s, 1.2H), 1.19 (d, J=6.4 Hz, 1.8H), 1.13 (d, J=6.4 Hz, 1.2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:17][C:18]1[NH:19][C:20](=[O:45])[C:21]2[N:22]=[CH:23][N:24]([C:43]=2[N:44]=1)[C@:25]1([C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:32][C@H:29]([CH2:30][OH:31])[C@@H:27]([OH:28])[CH2:26]1)([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:31][CH2:30][C@H:29]2[O:32][C@@:25]([C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([N:24]3[C:43]4[N:44]=[C:18]([NH:17][C:13]([CH3:14])([CH3:16])[CH3:15])[NH:19][C:20](=[O:45])[C:21]=4[N:22]=[CH:23]3)[CH2:26][C@@H:27]2[OH:28])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)Nc1nc2c(ncn2[C@@]2(C(=O)COc3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)(C)Nc1nc2c(ncn2[C@@]2(C(=O)COc3ccccc3)C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-t-butylphenoxyacetyldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/methanol mixture and evaporation to dryness, the product is taken up in chloroform/hexane (8/2) and purified on a silica column (elution 3% methanol). The product obtained is very soluble in organic solvents.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.COC(=O)CC(=O)C(Br)C.COC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:28][C:29]=2[CH3:35])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(CCO)c(C)s2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: COc1ccc(C(N)=S)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-methoxy-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-propionic acid as light yellow gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCNCC2)CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)CC1
Yield: 98.4 %

Procedure:
A solution of 4,6-dichloropyrimidine (8.60 g), 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]piperazine 15.64 g) and triethylamine (21.95 ml) in ethanol (300 ml) was stirred at room temperature for 30 minutes. Solvent was evaporated and the residue dissolved in dichloromethane and washed with water, saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give, as a pale yellow solid 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]-4-(6-chloro-pyrimidin-4-yl) piperazine (21.20 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](N)[C@@H](F)C1
Agent: Cl
Product: CC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-3-amino-4-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f70) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.375 g, 1.93 mmol), (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (0.513 g, 1.93 mmol), C2CO3 (0.943 g, 2.90 mmol) in anhydrous DMF (5.13 mL) was heated to 100° C. for 6 h. The reaction mixture was partitioned between EtOAc and H2O and separated and the aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The crude was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3] resulting in the title compound as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 12H), 1.47 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.79 (m, 3H), 3.81-3.92 (m, 1H), 4.90 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13](CC(C)C)=[CH:12][C:11](CC(C)C)=[C:10]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(NC2C(CC(C)C)=CC(C=C(C)C)=C(NC3CCCCC3)C=2)CCCCC1>>[CH:23]1([NH:22][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)Cc1cc(CC(C)C)c(NC2CCCCC2)cc1NC1CCCCC1
Agent: CC(C)=Cc1cc(CC(C)C)c(NC2CCCCC2)cc1NC1CCCCC1
Product: c1cc(NC2CCCCC2)cc(NC2CCCCC2)c1

Procedure:
Recrystallization from ethyl acetate provided an off-white product, mp 92-94° C., containing 42% of N1,N3-dicyclohexyl-4,6-diisobutyl-1,3-benzenediamine, along with 35% N1,N3-dicyclohexyl-4-isobutenyl-6-isobutyl-1,3-benzenediamine, as determined by GC/MS.