Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: CI
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(Br)cc(C(F)(F)F)c1=O
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (6 g, 25 mmol) stirred at rt in THF (5 mL) was added NaH (1.5 g, 37 mmol, 60% in mineral oil). After stirring for 30 min, methyl iodide (7.1 g, 50 mmol) was added. After stirring at rt for 3 h, the reaction mixture was treated with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (6 g, 97%) as a tan solid. The solid was carried forward without any further purification. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 3.60 (s, 3H). LCMS (M+H)+=256.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)CC[C:16](=[O:17])[CH:15]=3.C(N(CC)[CH:26]([CH3:28])[CH3:27])(C)C.CI.[CH2:33](OCC)C>CN(C=O)C.[Ag]=O>[CH3:33][O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[C@H:26]([CH3:27])[CH2:28]1)[CH2:13][CH2:12]3
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CCOCC
Agent: O=[Ag]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)[C@H](C)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h

Procedure:
Testosterone (50 g.) in DMF (500 ml.) is cooled to 5° in an ice bath and silver oxide (58 g.) and N,N-diisopropylethylamine (85 ml.) are added. The mixture is stirred and methyl iodide (142 g., 62 ml.) is added in a slow stream. The temperature remains about 5° initially, the stirring is continued without further addition of ice to the bath and the mixture comes to 20°-25°. After 18 hours, diethyl ether (2 l.) is added and the mixture is filtered thru a bed of celite. The filtrate is washed successively with water, dilute hydrochloric acid, again with water, dried over sodium sulfate, filtered and concentrated. The concentrate is column chromatographed over silica gel (1 kg.) eluting by a gradient between SSB (5 l.) and SSB-ethyl acetate (80:20, 5 l.). The appropriate fractions (TLC) are pooled and concentrated to give the title compound; m.p. 130°-145°; UV (ethanol) λ=240 nm (ε=15,000); IR (mull) 1670 cm-1 ; NMR (CDCl3) 0.8, 1.1, 1.21, 3.26, 3.32, and 5.71 δ; MS (m/e) 316.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3—[(R)—1—(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—5 —(4,4,5,5—tetramethyl—[1,3,2]dioxaborolan—2—yl)—pyridin—2—ylamine (4.2711 g, 10.0 mmol) and 4—(4—bromo—pyrazol—1—yl)—piperidine—1—carboxylic acid tert—butyl ester (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4—(4—{6—amino—5—[(R)—1—(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—pyridin—3—yl}—pyrazol—1—yl)—piperidine—1—carboxylic acid tert—butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>COCCO>[CH2:11]([NH:18][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2ccsc12
Reactant: NCc1ccccc1
Solvent: COCCO
Product: c1ccc(CNc2ncnc3ccsc23)cc1
Yield: 26.2 %

Procedure:
As described in the previous experiment 4-chlorothieno[3,2-d]pyrimidine (100 mg, 0.586 mmol) and benzylamine (710 μL, 0.645 mmol) in 2-methoxyethanol (2 mL) yields 4-benzylaminothieno[3,2-d]pyrimidine (37 mg, 26%). 1H NMR (DMSO) δ 8.42 (1H, s), 8.12 (1H, d, J=5.5 Hz), 7.39 (1H, d, J=5.3 Hz), 7.40-7.30 (4H, m), 7.24 (1H, t, J=6.8 Hz)
Reaction SMILES: [C:1]1([CH3:8])[C:6](O)=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH2:14]=[O:15].Cl.[OH2:17]>C1(C)C=CC=CC=1>[OH:15][C:14]1[CH:6]=[C:1]([CH3:8])[CH:2]=[CH:3][C:4]=1[CH:5]=[O:17]
Reactant: C=O
Reactant: O
Reactant: Cc1ccccc1O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of toluene (200 ml) containing cresol (108 g) under a nitrogen atmosphere was added tin tetrachloride (26 g) and tri-N-butylamine (54 g). This mixture was stirred at room temperature for 20 minutes and 66 g of paraformaldehyde added. This solution was then heated at 100° C. for 8 hours. After cooling to room temperature, the reaction mixture was added to water (500 ml) acidifed to pH 2 with hydrochloric acid (2N) and extracted with ether, washed with brine, dried (MgSO4) and evaporated to give 2-hydroxy-4-methylbenzaldehyde, m.p. --60°-61° C.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6]([O:5][CH2:2][CH2:15][CH2:14][NH:13][CH3:18])(=[O:12])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: c1ccncc1
Product: CNCCCOC(C)=O
Product: Cl

Procedure:
To a solution (40 mL) of bis(trichloromethyl)carbonate (1.19 g) in tetrahydrofuran was dropwise added a solution (2 mL) of pyridine (0.95 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., 3-(methylamino)propyl acetate hydrochloride (1.90 g) obtained in Reference Example 42 was added. A solution (2 mL) of triethylamine (1.68 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (40 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.99 g), triethylamine (1.50 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give the title compound (1.22 g) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C(=O)=O.CC(C)=O.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][C:6]=1[S:16]([Cl:15])(=[O:18])=[O:17]
Reactant: Clc1ccc(Cl)s1
Reactant: O=S(=O)(O)Cl
Agent: O=C=O
Solvent: CC(C)=O
Product: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 96.8-g (0.632 mol) sample of 2,5-dichlorothiophene was added dropwise to a cooled (dry ice/acetone bath, about -10° to -15° C.) and stirred solution of 163 g (1.39 mol) of chlorosulfonic acid. After the addition was completed, the reaction mixture was stirred at 50° C for 2 hours, cooled, and then poured into 200 g of ice. The aqueous reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate, and evaporated to give 87 g of 2,5-dichloro-3-thienylsulfonyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Br:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[Br:16])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Br)c1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Br)c1
Yield: 80.6 %

Procedure:
2-Chloro-N-(2-bromo-4-sulphamoylphenyl)-acetamide (16.4g) and aniline (9.0 g) were heated together for 60 min. on a water bath at 90° the product was worked up as in Example 1(b) to yield 15,5 g beige crystals m.p.: 179°-181°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][PH:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([O:21][P:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])([CH3:19])=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CO[PH](C)=O
Reactant: NS(=O)(=O)c1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)COP(C)(=O)c1ccccc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 11.8 g (0.05 mole) of 2-bromophenylsulfonamide in 14 ml (0.1 mole) of triethylamine and 30 ml of dimethylformamide is treated with 6.8 g (0.05 mole) of isobutyl methylphosphinate and 1.1 g (0.001 mole) of tetrakistriphenylphosphine-palladium complex. The yellow suspension is stirred for 15 hours at 100° C., cooled and filtered. After the filtrate has been evaporated, the residue is crystallised from toluene. This gives 4.12 g of 2-(i-butoxy-P-methylphosphinyl)-phenylsulfonamide, melting point 50°-52° C.
Reaction SMILES: C([CH:4]([S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)(=[O:10])=[O:9])[C:5](O)=[O:6])(C)C.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH:39]1(N=C=NC2CCCCC2)[CH2:44]CCC[CH2:40]1>C(Cl)Cl>[CH2:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]([CH2:4][S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:13]=1[CH:39]([CH3:44])[CH3:40])(=[O:10])=[O:9])=[O:6])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)c1ccc(OS(=O)(=O)C(C(=O)O)C(C)C)c(C(C)C)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(OS(=O)(=O)CC(=O)N(Cc2ccccc2)Cc2ccccc2)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a stirred solution of 2,4,6-triisopropylphenoxysulfonyl acetic acid (1.0 g, 2.92 mM) in 15 mL of methylene chloride at 0° C. was added a solution of dibenzylamine (0.59 g, 2.92 mM) and dicyclohexylcarbodiimide (0.62 g, 3 mM) in 10 mL of methylene chloride. The reaction mixture was stirred 1 hour at 0° C., warmed to 24° C., and stirred at that temperature for 12 hours. The reaction mixture was filtered to remove the solid precipitate. The filtrate was concentrated to an oil by evaporation of the solvent under reduced pressure. The oil was purified by chromatography over a silica gel column, eluting with hexane:ethyl acetate (1:1 v/v). The fractions showed by thin layer chromatography to contain the major component were combined and the solvent was removed by evaporation under reduced pressure to provide 0.5 g (76%) of 2,4,6-triisopropylphenyl N,N-dibenzylcarbamoylmethyl sulfonate, mp 107°-110° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:33])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (65 mg, 0.17 mmol) and 1-(2-methanesulfonylethyl)piperazine (38 mg, 0.20 mmol) in DCE (4 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol). The reaction mixture was stirred for 16 h then partitioned between brine and DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 312 as a cream solid (29 mg, 30%). LCMS (Method G): RT 5.97 min [M+H]+ 568.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.73 (m, 1 H); 7.30-7.24 (m, 2 H); 4.35 (m, 4 H); 3.90-3.83 (m, 7 H); 3.77 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 3.22-3.11 (m, 2 H); 3.04 (s, 3 H); 2.91 (t, J=6.4 Hz, 2 H); 2.59 (m, 8 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15]([C:24]3[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=3)=[CH:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1>ClCCl>[Cl:5][CH2:29][C:26]1[S:27][CH:28]=[C:24]([C:15]2[C:16]3[C:21](=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][CH:17]=3)[N:13]([CH2:12][CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:14]=2)[N:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c(-c3csc(CO)n3)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c(-c3csc(CCl)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methanesulfonyl chloride (174 μl, 2.25 mmol) was added to a solution of 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]7-methoxy-1H-indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Further methanesulfonyl chloride (87 μl, 1.12 mmol) was added and stirring continued for 0.5 h. The mixture was concentrated in vacuo and the resulting orange residue was purified by flash column chromatography eluting with dichloromethane to afford 3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole as a yellow oil (0.415 g). 3-[2-(Chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (0.08 g, 0.214 mmol) and diethylamine (221 μl, 2.14 mmol) were dissolved in acetonitrile (2 ml). The resulting mixture was exposed to microwave irradiation at 100° C. for 5 min. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane. The resulting product was taken up in diethyl ether and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The solution was concentrated in vacuo and the resulting solid triturated with ether, then dried to afford the title compound as a 1:1 hydrochloride salt (0.034 g). 1H NMR (400 MHz, CD3OD) δ 0.99-1.25 (5H, m), 1.43 (6H, t, J 7.5), 1.56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (2H, d, J 7.5), 4.75-4.80 (2H, s, masked by H2O peak), 6.75 (1H, d, J 8.0), 7.08 (1H, dd, J 8.0, 8.0), 7.64-7.68 (3H, m). EsIMS: m/z 412.1 [M+H]+, 339.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13](O)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([CH3:28])[N:10]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:13]1[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([CH3:28])[N:10]=[C:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-ol (760 mg, 2.0 mmol) and phosphorous oxychloride (5 mL) is heated at 80° C. under nitrogen with magnetic stirring for 2 h (until starting material is consumed as determined by LC/MS analysis). The reaction mixture is evaporated at reduced pressure, diluted with DCM (50 mL), extracted with sat. NaHCO3 (20 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a pale yellow oil. Purification by chromatography on silica gel (10-40% EtOAc/Hexanes) provides the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.08-7.25 (m, 4H), 6.88 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.28 (s, 2H), 2.91 (m, 1H), 2.74 (s, 3H), 2.21 (s, 3H), 2.14 (s, 6H), 1.28 (d, J=6.8 Hz, 6H); LC-MS found 395.4 (MH+), rt=3.33 min, Method 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]=2[CH:38]=1)#[N:14].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:22]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21](=[O:23])[N:20]([CH:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]=2[CH:38]=1)#[N:14]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)[nH]c2ccc(C#N)cc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)OC(C)(C)C)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.63 g (7.87 mmol) of 4-methoxybenzenesulfonyl chloride were added to a solution of 2.50 g (7.16 mmol) of tert-butyl (6-cyano-2-oxo-2,3-dihydro-benzimidazol-1-yl)phenylacetate (XIc), 1.98 ml (14.3 mmol) of triethylamine and a catalytic amount of DMAP in tetrahydrofuran (60 ml) while stirring at room temperature, and the mixture was then stirred at room temperature for 16 h. The reaction solution was mixed with water and extracted with ethyl acetate (3×60 ml). The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 10-40% ethyl acetate in cyclohexane). Yield: 2.90 g (78%) of colorless solid
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (10 g, 64.1 mmol) in DMF (65 mL) was added tert-butyl-piperazine carboxylate (13.1 g, 70.5 mmol) and K3PO4 (13.3 g, 96.2 mmol). The reaction mixture was stirred at 100° C. overnight. After adding 100 ml H2O into the solution, the precipitated yellow solid was filtered under vacuum then dried in vacuo to afford tert-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate as yellow solid (15 g, yield: 82%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C:14]2=[C:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=C(C#N)C(=O)O)CC[C@@H]32)C1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C#N)C(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
37 g. of the ethyl ester of 3β-acetoxy-20-cyano-5,17(20)-pregnadiene-21-oic acid is mixed in 450 ml. of tetrahydrofuran and 150 ml. of ethanol with 2.5 g. of 10% palladium-charcoal catalyst and 2 ml. of N/10 sodium hydroxide solution and hydrogenated under normal pressure with hydrogen at room temperature. The reaction mixture is worked up as set forth in Example 1(b), thus obtaining the ethyl ester of 3β-acetoxy-20-cyano-5-pregnene-21-oic acid (34 g.), m.p. 170° C.
Reaction SMILES: Br[CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[C-:28]#[N:29].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][C:28]#[N:29])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:27]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CC#N)cc1OC
Temperature: 90 °C
Yield: 71.3 %

Procedure:
To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (117 mg) in dimethylsulfoxide (2 mL) was added sodium cyanide (26.5 mg), and the mixture was stirred for an hour at 90° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-2-(2-cyano-1-methylethylamino)-N-(3,4-dimethoxybenzyl)benzamide (73 mg) as a solid substance.