Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18](C=O)([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C[O:30][C:31](=[O:33])[CH3:32].[Li+].[OH-].O.[CH2:37]1COCC1>CO>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][CH:18]([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH:15]4[CH:37]=[CH:32][C:31]([OH:30])=[O:33])[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=O)(CCC3)C4)nc2n(CCC)c1=O
Reactant: COC(C)=O
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC3C=CC(=O)O)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde (355 mg) was taken in THF (25 ml): Triphenyl-□□-phosphanylidene)-acetic acid methyl ester (614 mg) was added and refluxed overnight. Next day another 460 mg of Triphenyl-□□-phosphanylidene)-acetic acid methyl ester was added and refluxed for 24 hrs. Cooled to RT LiOH (210 mg), water (2 ml), MeOH (5 ml) were added and stirred at rt overnight. Solvent was removed under reduced pressure. Diluted with water (25 ml), extracted with ethyl acetate (3×25 ml). Aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (3×50 ml), dried over Na2SO4 and concentrated. Yield 254 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]2[N:53]=[C:52]([NH2:54])[CH:51]=[CH:50][N:49]=2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH2:54][C:52]1[CH:51]=[CH:50][N:49]=[C:48]([NH:47][C:44]2[CH:45]=[CH:46][C:41]([CH2:40][NH:39][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:42][CH:43]=2)[N:53]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCc1ccc(Nc2nccc(N)n2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(Nc4nccc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), N2-[4-(aminomethyl)phenyl]pyrimidine-2,4-diamine dihydrochloride (46 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:28])[CH3:27]
Reactant: C#CCN1CC[C@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCN1CC[C@H](OC(C)=O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5.0 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 6.7 ml of pyridine, 0.2 g of dimethylaminopyridine and 6.7 ml of acetic anhydride was stirred in a water bath for 3 hours. The mixture was diluted with 150 ml of dichloromethane, washed in succesion with water, sodium bicarbonate solution, 1N hydrochloric acid, sodium bicarbonate solution and brine, dried and concentrated, giving 6.4 g of (S)-3-(acetyloxy)-1-(2-propynyl)-2-pyrrolidinone [α]D26° =-45° (dichloromethane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[Cl:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:23])[C:17]=1[N:12]1[CH2:13][CH2:14][CH2:15][C:16]2=[C:8]([NH2:7])[N:9]([CH3:26])[N:10]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3NC(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a 0° C. solution of 287 mg of [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamic acid tert-butyl ester (Example 8c) in 9 mL of dichloromethane, was added 3 mL of trifluoroacetic acid. After 15 min, the cooling bath was removed and the reaction mixture was allowed to stir and warm to room temperature during 3 h. The reaction mixture was then diluted with dichloromethane and washed with dilute aqueous sodium hydroxide. The aqueous phase was washed with additional dichloromethane, after which the combined organics were dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a methanol/dichloromethane gradient to provide 182 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine, mp 234–236° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].ClS([N:13]=[C:14]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>C(#N)C>[C:14]([C:5]1[CH:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1)#[N:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1cccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1cc(C#N)cc1C=O
Temperature: -45 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
1-Methylpyrrole-2-carbaldehyde (10 g, 91.6 mmol) was dissolved in acetonitrile (100 ml) and cooled to −45° C. Chlorosulfonyl isocyanate (38.9 g, 274.9 mmol) in acetonitrile (40 ml) was added dropwise in the course of 40 minutes. The mixture was subsequently stirred for 12 hours at room temperature. After dropwise addition of dimethylformamide (35 ml), the mixture was warmed to 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice (200 ml) and 2N sodium hydroxide solution (286 ml). The precipitate formed was filtered off with suction. The filtrate was extracted with diethyl ether. The combined ether phases were washed until neutral with dilute sodium hydrogen carbonate solution and water and dried over sodium sulfate. The solvent was distilled out in a water pump vacuum and the residue was combined with the precipitate previously obtained. Recrystallization from petroleum ether gave 4-cyano-1-methylpyrrole-2-carbaldehyde (4.3 g) (see, for example, C. E. Loader et al. Can. J. Chem. (1981), 59, 2673-6) 1-H [sic] NMR (CDCl3) δ=4.0 (s, 3H); 7.2 (s, 1H); 7.3 (s, 1H); 9.6 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:18]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of 88.9 g of Compound (VI) [R2 =H, R3 =CN], 33.0 g of tert-butylamine, 89 g of anhydrous potassium carbonate, and 700 ml of anhydrous dimethylformamide were stirred at room temperature overnight. To the reaction solution was added 500 ml of chloroform to remove insoluble substances by filtration. The filtrate was condensed under reduced pressure to dryness. The residue was dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. The residue from which the solvent was evaporated was recrystallized in benzene to produce 73.6 g of 8-tert-butyl-3-cyano-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =H, R3 =CN in formula (I)] having a melting point of 220°-224° C. at a yield of 82.8%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH:19]4[CH:17]([CH:18]4[NH:21]C(=O)OC(C)(C)C)[CH2:16]3)[C:7]=2[CH:29]=1)#[N:2].NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:21][CH:18]1[CH:19]2[CH:17]1[CH2:16][N:15]([CH2:14][CH2:13][N:8]1[C:7]3[CH:29]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]1=[O:12])[CH2:20]2
Reactant: CC(C)(C)OC(=O)NC1C2CN(CCN3C(=O)COc4ccc(C#N)cc43)CC21
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: N#Cc1ccc2c(c1)N(CCN1CC3C(N)C3C1)C(=O)CO2

Procedure:
tert-Butyl {3-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate (Intermediate 94) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=O.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=[O:2]
Reactant: COC(=O)[C@@H]1SC[C@@H]2OC(C)(C)O[C@@H]21
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1SC[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
1.1 g (0.005 mol) of (3aS,4R,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester compound (7) from the aforementioned Experimental Example 7 were dissolved in 40 mL (0.080 mol) of 2N methylamine solution in tetrahydrofuran, which was stirred at 50° C. for 24 h in a sealed container. After concentration under reduced pressure, the obtained concentrate was purified by silica gel column chromatography using the eluant (hexane:ethyl acetate=2:1) to obtain 953 mg (yield: 87%) of (3aS,4S,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl amide as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH3:16])[CH2:11][C:12]([F:15])([F:14])[F:13])=[CH2:9])=[CH:4][CH:3]=1.[OH-:17].[Na+].OO.[Cl-].[Na+]>C1COCC1.O>[F:15][C:12]([F:14])([F:13])[CH2:11][CH:10]([CH3:16])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][OH:17]
Reactant: [OH-]
Reactant: C=C(c1ccc(C)cc1)C(C)CC(F)(F)F
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(CO)C(C)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under argon, 9.4 g (41.2 mmol) of 1-methyl-4-(5,5,5-trifluoro-3-methylpent-1-en-2-yl)benzene were dissolved in 130 ml of THF, 57.6 ml of a 1 M borane/THF complex solution were added and the mixture was stirred at room temperature for 24 h. With vigorous stirring, initially 79 ml of water, then 24 ml of 6 M aqueous sodium hydroxide solution and finally 14.5 ml (475 mmol) of 30% strength aqueous hydrogen peroxide solution were added. Subsequently, the reaction solution was added to 200 ml of saturated sodium chloride solution, the organic phase was separated off and the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→2:1). This gave 5 g (20.3 mmol, 49% of theory) of the title compound as a colorless oil.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:41])([F:40])[C@:16]([C:19]3[CH:24]=[C:23]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[CH:21][C:20]=3[F:39])([CH3:18])[N:17]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl.O1CCOCC1.Cl>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([F:39])=[C:19]([C@:16]2([CH3:18])[C:15]([F:40])([F:41])[CH2:14][O:13][CH2:12][C:11]([NH2:10])=[N:17]2)[CH:24]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of crude (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in dichloromethane (20 ml) was added at 22° C. trifluoroacetic acid (2.6 ml) and stirring was continued for 1 h. The mixture was diluted with 1,4-dioxane (40 ml) and aqueous hydrochloric acid (1 M, 33 ml) and vigorous stirring of the emulsion at 22° C. was continued for 16 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaCl and ethyl acetate, the aqueous layer was separated, the pH was adjusted to 14 using saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silica-NH2 using dichloromethane to give (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine as a colorless oil. MS (ISP): m/z=274.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:38][CH3:39]>ClCCl.N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:38][CH3:39])[CH:17]=3)[C:29]=12
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (35 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more 4-(trifluoromethyl)-1-benzenecarbonyl chloride (18 mg, 0.086 mmol) was added. 2 hours later, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide (85 mg, 95%). 1H NMR (CDCl3) δ 2.10 (m, 2H), 2.37-2.59 (m, 7H), 3.15 (m, 2H), 4.02 (s, 3H), 4.83 (m, 1H), 5.68 (s, 2H), 7.34 (m, 2H), 7.80 (d, J=8.21 Hz, 2H), 8.04 (d, J=8.10 Hz, 2H), 8.38 (s, 1H), 8.67 (m, 2H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=526.3, Rt=1.93 min.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:11][SiH:12]([CH3:14])Cl.Cl>BrCCBr.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:11])=[CH:6][CH:5]=1
Reactant: C[SiH](C)Cl
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc([SiH](C)C)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In a flask under a nitrogen atmosphere were placed 2.54 g (0.104 mole) of magnesium metal and approximately 25 mL of dry tetrahydrofuran. To this mixture was added a few drops of 1,2-dibromoethane. This was followed by the slow addition of a solution of 19.54 g (0.104 mole) of 4-methoxybromobenzene in 30 mL of tetrahydrofuran. After completion of addition, this reaction mixture was heated at reflux for one hour and was then cooled to room temperature. Slowly 9.89 g (0.105 mole) of dimethylchlorosilane was added to the reaction mixture which was then heated at reflux for one hour. To this was added 50 mL of 1 N hydrochloric acid, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with 50 mL of diethyl ether, and these washes were combined with the organic phase. The combined extracts were then washed with 200 mL of a saturated, aqueous solution of sodium chloride and were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, leaving a residue. Distillation of this residue yielded 14.4 g of (4-methoxyphenyl)dimethylsilane as a clear, yellow liquid, b.p. 80-90° C. at 9 mm of Hg. The proton nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)=[CH:24][C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[O:30][N:29]=2)=[CH:24][C:20]=1[C:21]([NH:15][CH2:14][C:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)([CH3:17])[CH3:16])=[O:22]
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cc(-c2noc(C(F)(F)F)n2)ccc1F
Product: CC(C)(CNC(=O)c1cc(-c2noc(C(F)(F)F)n2)ccc1F)c1coc(-c2ccc(F)cc2)n1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 32%) as a yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.46-8.43 (dd, J=6.8 Hz, 2.3 Hz, 1H), 8.29-8.25 (ddd, J=8.7 Hz, 4.8 Hz, 2.4 Hz, 1H), 8.09-8.05 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.77 (s, 1H), 7.47-7.42 (dd, J=10.3 Hz, 8.8 Hz, 1H), 7.25-7.20 (t, J=8.9 Hz, 2H), 3.67 (s, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C23H17F6N4O3: 492.12. found: 493.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[NH:12]1[CH2:14][CH2:13]1.C[C:16]#[N:17]>>[C:16]([C:11]1[C:1]2[C:6]([C:13]([C:14]#[N:12])=[C:1]3[C:6]=1[CH:5]=[CH:4][CH:3]=[CH:2]3)=[CH:5][CH:4]=[CH:3][CH:2]=2)#[N:17]
Reactant: C1CN1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC#N
Product: N#Cc1c2ccccc2c(C#N)c2ccccc12

Procedure:
1/5 of a 4-toluenesulfonic acid solution (PTSA H2O, 43.28 g; 0.228 mol) in CH3CN (400 mL) was added to a solution of the aziridine obtained at the previous step (229.13 g; GC 89%; 0.805 mol) and 9,10-dicyanoanthracene (DCA) (1.69 g; 7.40 mmol) in CH3CN (4.5 L). After 45 min, the remaining acid catalyst was added drop by drop to the reaction mixture in 6 hours, by means of the syringe pump. After 7.5 hours, heating and lighting were stopped. After 18 hours, water (0.5 L) and solid K2CO3 (40 g) were added with strong stirring. The organic solvent was evaporated off and the aqueous phase was extracted with CHCl3. The combined organic phases were washed with buffer 0.1M KH2PO4 /K2HPO4 at pH 7 (0.5 L), then dried over MgSO4. The crude oil resulting from the evaporation of the solvent (272.5 g) was purified by flash chromatography (CH3Cl/CH3OH/25% NH4OH (w/w) 1000:13:3 (v/v)), thereby obtaining the desired compound (51.64 g; 51.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=[CH:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C(/OC)c1ccccc1C=Cc1csc(-c2ccc(F)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)/C=C(/OC)c1ccccc1/C=C\c1csc(-c2ccc(F)cc2)n1
Solvent: CO
Product: COC(=O)/C=C(/OC)c1ccccc1CCc1csc(-c2ccc(F)cc2)n1

Procedure:
3 g (7.6 mmol) of methyl 2-{2-[2-(4-fluorophenyl)-4-thiazolyl]-(Z)-ethenyl}-(E)-β-methoxycinnamate in 100 ml of methanol are hydrogenated in the presence of 0.2 g of Pd/C (10%) under a gage pressure of 0.05 bar of hydrogen and at 20°-25° C. until hydrogen uptake ceases (1 h). The mixture is then filtered and concentrated.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:30]([N:39]2[CH:43]=[N:42][N:41]=[CH:40]2)[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:30]([N:39]2[CH:43]=[N:42][N:41]=[CH:40]2)[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N(C(c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(C(c2ccc(O)cc2)c2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-{[Bis-(4-benzyloxy-phenyl)-methyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02068, 564 mg, 1.0 mmol) was dissolved in ethanol, (50 mL) and palladium on charcoal (50 mg, 10% Pd) was added. The mixture was stirred under hydrogen atmosphere (balloon) for 48 h (TLC monitored) until all starting material was consumed. The Pd/C was filtered off (celite) and the solution was concentrated under reduced pressure. A yellow solid was obtained, which was dissolved in ethyl acetate (10 mL) upon heating. After cooling to room temperature the white precipitate was filtered off and dried under high vacuum. Yield: 312 mg (81%). 1H-NMR (400 MHz, d6-DMSO)=5.74 (s, 2H, 2×—OH); 6.28 (s, 1H), 6.53 (d, J=9.0 Hz, 2H), 6.61 (d, J=8.6 Hz, 4H), 7.10 (d, J=8.6 Hz, 4H), 7.65 (d, J=−9.0 Hz, 2H), 8.83 (s, 2H). LRMS (FAB+): 199.1 (100), 384.1 (50, [M+H]+). LRMS (FAB−) 184.1 (100), 382.1 (41, [M−H]−).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]([OH:8])([CH3:7])[CH3:6].[O:9]=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12]>>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]([NH:1][C:2]([NH:4][CH2:6][CH:5]([O:8][CH:10]([OH:9])[C:11]([Cl:14])([Cl:13])[Cl:12])[CH3:7])=[O:3])[OH:9]
Reactant: CC(C)O
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NC(N)=O
Product: CC(CNC(=O)NC(O)C(Cl)(Cl)Cl)OC(O)C(Cl)(Cl)Cl
Temperature: 85 °C

Procedure:
59 g. (0.5 mole) of monoisopropanol urea was heated to 80° C.; 149.0 g (1.01 moles) of chloral was added dropwise thereto between 80°-90° C. with stirring. After the addition, the reaction mixture was stirred and heated between 80-90° C. for an additional hour. On cooling a clear viscous liquid product was obtained that weighted 205 g.
Reaction SMILES: C([N-][CH:5]([CH3:7])C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CO[C:23]1[CH:24]=[C:25]([CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31](C)[C:30]2=[O:37])[CH:26]=[CH:27][CH:28]=1.C(Br)C.C1C[O:44][CH2:43]C1>CCCCCC>[CH2:5]([C:29]1([C:25]2[CH:24]=[CH:23][CH:28]=[CH:27][C:26]=2[O:44][CH3:43])[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:37])[CH3:7]
Reactant: C1CCOC1
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCBr
Solvent: CC(C)NC(C)C
Product: CCC1(c2ccccc2OC)CCCCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide, prepared by adding 15% butyl lithium in hexane (15.7 ml) to diisopropylamine (3.15 ml) at -10° C. under nitrogen, was treated with a solution of hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one in THF. After 30 minutes, ethyl bromide (1.0 ml) was added. The mixture was allowed to warm to ambient temperature. After a further 2 hours the reaction was quenched with water. The organic layer was evaporated to give an oil that crystallised on scratching. The solid was recrystallised from ethyl acetate to give the title compound (1.68 g) m.p. 85°-87° C.