Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([F:20])[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+].[O:23]1CCC[CH2:24]1>O.CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:24]=[O:23]
Reactant: C1CCOC1
Reactant: Fc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)cccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (2.65 mL) in tetrahydrofuran (30 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 7.03 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added 3-bromofluorobenzene (3 g), and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added N,N-dimethylformamide (1.45 mL), and the mixture was stirred at the same temperature for 10 minutes, then a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was stirred under ice-cooling for 5 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.43 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3C=CCCC3)c2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-6-(cyclohex-2-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in a mixture of methanol (6 ml) and tetrahydrofuran (16 ml) was added 20% palladium hydroxide/carbon (400 mg, 0.74 mmol). After stirring for 13 hr under hydrogen atmosphere (3.4 atm) at room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated. The precipitated solid was collected by filtration. The solid was washed with diisopropyl ether (5 ml×3), and dried under reduced pressure to give methyl 5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.12 g, yield 82%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]#[N:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]#[N:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: N#CCCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (70 mg, 0.51 mmol, 4 eq) and chloroacetonitrile (17 mg, 0.231 mmol, 1.8 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (29 mg, 48%). MS(ES)+ m/e 468.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4OC(C)C)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O)(=O)C>CO>[C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4[N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(OC(C)C)c(=O)c1=O
Reactant: C1COCCN1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(N2CCOCC2)c(=O)c1=O

Procedure:
A solution of methyl (S)-3-[4-(3-phenyl-1-isoquinolinylamino)phenyl]-2-(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)propanoate (20 mg, 0.08 mmol) [prepared in a similar manner to the compound of Example 1]in MeOH (0.2 ml) was treated with morpholine (0.011 ml, 0.12 mmol) and the resulting mixture heated at 60° for 24 h. The mixture was concentrated to dryness then redissolved in anhydrous THF (1.0 ml) and treated with polystyrene methylisocyanate resin (Argonaut Technologies, 120 mg, 2.0 mmol/g, 0.24 mmol) at room temperature for 24 h. The resulting mixture was filtered, and the resin was washed with MeOH(1.0 ml). The combined filtrate was evaporated to dryness then redissolved in THF (0.2 ml) and treated with an aqueous solution of lithium hydroxide monohydrate (0.2 ml of a solution of 100 mg in 4.0 ml water, 0.12 mmol) at room temperature for 24 h. The reaction mixture was quenched with glacial acetic acid (0.007 ml, 0.12 mmol), then evaporated to dryness to give the crude product which was purified by preparative HPLC to afford the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Li]CCCC.[F:21][C:22]([F:42])([F:41])[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[N:29]=[CH:28]2)=[O:24]>CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:29]=[CH:28]3)([OH:24])[C:22]([F:41])([F:21])[F:42])[N:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Br)cs1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66.6 %

Procedure:
To a chilled (−78° C.) solution of 4-bromo-2-(tert-butyldimethylsilanyloxymethyl)thiazole (339 mg, 1.10 mmol) (prepared according to a procedure described by Nicolaou et al., Bioorg. Med. Chem. 1999, 7, 665-697) in dry ether (5 mL) was added n-BuLi (440 μL, 2.5 M in hexane, 1.10 mmol). After 2 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (308 mg, 1.00 mmol) in 5 mL of dry ether added. After 15 minutes, the mixture was warmed to room temperature and quenched with 20 mL of saturated aqueous ammonium chloride and extracted with three 20 mL portions of diethyl ether. The combined organic layers were washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-30% ethyl acetate in hexanes, gradient) to afford 358 mg (67%) of 1-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol. MS m/z 538.97 (MH+).
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH3:17].CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1>[Si:7]([O:6][C:5]1[CH:14]=[C:15]([CH3:16])[C:2]([B:29]([OH:34])[OH:30])=[C:3]([CH3:17])[CH:4]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1B(O)O
Temperature: -78 °C
Yield: 53.5 %

Procedure:
To a solution (250 mL) of (4-bromo-3,5-dimethylphenoxy)(tert-butyl)dimethylsilane (39.2 g, 124 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 90.0 mL, 144 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 2 hr, and triisopropyl borate (40.0 mL, 173 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 hr. To the reaction mixture was added 2 M hydrochloric acid (180 mL), and the mixture was stirred for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/4) to give the title compound (18.6 g, yield 53%) as pale-yellow prism crystals.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].CC(O)=O>O1CCOCC1>[C:20]1([C@@H:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](Nc5ccccc5)C4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: c1ccc(N[C@@H]2CC[C@@H](c3nnc4cnc5[nH]ccc5n34)C2)cc1
Temperature: 60 °C
Yield: 74.3 %

Procedure:
To N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (0.106 g, 0.224 mmol) in 1,4-dioxane (1 mL) was added NaOH (1 N aqueous, 1.12 mL, 1.12 mmol). The reaction mixture was heated at about 60° C. for about 1 h. AcOH (0.5 mL) was added and the crude reaction mixture was purified by RP-HPLC (Table 1, Method j) to give N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)aniline (0.053 g, 74%) as a light yellow solid: LC/MS (Table 1, Method b) Rt=1.84 min; MS m/z: 319 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:10](=[O:23])[CH2:11][NH:12][C:13](OCC1C=CC=CC=1)=[O:14])[C:3]1(C(OC)=O)[CH2:5][CH2:4]1>CO>[CH3:1][N:2]1[C:10](=[O:23])[CH2:11][NH:12][C:13](=[O:14])[C:3]21[CH2:5][CH2:4]2
Reactant: COC(=O)C1(N(C)C(=O)CNC(=O)OCc2ccccc2)CC1
Solvent: CO
Product: CN1C(=O)CNC(=O)C12CC2
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl 1-[methyl(N-{[(phenylmethyl)oxy]carbonyl}glycyl)amino]cyclopropanecarboxylate (3.66 g, 11.42 mmol) was dissolved in 50 mL of MeOH, degassed and placed under argon. 10% Pd/C (2.04 g) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through Celite, washing with MeOH. The filtrate was concentrated in vacuo. The residue was dissolved in MeOH (100 mL) and heated to 60° C. with stirring for 4 h. The solvent was removed in vacuo to provide pure 4-methyl-4,7-diazaspiro[2.5]octane-5,8-dione (1.76 g, 99%). LCMS: (M+H)+: 155.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)=[O:20])=[CH:13][C:12]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].CCN(CC)CC.ClC(OCC)=O>C1COCC1>[OH:2][CH2:1][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26]3)=[O:20])=[CH:13][C:12]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cccc(C(=O)O)c3)c([N+](=O)[O-])c2)CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cccc(CO)c3)c([N+](=O)[O-])c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirred solution of benzoic acid from Example 92A (255 mg, 0.56 mmol) in 5 mL of anhydrous THF at 0° C. was added in turn Et3N (102 mL, 0.73 mmol) and ethyl chloroformate (70 mL, 0.73 mmol). After 60 minutes, the reaction mixture was filtered through celite plug into a stirred solution of NaBH4 in water at 0° C. The resulting reaction mixture stirred at 0° C. for 2 hours before it was extracted with EtOAc (2×20 mL). The combined organic layers were washed with 3N HCl, brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The crude product was purified using Gilson Preparative HPLC as described in Example 38B to give the title compound (80 mg, 32% yield) as a light-yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.40-3.79 (m, 8H), 4.56 (s, 2H), 5.38 (br s, 1H), 6.85 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (br s, 3H), 7.57 (br s, 2H), 7.91 (dd, J=2.1, 8.7 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H). MS (APCI+) (M+NH4)+ at m/z 459.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C[OH:10]>>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CO
Reactant: N#Cc1cccnc1
Product: NC(=O)c1cccnc1
Reaction time: 0.17 h

Procedure:
A reaction mixture comprising 3-cyanopyridine (0.5 M; 0.500 ml), nitrile hydratase solution (0.697 μmol/min; 0.025 ml) and different buffers in the pH range from 4 to 11 (0.1 M; 0.0475 ml) was incubated at 20° C. for 10 min. The reaction was stopped by adding MeOH. The amount of nicotinamide produced was determined by means of HPLC according to Example 1. The pH optimum of nitrile hydratase was in the range from 6.0 to 6.5 (FIG. 16).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:5]1[CH:6]=[N:7][C:3]([CH2:2][O:29][C:26]2[CH:27]=[CH:28][N:23]([C:21]3[S:22][C:18]([C:16]([NH:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[O:17])=[C:19]([CH3:31])[N:20]=3)[C:24](=[O:30])[CH:25]=2)=[N:4]1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: ClCc1ncon1
Product: Cc1nc(-n2ccc(OCc3ncon3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 3-(chloromethyl)-1,2,4-oxadiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.9 Hz, 1H), 8.66 (d, J=8.1 Hz, 1H), 7.36-7.17 (m, 6H), 6.42 (dd, J=8.1, 2.8 Hz, 1H), 6.33 (d, J=2.8 Hz, 1H), 5.26 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.55 (s, 3H); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:28])[CH2:27][CH2:26][C:23]4([CH2:25][CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:28])[CH2:27][CH2:26][C:23]4([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoate (0.277 g, 0.713 mmol) and anisole (0.11 mL, 1.07 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.75 mL, 9.61 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with water (5 mL). The reaction was diluted with dichloromethane (20 mL) and washed with water (4×10 mL) until the last wash was neutral as monitored by pH paper. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (0.213 g, 90%) as a white solid: MS (ES−) m/z 331.3 (M−1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC(C)([O-])C.[K+].Br[CH2:22][C:23]#[N:24]>CS(C)=O>[C:23]([CH2:22][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)#[N:24]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)N(CC#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.24 g (15 mmol) of N-methylsulphonyl-4-nitroaniline are dissolved in 25 ml of DMSO and a total of 2.0 g (18 mmol) of potassium tert.butoxide are added batchwise. After 1 hour stirring at ambient temperature 2.7 g (23 mmol) of bromoacetonitrile are added dropwise. After 3 hours stirring at ambient temperature the mixture is poured onto ice water and extracted with ethyl acetate. The organic phase is washed with water and the solvent is eliminated in vacuo. The residue thus obtained is recrystallised from ethanol.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[CH:28][N:27]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:31]=[C:30]([C:32]([CH3:34])([CH3:33])[CH3:35])[CH:29]=[CH:28][N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)c1ccnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccnc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 63.4 %

Procedure:
In a round-bottomed flask, 2-(4-tert-butyl-pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (62 mg, 0.091 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.28 mL) was added. The yellow reaction mixture was stirred at room temperature for 2.75 h then concentrated under reduced pressure. The residue was dissolved in dichloromethane (0.5 mL) and ethylenediamine (0.37 mL) was added. The reaction mixture was stirred at room temperature for 1.25 h then quenched with 5 mL water and extracted with EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 8 g SiO2 with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-4% MeOH). All fractions containing product were combined and concentrated to afford 28 mg (61%) of 2-(4-tert-butyl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow foamy solid. MS: (M+H)+=486.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N:16]=[C:17]=[S:18])(=O)C1C=CC=CC=1>C(O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:17]([NH2:16])=[S:18]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cnccn1
Solvent: CCO
Product: NC(=S)Nc1cnccn1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Aminopyrazine (2 g, 21.03 mmol) is dissolved in ethanol (20 ml) and benzoylisothiocyanate (2.82 ml) is added dropwise. The mixture is heated to 80° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (30 ml) and heated under reflux for 1 hour. The resultant suspension is filtered and the solid washed with water and a little cold methanol. The solid is dried in vacuo to yield the title compound, m.p. 239–239.5° C., m.s. (AP+) 138 (M+—NH3). Other thioureas of formula III are prepared in an analogous manner from the appropriate starting amine.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1.[CH2:55]([C@@H:60]1[O:62][C@H:61]1[CH2:63]O)[CH2:56][CH2:57][CH2:58][CH3:59]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:63][C@H:61]2[C@H:60]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:62]2)=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCCCC[C@@H]1O[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
0.44 g (2.55 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 0.67 g (2.55 mmol) of triphenylphosphine in 15 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.54 g (1.70 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared by EXAMPLE 3) and 0.25 g (1.70 mmol) of (2S,3S)-3-pentyl-2-oxiranylmethanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 8:2hexane/ethyl acetate ). Recrystallization from 8:2hexane/ethyl acetate gives 0.28 g of (2S,3S)-3-pentyloxiran-2-ylmethyl 2-fluoro-6-(4-octyloxyphenyl)pyridin-3-yl ether having an [α]D° (2.4% in CH2Cl2) of -15.75°. ##STR70##
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[C:7]([F:20])[C:8]3[C:13]([C:14]=2[O:16][CH3:17])=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:20][C:7]1[C:8]2[C:13]([C:14]([O:16][CH3:17])=[C:15]3[C:6]=1[CH:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=[C:2]3[O:1][CH3:26])=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)c2c(OC)c3cc(OC)ccc3c(F)c2c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1cc(OC)c2c(OC)c3cc(OC)ccc3c(F)c2c1
Reaction time: 2 h

Procedure:
Ethyl 4-hydroxy-6,10-dimethoxy-9-fluoroanthracene-2-carboxylate (4 g) was dissolved in acetonitrile. Potassium carbonate (2.5 g) and iodomethane (3 g) were added. The mixture was heated under reflux with vigorous stirring under nitrogen for 2 hours. The solution was filtered to remove solids and washed with water. The organic phase was washed, dried (MgSO4), filtered and concentrated to give the above compound as a yellow solid.