Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:19]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
In 200 ml of DMF, 41.4 g of N-hydroxyphthalimide and 18 g of potassium carbonate were suspended. Fifty grams of cinnamyl bromide were added, followed by stirring at 120° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled and then poured into about 500 ml of water. Crystals thus precipitated were collected by filtration, dried and then recrystallized from a mixed solvent of acetone and isopropyl ether, thereby obtaining 41.9 g of N-cinnamyloxyphthalimide. Yield: 59.1%
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(Cl)=[O:4].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH:34][C:35](=[O:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][OH:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C1COCC1>[CH3:1][O:2][P@@:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[O:33][CH2:32][CH:31]([NH:34][C:35](=[O:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:25][CH:26]=1
Reactant: O=C(CCCCCCc1ccccc1)N[C@@H](CO)Cc1ccc(OCc2ccccc2)cc1
Reactant: COP(=O)(Cl)CCCOc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[P@](=O)(CCCOc1ccccc1)OCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
With ice-bath cooling, phosphonochloridate 53 (123 mg, 0.50 mmol) in dry THF (1.0 mL) was added dropwise to a solution of 55 (100 mg, 0.22 mmol) and Et3N (94 μL, 0.67 mmol) in dry THF (0.5 mL). After 10 min, the mixture was warmed to rt and stirred overnight. The Et3N.HCl precipitate was removed by filtration and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc, washed successively with KHSO4 (5% w/v), saturated NaHCO3, water, brine and dried (MgSO4). The solvent was removed in vacuo and the residue (209 mg) was purified on a C-18 reverse phase column to provide a diastereomeric mixture of 56a,b (82 mg, 56%) as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[Cl:3][C:4]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][O:11][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 40 °C
Yield: 51 %

Procedure:
3.25 parts by weight of 80% strength sodium hydride were suspended in 100 parts by volume of absolute tetrahydrofuran and a solution of 30 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl alcohol in 50 parts by volume of absolute tetrahydrofuran was then added, a little at a time. The mixture was stirred at 40° C. for half an hour and a solution of 15 parts by weight of methyl bromoacetate in 50 parts by volume of absolute tetrahydrofuran was added. The reaction mixture was then stirred at the boil for 2 hours, and was cooled and concentrated under reduced pressure. The oily residue was taken up in ether, and the organic phase was extracted with water, dried with magnesium sulfate and evaporated down under reduced pressure. Fractional distillation of the residue gave 19 parts by weight (51% of theory) of methyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzoxyacetate (compound No. 4) of boiling point 150°-160° C./0.2 bar and refractive index nD25 : 1.5268.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnc2c1cnn2-c1cccc(NC(=O)c2ccsc2)c1
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.1 eq, 0.17 mmol) was added to a solution 3-thiophenecarboxylic acid (20 mg, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.16 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 17 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (10 mg, 0.03 mmol, 17%). LCMS: [M+H]+=337, Rt=1.58 min, 100% purity.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[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].[CH:33](=O)[CH2:34][CH:35]([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[ClH:58]>C(Cl)Cl.C(OCC)C.CCOC(C)=O>[ClH:58].[ClH:58].[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCN[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-phenyl-propan-1-one (0.500 g, 1.15 mmol, Example 52) and isovaleraldehyde (0.123 mL, 1.15 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 (0.365 g, 1.72 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 5 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 1.0 and 0.29. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.29) was isolated by flash chromatography (60% EtOAc in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 138 mg (20%) of the pure titled compound as a white foam: mp 172-186° C. APCI-MS m/z 506.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a light brown solid (207 mg).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.[Cl-].[Na+].O>[OH:1][N:2]=[C:3]([C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1)[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (1.3 g, 5.0 mmol) [made according to Example 1, steps A through E] was stirred in water (10 mL) and warmed to 60° C. for 5 minutes. 3-(trifluoromethyl)aniline [Aldrich, product #A41801] (880 mg, 5.5 mmol) was added in one portion and the reaction stirred for 15 minutes. While remaining at 60° C., a solution of sodium bicarbonate (630 mg, 7.5 mmol) in water (10 mL) was added dropwise over 5 minutes. The reaction was stirred at 60° C. for an additional 50 minutes, and then allowed to cool to room temperature. Ethyl acetate (20 mL) and brine (30 mL) were added to the flask and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product as an orange solid (1.4 g, 80%). LCMS calculated for C13H15F3N5O3 (M+H)+: m/z=346.1. 1H NMR (400 MHz, CD3OD): δ 7.36 (t, J=8.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.60 (t, J=5.2 Hz, 2H), 3.46 (t, J=5.2 Hz, 2H), 3.38 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:16])([C:13](O)=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CC(C)=O.O>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:16])([C:13]([N:31]=[N+:32]=[N-:33])=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C)(C(=O)O)CC2C1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC2CC(C)(C(=O)N=[N+]=[N-])CC2C1
Yield: 62.8 %

Procedure:
Upon cooling by an ice-water bath, 2-dimethylcarbamoyl-5-methyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (1.0 g, 4.2 mmol) was dissolved in 25 mL of acetone with stirring, followed by dropwise addition of a solution of triethylamine (463.5 mg, 4.58 mmol) and ethyl chloroformate (497 mg, 4.58 mmol) in 10 mL of acetone at −5° C. The reaction mixture was reacted for 15 minutes at −5° C. followed by addition of a solution of sodium azide (546 mg, 8.4 mmol) in 10 mL of water. Then the reaction mixture was stirred for another 30 minutes at −5° C., and quenched with 25 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound 2-dimethylcarbamoyl-5-methyl-hexahydro-cyclopenta[c]pyrrole-5-carbonylazide 12d (700 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:31][C:32]([CH3:36])=[CH:33][CH2:34]Br.O>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH:33]=[C:32]([CH3:36])[CH3:31])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=CCN(C(=O)OC(C)(C)C)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 21.9 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-tert-butyloxycarbonylaminophenyloxy)piperidine (0.9 g) in acetone (20 ml) were added solid potassium hydroxide (0.13 g) and 3-methyl-2-butenyl bromide (0.34 g) and the mixture was heated under reflux overnight. Water was added to the reaction mixture and the mixture was extracted with methylene chloride (50 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[4[N-tert-butyloxycarbonyl-N-(3-methyl-2-butenyl)amino]-phenyloxy]piperidine (0.23 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:7]([N+:22]([O-:24])=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:31](C(OC(C)(C)C)=O)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=O>CN(C=O)C>[CH3:36][C:35]([O:34][C:32](=[O:31])[N:11]([C:8]1[N:7]([N+:22]([O-:24])=[O:23])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)([CH3:38])[CH3:37]
Reactant: Cc1cccc2c1nc(Nc1cccc(C(F)(F)F)c1)n2[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(N(C(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1)n2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.7 %

Procedure:
(Methyl-nitro-1H-benzoimidazol-2-yl)-(3-trifluoromethyl-phenyl)-amine (2.34 g) and cesium carbonate (5.61 g, 17.2 mmol) was stirred in DMF for 15 min., then (BOC)2O (2.81 g, 12.9 mmol) was added. The resulting mixture was stirred at room temperature for 4 days, the reaction mixture was then concentrated and the residual was taken into EtOAc and washed by water, then brine, drying and concentration, silica flash, which gave 1.45 g of the title compound as a yellow foam: LC/MS(m/e) 437 [M+H]+, Rt at 2.34 min.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: CC(O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 4-bromo-methylbenzyl alcohol (184 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (65 mg, 13%). MS (ISP) 475.2 [(M+H)+]; mp 157-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:11](\[C:17]#[N:18])/C(OCC)=O)/[CH2:6][CH2:5]2.[C-:19]#[N:20].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:11][C:17]#[N:18])([C:19]#[N:20])[CH2:6][CH2:5]2
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)ccc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCc2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 21 h
Yield: 43.7 %

Procedure:
To a solution of (E)-ethyl 2-(5-chloro-2,3-dihydro-1H-inden-1-ylidene)-2-cyanoacetate (Prep5, 100 g, 0.38 mol) in ethanol (800 ml) a solution of KCN (67.5 g, 1 mol) in water (230 ml) was added and the reaction mixture was warmed to 65° C. and stirred for 21 h. Then the solvent was removed under vacuum The residue was treated with ether and the organic phase washed with water. Solvent was evaporated and the crude obtained was purified by crystallization from ethanol to obtain the title compound (36 g, y=43.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2].[OH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[OH:17])=[O:29])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCC1
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCC1

Procedure:
(2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-cyclobutylmethyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C23H29N2O4 [(M+H)+] 397.0, obsd. 397.2.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].OS(O)(=O)=O>O>[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:16])([F:17])[F:18])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([OH:4])=[O:3]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
5-chlorosulfonyl-2-trifluoromethoxy-benzoic acid (1.0 g, compound 2.9.a) was added portionwise onto a solution of sodium sulfite (3.1 g) in 16 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 45 minutes. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. The solution was then extracted several times with diethyl ether and ethyl acetate. The combined organic phases were dried (sodium sulfate) and concentrated in vacuo to yield the title compound as a white solid (0.88 g).
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)[NH2:8].C(O)(=O)C>C(O)C>[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:8]=1
Reactant: Cc1cccc(NN)n1
Reactant: C/C=C(\N)C#N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(-n2nc(C)cc2N)n1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To an ice-cold solution of aminocrotononitrile (20.5 g, 0.25 mol) and 2-hydrazino-6-methylpyridine (31.0 g, 0.252 mol) in ethanol (200 mL), acetic acid (30 g, 0.5 mol) was added and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and the reaction solvent was concentrated and evaporated under reduced pressure, and water was added to the residue. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to give the title compound (41.3 g, 88% yield).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: O=C(c1ccccc1)c1ccccc1O
Product: Cc1cc(Oc2cccc(Oc3ccccc3C(=O)c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.020 g (14%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z mass calculated for C29H24O5 453.1702, found 453.1699.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][O:9][CH2:10][C:11]=1[NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:7][CH2:8][O:9][CH2:10][C@H:11]1[NH:12][C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)COCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CCOC[C@H]1N[C@H](C)c1ccccc1
Reaction time: 17 h
Yield: 35.6 %

Procedure:
A solution of crude (R)-5-(1-Phenyl-ethylamino)-3,6-dihydro-2H-pyran-4-carboxylic acid ethyl ester (4.53 g, ca. 16.5 mmol) was dissolved in trifluoroacetic acid (45 mL) and treated with triethylsilane (7.9 mL, 49.4 mmol). The mixture was stirred for 17 h and then concentrated. The residue was dissolved in water and adjusted to pH 10 with 50% sodium hydroxide. The mixture was extracted with dichloromethane, and the combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (40% diethyl ether/petroleum ether) to provide the product as a colorless oil (1.63 g, 36%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:3][CH:2]=1.C(C1C=CN=CC=1)(=O)C.[NH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]#[N:32]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[CH:28]=[N:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reactant: N#Cc1[nH]cnc1N
Agent: CC(=O)c1ccncc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccncc3)nc12
Yield: 26.6 %

Procedure:
Reaction of 1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 4-acetylpyridine according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (77 mg, 27%). MS (ISP) 289.8 [(M+H)+]; mp 254° C.