Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH3:15][C:16]([CH3:1])([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC(C)(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3,3-dimethyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (d, J=6.7, 0.5H), 8.13 (d, J=7.1, 0.5H), 7.74-7.70 (m, 1H), 7.69-7.66 (m, 1H), 7.61 (t, J=8.6, 3H), 7.48-7.43 (m, 1H), 7.37-7.24 (m, 3H), 4.48-4.39 (m, 0.5H), 4.36-4.28 (m, 0.5H), 3.51 (q, J=13.1, 0.5H), 3.41 (d, J=17.1, 1H), 3.35 (d, J=13.3, 0.5H), 3.13 (d, J=13.4, 0.5H), 2.98 (qd, J=4.0, 8.2, 0.5H), 2.81 (dd, J=3.9, 9.5, 0.5H), 2.74 (ddd, J=3.4, 7.8, 16.6, 0.5H), 2.49-2.37 (m, 2H), 2.31 (dd, J=3.4, 9.6, 0.5H), 2.24-2.15 (m, 2H), 2.01-1.94 (m, 0.5H), 1.84 (ddd, J=8.1, 11.7, 14.5, 0.5H), 1.73-1.65 (m, 1H), 1.64-1.56 (m, 0.5H), 1.52-1.38 (m, 1H), 1.27 (dt, J=5.6, 12.2, 1H), 1.16 (s, 4.5H), 1.11 (s, 4.5H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:10].C(=O)([O-])[O-:30].[K+].[K+].CS(C)=O.OO>CO.O>[NH:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]3[NH:10][C:9](=[O:30])[C:5]4[N:4]([CH:8]=[CH:7][CH:6]=4)[CH:3]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cccc12
Reaction time: 8 h

Procedure:
1-(2-Oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carbonitrile (1.40 g; 3.60 mmol) is slurried in methanol (10 ml). Potassium carbonate (2.49 g; 17.98 mmol), dry dimethylsulfoxide (0.77 ml; 10.79 mmol) and hydrogen peroxide (1.10 ml; 10.79 mmol) are added (caution: strong exothermic reaction after the addition of hydrogen peroxide). The yellow suspension is stirred overnight. The reaction mixture is diluted with water, the precipitate is filtered off by suction, washed with water and dried under vacuum at 50° C. The crude product is purified by flash chromatography. The combined fractions are evaporated to dryness. The residue is triturated with diethylether, filtered off by suction and dried under vacuum at 50° C. to afford 3-(4-piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as off-white solid;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.1 g, 0.25 mmol), 4-methylphenylboronic acid (0.04 g, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 31 mg of the title compound as a yellow oil. MS: [M+H]+=360.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][O:14][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1
Reactant: Cn1nnc(-c2ccccc2F)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of (4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (100 mg, 0.48 mmol) in THF (1.4 mL) was added dropwise at 0° C. to a suspension of NaH (60% in oil, 21 mg, 0.53 mmol) in THF (0.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (91 mg, 0.53 mmol) in THF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (110 mg, 67%) as a colourless gum. MS: m/e=343.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CN1CCN(C(=O)c2cncc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CN1CCN(C(=O)c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (70 mg, 0.287 mmol, 1 eq) and (6-chloropyrazin-2-yl)(4-methylpiperazin-1-yl)methanone (60) (69 mg, 0.287 mmol, 1.0 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (140 mg, 0.430 mmol, 1.5 eq) followed by addition of Pd(dpp)Cl2 (13.2 mg, 0.0114 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1-2% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(4-methylpiperazin-1-yl)methanone 139 in 20 mg quantity. The compound 139 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.98 (s, 1H), 9.45 (s, 1H), 9.04 (d, J=1.95, 1H), 8.76 (m, J=12.43, 2H), 7.63 (m, J=2.68, 1H), 6.64 (m, J=1.58, 1H), 3.76 (s, 2H), 3.59 (m, J=69.03, 2H), 2.42 (m, 4H), 2.28 (s, 3H); MS m/z 321.4 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[NH2:27]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:23][C:24]1[CH:25]=[C:26]([NH:27][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
Commercially available Boc-L-proline (16, 2.3 g; 10.7 mmol) is dissolved in DCM (20 ml) and cooled to 0° C. followed by the addition of NEt3 (1.12 g; 11.22 mmol) and ethyl chloroformiate (1.22 g; 11.22 mmol) and finally commercially available 3,5-dimethylaniline (15) (1.36 g; 11.22 mmol). The reaction mixture is stirred at rt for 60 minutes. Brine (50 ml) is added and the organic layer is separated. The aq. layer is extracted with DCM (2×30 ml). The combined organic layers are dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 4.07 g of crude (S)-tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)pyrrolidine-1-carboxylate (17) which is used in the next step without further purification. LC-MS: tR=0.81 min; [M+H]+=319.11.
Reaction SMILES: O.O.Br[C:4]1[C:5]([CH3:16])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([OH:13])(=[O:12])=[O:11])[CH:9]=1>CO.[Pd]>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([CH3:16])[CH:4]=[CH:9][C:8]=1[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: COc1cc(C)c(Br)cc1S(=O)(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1cc(C)ccc1S(=O)(=O)O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
To a solution of 5-bromo-2-methoxy-4-methylbenzenesulfonic acid dihydrate (from (a), 125 g, 0.394 moles) in methanol (1.25 liters, 10 ml/g) was added 5% Palladium on carbon catalyst (12.5 g, 0.1 g/g) and the suspension was hydrogenated at 60° C. and 414 kPa (60 psi) for 16 hours. The reaction mixture was filtered over celite and concentrated to dryness. The crude product was slurried in dichloromethane (250 ml), cooled to 0-5° C. and the subtitle compound (67.5 g, 75% yield) isolated in two crops as a white crystalline solid
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:34][O:35][CH3:36])[C:12]([NH:14][C@H:15]2[C@@H:18]([O:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:17]([S:29]([O-:32])(=[O:31])=[O:30])[C:16]2=[O:33])=[O:13])[N:10]=1)=O.[Na+:37].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:34][O:35][CH3:36])[C:12]([NH:14][C@H:15]2[C@@H:18]([O:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([S:29]([O-:32])(=[O:30])=[O:31])[C:16]2=[O:33])=[O:13])[N:10]=1.[Na+:37]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1OC(=O)Cc1ccccc1)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1OC(=O)Cc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.7 %

Procedure:
To a solution of 0.10 g of sodium (3S,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylacetoxy-2-oxoazetidine-1-sulfonate in 7 ml of water is added number ice-cooling 0.027 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 1.5 hours. Insolubles are filtered off, and the filtrate is purified on an XAD-II column to yield 0.044 g of sodium (3S,4R)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-phenylacetoxy-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[CH:16]=[N:15][C:14]=2[C:26]#[N:27])=[CH:8][CH:7]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]([C:26]([NH2:27])=[O:34])=[N:15][CH:16]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[N:18]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(6-(4-(1,3,4-oxadiazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)butanamide (57 mg, 0.156 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 383.3 (M+H); UV 204.7, 275.5, 329.8 nm; t 0.449 min.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].CN(C=[O:39])C>>[F:3][C:4]1[CH:9]=[C:8]([NH:29][CH2:33][CH2:32][CH2:31][C:30]([OH:34])=[O:39])[CH:7]=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2
Reactant: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C1CCCN1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCCNc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% w/w in mineral oil) (3.7 mg, 93 μmol) was added to a mixture of 2-(2,4-difluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (28.2 mg, 77 μmol) and pyrrolidin-2-one (5.9 μl, 77 μmol) in DMF (0.8 mL) and the resulting mixture was stirred at 25° C. for 30 min, then heated at 40° C. for 15 h. Additional pyrrolidin-2-one (5.9 μl, 77 μmol) and sodium hydride (60% w/w in mineral oil) (3.7 mg, 93 μmol) were then added, and the resulting mixture was heated at 60° C. for 1 h. The reaction mixture was then cooled to 25° C. and partitioned between EtOAc (70 mL) and sat. aq. ammonium chloride (30 mL). The organic layer was separated and sequentially washed with water and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc-Hexanes) provided 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)butanoic acid as a light yellow solid. MS (ESI) m/z: Calculated: 447.1; Observed: 448.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:48])[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=1[F:47].O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10]([C:24]3[CH:23]=[CH:22][C:21]([NH:35][C:36](=[O:48])[C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:38]=4[F:47])=[C:20]([O:19][CH3:18])[CH:25]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3C=CC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.12 g, 0.35 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-trifluoromethylbenzamide (0.23 g, 0.53 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.02 g, 0.02 mmol) and sodium carbonate monohydrate (0.11 g, 0.88 mmol) was heated in a mixture of ethylene glycol dimethyl ether (6 mL) and water (3 mL) at 85° C. for 6 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC to yield N1-{4-[4-amino-1-(4-hydroxy-2-cyclopentenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.18 g, 0.34 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.89 (dd, 1H), 8.31(d, 1H), 8.26 (s, 1H), 8.00 (t, 1H), 7.88 (d, 1H), 7.75 (d, 1H), 7.32 (s, 1H), 7.29 (d, 1H), 6.90 (br, 2H), 6.09 (d, 1H), 5.93 (d, 1H), 5.76 (m, 1H), 5.31 (m, 1H), 4.74 (m, 1H), 3.94 (s, 3H), 2.84 (m, 1H), 2.02 (m, 1H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 8.50 min. MS: MH+ 529.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1nc(-c2ccccc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
A mixture of 2-methyl-6-phenylpyrimidin-4(3H)-one (15 g) and POCl3 (150 ml) was refluxed under nitrogen for 20 h. The excess POCl3 was distilled off and the residue was diluted with ethyl acetate (500 ml) and washed with 10% solution of sodium bicarbonate (100 ml), water, brine and dried. The solvent was removed under reduced pressure and the residue was purified by chromatography (silica, 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 11 g (67%) of the titled as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:11][C:10]=1[C:33]1[N:37]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[N:36]=[N:35][N:34]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:37]1[C:33]([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:34][N:35]=[N:36]1
Reactant: [H][H]
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
5% Pd/C was wetted carefully with MeOH under N2, then 5-(4,6-bis-benzyloxy-3′-trifluoromethyl-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (90 mg, 0.16 mmol) solution in methanol was added. The reaction system was vacuumed and filled with hydrogen three times. The reaction was stirred under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give 5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-3′-trifluoromethyl-biphenyl-2,4-diol (50 mg, 82%). M.p.: 144-182° C.; 400 MHz 1H NMR (CDCl3) δ: 10.82 (s, 1H), 7.62 (s, 1H), 7.72-7.58 (m, 4H), 6.76 (s, 1H), 5.70 (s, 1H), 4.74 (t, J=7.6 Hz, 2H), 3.41 (t, J=6.8 Hz, 2H), 3.10 (s, 3H), 2.31-2.23 (m, 2H); LCMS: 395 [M+H].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH:18]([CH3:23])[C:19]2=O)=[CH:15][CH:14]=1.ClCCl.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.O>[CH2:31]([O:30][C:27](=[O:29])[CH2:28][C:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:21]=2)[CH2:17][C:18]=1[CH3:23])[CH3:32]
Reactant: CCOC(C)=O
Reactant: CC1Cc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1=C(C)Cc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 1 h

Procedure:
Triethylphosphonoacetate (22.41 g, 100 mmole) is added dropwise under nitrogen to a stirred and cooled (0° C.) slurry of Nail (57% in oil, 4.27 g, 100 mmole) in dry toluene (250 mL). The cooling bath is removed and stirring continued at room temperature for 60 minutes whereby an almost homogeneous solution is obtained. A solution of the indanone (15.15 g, 50 mmole) of Step E, in toluene (50 mL) is then added dropwise. The flask is placed in an oil bath heated at 95° C. for 19 hours (TLC, traces of starting material present, dichloromethane-ethyl acetate 9:1, UV, Vaughn's). The reddish solution is cooled, diluted with water and extracted with ethyl acetate (3 times). The combined extracts are washed with brine, dried (anhydrous K2CO3) and evaporated to dryness. The residue (heavy brown oil) is flash chromatographed (on silica Merck-60, eluted using a gradient dichloromethane AE dichloromethane:ethyl acetate 84:16) to provide the title compound as a mixture of endo and exo isomers (16.3 g, 87.4%, oil that solidifies upon standing) together with unreacted, more polar starting material (1.84 g, 12% recovery).
Reaction SMILES: C(O[C:9]1C=C[C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:17]([CH2:25][C:26]([O:28]CC)=O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:31](OCC)(=O)[CH2:32][C:33]([CH3:35])=O>>[CH3:9][C:10]1[CH:11]=[C:12]([N:15]2[C:26](=[O:28])[CH:25]=[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:16]2)[CH:31]=[CH:32][C:33]=1[CH3:35]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Product: Cc1ccc(-n2[nH]c(-c3ccccc3)cc2=O)cc1C

Procedure:
Following the procedure of Example 3b), except substituting 3,4-dimethylphenylhydrazine for 4-benzyloxyphenylhydrazine and ethyl benzoylacetate for ethyl acetoacetate, the title compound was prepared (16.0 g; 61%). MS(ES) m/z 265 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27](=NO)(N)[CH2:28][CH2:29][CH2:30]C>CN(C)C=O>[CH2:27]([C:19]1[N:18]=[C:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=4[C:8](=[O:26])[N:9]4[CH2:25][CH2:24][CH2:23][C@H:10]4[C:11]=23)[O:17][N:20]=1)[CH2:28][CH2:29][CH3:30]
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: CCCCC(N)=NO
Solvent: CN(C)C=O
Product: CCCCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 2 h

Procedure:
11.0 g (30 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 50 ml of N,N-dimethylformamide, whereupon the solution is treated with 3.96 g (34 mmol) of valeramidoxime and the mixture is heated to 85° for 3 hours. The reaction mixture is evaporated to dryness. The residue is dissolved in 50 ml of glacial acetic acid and the mixture is stirred at 110° for 2 hours. The reaction mixture is subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. After evaporation of the eluate there is obtained (S)-1-(3-butyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 181°-182°.