Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[OH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C:32](=[O:33])[C@@H:31]([OH:30])[CH3:35])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H](O)C(=O)O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)[C@H](C)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methyl phenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.033 mmol, chiral intermediate from Example 1, Step 7, peak 1), mixture of (2S)-2-hydroxypropanoic acid (4.3 μL, 0.049 mmol) (L-lactic acid, 85% aq.) and triethylamine (14 μL, 0.098 mmol) in N,N-dimethylformamide (0.2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19 mg, 0.049 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with MeOH and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.0 mg (20%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C22H28ClN6O3 (M+H)+: m/z=459.2; Found: 459.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:39].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O1CCCC1.O>[F:39][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (7 mL) and water (0.5 mL) was added SELECTFLUOR® fluorinating reagent (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]-octane bis(tetrafluoroborate) (212.0 mg, 0.60 mmol). The reaction mixture was sealed and stirred at 70° C. for 1 h and then additional SELECTFLUOR® fluorinating reagent (212.0 mg, 0.60 mmol) was added. The reaction mixture was sealed again and stirred at 70° C. overnight. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep.—HPLC. The purification afforded 61 mg (30% yield) of the desired product as white solid. LC/MS found: 513.0 (M+1)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13](Cl)(=[O:23])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[C:13]([O:12][CH2:11][CH2:10][N:8]([CH3:9])[CH3:7])(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN(C)CCO
Reactant: CCCCCCCC=CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C(=O)OCCN(C)C

Procedure:
Thionyl chloride (8 ml) was added to trans-2-decenoic acid (3.4 g, 0.02 mol) followed by refluxing on a hot water bath for 2 hours. An excessive thionyl chloride was evaporated in vacuo to give 2-decenoic acid chloride. Pyridine (1 ml) was added to a solution of N,N-dimethylaminoethanol (2.0 g, 0.022 mol) in tetrahydrofuran (30 ml) followed by dropping into a solution of 2-decenoic acid chloride in tetrahydrofuran (20 ml). The reaction solution was heated to reflux on a hot water bath for 3 hours, tetrahydrofuran was evaporated in vacuo, water and ethyl acetate were added to the residue to partition and an ethyl acetate layer was collected therefrom. The ethyl acetate layer was washed with water and evaporated followed by purifying by silica gel column chromatography (developer: chloroform) to give the aimed compound as a light brown oily product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[C:15]([CH2:17][CH:18]([C:20]([OH:22])=[O:21])[NH2:19])[N:14]=[CH:13]1.C1COCC1.[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:28]1([CH:34]([O:21][C:20](=[O:22])[CH:18]([CH2:17][C:15]2[N:14]=[CH:13][S:12][CH:16]=2)[NH2:19])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: NC(Cc1cscn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(Cc1cscn1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
After 21.84 g (123.6 mmol) of the compound (48) was dissolved in ethanol (200 ml) and THF (100 ml) with heating to the solution was added diphenyldiazomethane (24 g, 123.6 mmol) under ice-cooling over 35 min. little by little. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent, and the mixture was concentrated in vacuo. The residue was crystallized from ether and ethanol to yield 31.63 g (97.7%) of the compound (49).
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.Br[C:20]1[N:25]=[C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:23]=[N:22][CH:21]=1>COCCOC.C(Cl)(Cl)Cl.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>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])[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: O=C1CCCN1c1cncc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C1CCCN1c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
To the starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-bromopyrazin-2-yl)pyrrolidin-2-one (46) (49 mg, 0.205 mmol, 1 eq) in DME (5 mL), was added Pd(PPh3)4 (7.1 mg, 0.00614 mmol, 0.02 eq) Cs2CO3 (133 mg, 0.410 mmol, 2 eq) and degassing and purging under argon for additional 10 min was performed. The reaction mixture was heated at 100° 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% MeOH/CHCl3 to obtain pale yellow solid compound 1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)pyrrolidin-2-one 131 in 9 mg quantity. The compound 131 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.90 (s, 1H), 9.46 (s, 1H), 9.02 (d, J=10.48, 2H), 8.71 (s, 1H), 7.56 (s, 1H), 6.58 (s, 1H)], 4.13 (m, J=7.0, 2H), 2.65 (m, J=8.04, 2H), 2.14 (m, J=192.19, 2H); MS m/z 279.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.C(N(CC)CC)C.[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:87][CH3:88])[CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH2:77])=[CH:72][C:71]=1[S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH:77][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[CH:72][C:71]=1[S:80]([C:83]([F:85])([F:86])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:87][CH3:88])([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:43]
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 88 mg, 0.20 mmol), EDC (77 mg, 0.40 mmol), and DMAP (49 mg, 0.40 mmol), triethylamine (28 μl, 0.20 mmol) in 5 ml of DCM was added (R)-di-tert-butyl 2-(ethyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate (INTERMEDIATE 50, 150 mg, 0.20 mmol). The mixture was stirred at r.t overnight. The reaction solution was diluted with DCM (20 ml) and washed with water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to an oil. This material was purified by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc) to provide the title compound (137 mg, yield: 59%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.[NH:25]1[CH2:28][CH:27]([C:29]#[N:30])[CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:25]3[CH2:28][CH:27]([C:29]#[N:30])[CH2:26]3)=[O:20])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N#CC1CNC1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a solution of 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylic acid (70 mg, 0.2 mmol), azetidine-3-carbonitrile hydrochloride (30 mg, 0.25 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (25 mg, 30% in 3 steps). LCMS calculated for C21H19ClFN2O3 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10].[S:11]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+]>CO.[Cu]>[F:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][S:11]1(=[O:18])=[O:17]
Reactant: COc1cccc(F)c1Br
Reactant: O=S1(=O)CCCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cccc(F)c1N1CCCCS1(=O)=O
Reaction time: 18 h

Procedure:
2-Bromo-1-fluoro-3-methoxybenzene (200 mg, 0.975 mmol), 1,2-thiazinane 1,1-dioxide (264 mg, 1.951 mmol), copper (62 mg, 0.975 mmol) and potassium carbonate (270 mg, 1.95 1 mmol) were combined and heated to 170 C for 5 hours. After this time, the mixture was suspended in methanol (15 ml) and vortexed for 18 hours. This mixture was filtered through Gelman Acrodisc and evaporated in vacuo. The resulting residue was partitioned between EtOAc (2×10 ml) and aq NH4Cl (5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. This residue was purified by column chromatography eluting with a 0-10% EtOAc/CH2Cl2 to give 2-(2-fluoro-6-methoxyphenyl)-1,2-thiazinane 1,1-dioxide. Low resolution mass spectrometry: (M+H+)=260.1. 1H NMR (400 MHz, CDCl3) δ 7.21 (dt, 1H, J=8.1 and 4.3 Hz), 6.69-6.77 (m, 21), 3.88 (s, 3H), 3.75-8.74 (m, 1H), 3.65 (dq, 1H, J=4.6, 6.0 and 14 Hz), 3.24 (dd, 2H, J=5.6 and 7.4 Hz), 3.27 (quin, 2H, J=6.1 Hz) and 1.78-1.90 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[OH:6])[CH3:2].I[CH3:20]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[O:6][CH3:20])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(O)c1c(F)cc(OCC)cc1F
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC)c1c(F)cc(OCC)cc1F
Temperature: 60 °C
Yield: 97.3 %

Procedure:
To a solution of (4-ethoxy-2,6-difluoro-phenyl)-hydroxy-acetic acid ethyl ester (4.0 g, 15.37 mmol, 1.0 equiv) in toluene (50 mL) was added iodo-methane (21.82 g, 9.78 mL, 153.70 mmol, 10.0 equiv) and silver(I) oxide (7.12 g, 30.74 mmol, 2.0 equiv) and the reaction mixture heated to 60° C. for 18 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.1 g (97%) of the title compound. 1H NMR (300 MHz, CDCl3): 1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 292.3 [M+NH4]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](F)=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CS(C)=O.CCOCC.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:19][C:16]2[CH:17]=[N:18][C:13]([C:12]([C:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH2:11][O:10]3)([F:20])[F:21])=[CH:14][CH:15]=2)=[N:27][CH:28]=1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: Fc1ccc(Cl)cn1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ccc(Cl)cn4)cn3)CO2)c(F)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (400 mg, 1.337 mmol) and 5-chloro-2-fluoropyridine (805 μL, 8.02 mmol) in dry DMSO (13.4 mL) was added cesium carbonate (871 mg, 2.67 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 75° C. for 2 h, then rt for 12 h. The reaction as heated to 75° C. for an additional 30 min then cooled to rt, diluted with Et2O and poured into a separatory funnel containing water. The aqueous layer was extracted with Et2O (3×) and then the combined organic layers were washed with 1:1 brine:H2O (3×) then once with brine and dried by passing through a phase separator. Volatiles were removed by rotary evaporation and the crude residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 10% EtOAc/Hexanes for 5 min then ramp to 25% over 8 min-paused gradient at 25%) to yield the title compound as a colorless oil (91 mg, 16.6%): 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=2.4 Hz, 1H), 8.14-8.07 (m, 1H), 7.72 (dd, J=8.7, 2.7 Hz, 1H), 7.57 (dd, J=8.6, 2.5 Hz, 1H), 7.52 (dd, J=8.6, 0.6 Hz, 1H), 7.40 (dd, J=14.7, 8.2 Hz, 1H), 7.00 (dd, J=8.6, 0.4 Hz, 1H), 6.88-6.82 (m, 1H), 6.76 (ddd, J=9.9, 9.0, 2.5 Hz, 1H), 3.46 (d, J=5.1 Hz, 1H), 3.03-2.96 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −106.83 (dd, J=257.5, 8.3 Hz, 1F), −107.38-−108.26 (m, 2F), −109.27 (q, J=8.4 Hz, 1F); ESIMS m/z 412 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.CO>[C:20]1([CH2:26][C:27]([NH:2][CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cc1ccccc1)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a suspension of 0.55 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 30 ml of anhydrous dimethylformamide are added successively, at a temperature in the region of 5° C., 0.63 g of phenylacetyl chloride and, over 5 minutes, a solution of 0.4 g of triethylamine in 2 ml of anhydrous dimethylformamide. After stirring for 1 hour at the same temperature and then for 30 minutes at 20° C., the insoluble product formed is isolated by filtration and washed twice with 3 ml in total of dimethylformamide. The filtrate and the washing are combined, 80 ml of distilled water are added and the insoluble product formed is isolated by filtration, washed twice with 2 ml in total of distilled water and then air-dried. The product obtained (0.27 g) is suspended for 5 minutes in 3 ml of boiling methanol and, after cooling and storing for 1 hour at 5° C., the solid formed is isolated by filtration, washed twice with 1 ml in total of methanol and dried under reduced pressure (5 mmHg; 0.65 kPa) at 60° C. 0.16 g of 10-phenylacetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [300 MHz; (CD3)2SO-d6 ; δ in ppm): 3.56 (s, 2H: Ar--CH2 --CO--); 6.12 (d, J=8.5 Hz, 1H: --CH-- 10); from 7.25 to 7.60 (mt, 7H: --H of the phenyl --H 7 and --H 8); 7.38 and 7.48 (2s, 1H each: --H of the imidazole); 7.45 and 7.86 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 8.83 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.50 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:11]=1
Reactant: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid ethyl ester (5.1 g, 10.7 mmol) in tetrahydrofuran (30 mL), methanol (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (2.2 g, 53.5 mmol). The reaction was stirred for 18 hour at ambient temperature. The reaction was then concentrated in vacuo and the remaining solution was acidified with a 1M aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was diluted with minimal dichloromethane and diethyl ether was added. A white precipitate was collected by filtration to give the title compound (3.93 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:24][C@@H:22]1[CH2:23][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[C@H:20]([C:25]([O:27][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:26])[CH2:21]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (505 mg, 1.82 mmol) in MeCN (18 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) and triethyl amine (0.27 mL, 2.0 mmol). After stirring for 15 h, the solution was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/hexanes) to afford (2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (748 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:28]([CH:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=O)[CH3:29]>ClCCCl>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:31]1[CH2:32][CH2:33][C:34](=[O:35])[C:30]=1[CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH2:24][CH3:25])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1
Reactant: CCC1C(=O)CCC1=O
Solvent: ClCCCl
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nc(CC)cc3ccccc23)cc1)NC1=C(CC)C(=O)CC1
Yield: 52.3 %

Procedure:
A solution of (S)-ethyl-3-[4-(3-ethyl-isoquinol-1-yl amino)phenyl]-2-aminopropionate [prepared from 1-chloro,3-ethyl-isoquinoline (from reaction of o-toluic acid with propionitrile and subsequent treatment with phosphorous oxychloride) and N-BOC-L-4-aminophenylalanine ethylester] (750 mg, 2.07 mmol) and 2-ethyl-1,3-cyclopentanedione (273 mg, 2.17 mmol) in 1,2-dichloroethane (10 ml) was treated with 4 Å sieves (˜1 g) and heated at 90° for 3 days. The solution was filtered, concentrated in vacuo and the residue purified by chromatorgaphy (SiO2, 100:1 DCM/MeOH) to give the title compound as a brown solid (511 mg, 52%). δ H (d6-DMSO) 9.05 (1H, s), 8.46 (1H, d, J 7.0 Hz), 7.91 (2H, d, J 8.6 Hz), 7.72 (1H, d, J 7.0 Hz), 7.64 (1H, t, J 7.0 Hz), 7.51 (1H, t, J 7.0 Hz), 7.23 (2H, d, J 8.6 Hz), 6.99 (1H, s), 4.32 (1H, m), 4.15 (2H, q, J 7.1 Hz), 3.15 (1H, dd, J 13.5, 3.5 Hz), 3.01 (1H, dd, J 13.5, 9.6 Hz), 2.69 (2H, 1, J 7.5 Hz), 2.29 (1H, m), 2.18 (1H, m), 2.06 (4H, m), 1.28 (3H, t, J 7.5 Hz), 0.91 (3H, t, J 7.4 Hz). m/z (ESI, 70V) 472 (MH+).