Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].I[CH3:35]>>[CH3:1][O:2][C:3]1[C:12]([N:13]([CH3:35])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
1-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(106 mg, 0.25 mmol) was dissolved in dimethylfonnamide(15 ml) and sodium hydride(6.0 mg, 0.25 mmol) was added and the solution was stirred at room temperature for 15 min. Iodomethane(35 mg, 0.25 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:18]([OH:22])[C:19]([CH3:21])=[CH2:20])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:38]O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V].CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]([C@@:19]2([CH3:21])[CH2:20][O:38]2)=[O:22])=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OO
Reactant: C=C(C)[C@@H](O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C

Procedure:
Allylic alcohol 13 (1.79 g, 3.94 mmol) was dissolved in DCM (25 mL) and cooled to 0° C. after which vanadyl acetylacetonate (0.1 eq., 0.4 mmol, 107 mg) and tBuOOH (3 eq., 12.0 mmol, 2.18 mL; 5.5 M in decane) were added and the mixture was stirred at 0° C. until TLC analysis indicated complete consumption of starting material after 2 hours. The mixture was concentrated under reduced pressure, redissolved in EtOAc and extracted with half sat. aq. NaHCO3, H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The resulting product was quickly purified by column chromatography (20%->60% EtOAc/PE) and immediately subjected to the next step because of the possible instability of the intermediate. The compound was dissolved in DCM (25 mL) and Dess-Martin periodinane (3 eq., 11.0 mmol, 4.50 g) was added. The mixture was stirred at room temperature for 12 hours after which TLC analysis indicated complete conversion. Next, a 1:4 (v/v) mixture (150 mL) of NaHCO3 (sat. aq.)/Na2S2O3 (1 M aq.) and the resulting emulsion was stirred vigorously for 30 minutes after which the layers were separated and the aqueous layer extracted with DCM. The combined organic layers were extracted with sat. aq. NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (20%->30% EtOAc/PE) as a colourless oil (yield: 1.03 g, 2.20 mmol, 56%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.22 (m, 5H), 7.16 (d, J=7.94 Hz, 2H), 7.08 (d, J=7.95 Hz, 2H), 5.51 (d, J=8.19 Hz, 1H), 5.06-5.01 (m, 1H), 4.97 (d, J=4.39 Hz, 2H), 4.60 (dd, J=12.65, 7.86 Hz, 1H), 4.24 (d, J=4.36 Hz, 2H), 3.26 (d, J=4.62 Hz, 1H), 3.08 (dd, J=13.96, 4.48 Hz, 1H), 2.87 (d, J=4.53 Hz, 1H), 2.70 (dd, J=13.88, 8.12 Hz, 1H), 1.49 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=207.77, 155.74, 155.66, 137.61, 135.97, 134.62, 129.32, 128.26, 127.91, 127.76, 127.44, 79.15, 66.62, 58.99, 54.07, 52.12, 44.07, 36.61, 28.21, 16.34 ppm. [α]D23=+82.2 (c=1, CHCl3).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]3[CH2:18][N:17]([C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=4)[C:22]#[N:23])[C:16](=[O:27])[CH2:15]3)[CH:10]=[CH:11][C:12]=2[OH:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1.CCl>CN(C=O)C.CCOC(C)=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]3[CH2:18][N:17]([C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=4)[C:22]#[N:23])[C:16](=[O:27])[CH2:15]3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:37][CH:34]2[CH2:36][CH2:35]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(N2CC(c3ccc(O)c(OC4CCCC4)c3)CC2=O)c1
Reactant: BrCC1CC1
Agent: CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(N2CC(c3ccc(OCC4CC4)c(OC4CCCC4)c3)CC2=O)c1
Reaction time: 20 h
Yield: 83 %

Procedure:
A mixture of 3-[4-(3-cyclopentyloxy-4-hydroxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (1 mmol), potassium carbonate (2.5 mmol), cyclopropylmethyl bromide (2 mmol) in DMF was created in a dry round bottom flask. The mixture was stirred for 20 h, diluted with EtOAc (or CH3Cl) and filtered through celite. The filtrate was washed with water and then brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give pure product. Yield: 83%.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([CH:22]3[C:26]4[NH:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=5[C:34](=[O:35])[C:25]=4[CH2:24][NH:23]3)=[CH:16][C:15]=2[O:14]1>CN(C=O)C.O>[N:3]1([C:1]([N:23]2[CH2:24][C:25]3[C:34](=[O:35])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:27][C:26]=3[CH:22]2[C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:13][O:14][C:15]=3[CH:16]=2)=[S:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(C(=S)n1ccnc1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1,1′-thiocarbonyldiimidazole (0.192 g, 1.08 mmol) in DMF (5 mL, anhydrous) at 0° C. was added 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (0.30 g, 0.98 mmol) (prepared as in Example 5). The mixture warmed to room temperature and stirred for 20 h. The solution was diluted with water and extracted into ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, dried with MgSO4 and concentrated in vacuo, to yield the product as a light tan solid.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-].C1(C=CC(O)=CC=1)O>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][CH:1]=[CH:2][CH:3]=[CH2:4]
Reactant: C/C=C/C=O
Reactant: C[Si](C)(C)Cl
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC=CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of crotonaldehyde (31.8 g, 0.454 mole) and triethylamine (51.4 g, 1.1 eq) in benzene at 25° C., was added hydroquinone (0.95 g) and zinc chloride (0.75 g) rapidly with efficient stirring. This was followed by the addition of freshly distilled trimethylsilyl chloride (46 ml, 0.9 eq) over 1-2 minutes, whereupon a white precipitate rapidly formed. After stirring the mixture for 30 minutes at 25° C., a further 0.2 eq of trimethylsilyl chloride were added. The reaction was then warmed to 70° C. and stirred at this temperature for 12 hours. It was then cooled to 0° C., quenched by addition of saturated aq. NaHCO3 (75 ml), poured into a separatory funnel, and the organic layer separated. The aqueous layer was extracted with further portions of benzene (3×50 ml), the organic extracts combined, washed with 10% KHSO4, and the benzene removed in vacuo to leave a dark brown liquid. Distillation through a short Vigreaux column yielded 28.4 g (46%) of pure 1-trimethylsilyloxy-1,3-butadiene as a colorless liquid (bp 78°-80° C./68 mm Hg). 1H NMR (200 MHz, CDCl3): δ 6.66(1H,d,J=11.9 Hz), 6.35(1H,dt,J=17.1, 10.6Hz), 5.84(1H,t,J=11.4 Hz), 5.11(1H,dd,J=16.8, 1.8 Hz), 4.94(1H,dd,J=10.3, 1.8 Hz), 0.37(9H, s).
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[O:1]([CH2:8][CH2:9][C:10]([NH:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]2)=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)CCOc1ccccc1
Product: O=C(CCOc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 3-phenoxypropionic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (52% yield). 1H NMR (300 MHz, CDCl3) δ 10.08, 8.40, 7.74, 7.61, 7.55, 7.34, 7.26-7.22, 7.05, 6.93, 6.88, 4.34, 4.01-3.96, 3.92-3.86, 3.68-3.60, 3.55-3.53, 3.29-3.27, 3.08. MS (ES+) m/z 500.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[C@:4]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:8][C:7](=O)[CH2:6][N:5]1C(=O)NC1C=C(Cl)C=C(Cl)C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@:4]2([C:3]([OH:29])=[O:2])[CH2:8][CH2:7][CH2:6][NH:5]2)=[CH:27][CH:26]=1
Reactant: COC(=O)[C@]1(Cc2ccc(Br)cc2)CC(=O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@]1(Cc2ccc(Br)cc2)CCCN1

Procedure:
means resin polymer.) (1) A mixture of N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline ethyl ester (3.00 g), LiOH (10 mmol), THF (25 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature overnight. The mixture was then heated at 74° C. overnight. The mixture was concentrated in vacuo, and water was added. The mixture was washed with Et2O and the aqueous layer was made acidic with the addition of 1N H2SO4. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and evaporated to give N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (3.02 g). MS (m/z) 284 (MH+-t-Boc); mp: 143.9° C. (2) To a solution of the compound obtained above (2.45 g) in DMF (100 mL) was added Merrifield Resin (4.70 g) and KF (1.1 g). The resulting mixture was stirred under N2 at 80° C. overnight. The resin was filtered, and washed thoroughly with MeOH, H2O and CH2Cl2, then dried in vacuo overnight to yield the resin-bound N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (6.66 g); FTIR (cm−1) 1740, 1697, 1397, 1131, 1011. (3) The compound obtained above was then deprotected using a 50% solution of TFA in CH2Cl2, followed by thorough washing, to give the resin-bound 2-(4-bromobenzyl)proline (6.09 g); FTIR (cm−1) 1722. (4) To the compound obtained above (200 mg) was added a DMF solution of 2,6-dichloro-4-pyridyl isocyanate (5 equiv.). This mixture was shaken at room temperature in a sealed receptacle overnight. The mixture was filtered, and the resin was washed with DMF, water and MeOH, and air-dried to give the resin-bound N-[(2,6-dichloro-4-pyridyl)carbamoyl]-2-(4-bromobenzyl)proline. (5) A solution of DIEA (350 μL) in DMF (5 mL) was added to the compound obtained above, and the resulting mixture was then shaken at 50° C. for 2 hours, then at room temperature overnight. The resin was filtered and washed with MeOH, and the filtrate was evaporated. The residue was purified by reverse phase HPLC (gradient of 0%-70% CH3CN in water) to yield 3-(2,6-dichloro-4-pyridyl)-5-(4-bromobenzyl)-1,3-diazabichclo[3.3.0]octane-2,4-dione (58.0 mg). MS (m/z): 456 (MH+); mp: 76.3° C.;
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:19])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12
Reactant: CN(C)CCN
Reactant: COc1cc(OCC(=O)O)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)NCCN(C)C)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Temperature: 25 °C

Procedure:
A mixture of {[3-amino-7-methoxy-2-(2-methylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl]oxy}acetic acid (80 mg), N,N-dimethylethylenediamine (33 μl), (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (58 mg), 1-hydroxybenzotriazole (41 mg), triethylamine (43 μl) and N,N-dimethylformamide (2 ml) was stirred at room temperature for one night. The reaction mixture was concentrated under reduced pressure, and the residue was purified with column chromatography to obtain the target compound (61 mg).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].C([Li])CCC.[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]=[O:27])=[C:21]2[CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.CCOCC>[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]([OH:27])[C:3]#[C:2][CH2:1][O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[C:21]2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCOC1CCCCO1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OC(C#CCOC1CCCCO1)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a cold (−78° C.) solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (0.5 mL, 3.6 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.05 mL, 1.6 M in hexanes, 3.3 mmol) dropwise. The reaction mixture was allowed to warm to 0° C., then cooled to −78° C. A separate solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (200 mg, 0.73 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. The alkynyllithium solution was added to the aldehyde solution via canula. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added followed by ether. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-ol (301 mg, 99%) as a mixture of diastereomers. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.79 (m, 2H), 7.17 (m 3H), 6.99 (m, 1H), 5.79 (s, 1H), 4.81–4.74 (m, 1H), 4.39–4.25 (m, 2H), 3.81 (m, 1H), 3.52 (m, 1H), 3.15 (broad, 1H), 1.90–1.48 (m, 6H); 19F NMR (CDCl3) δ −113.01; MS m/z 437 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[N+]=[N-])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: NCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a stirred solution of azide 55 (0.75 g, 3.54 mmol) in anhydrous methanol (10 mL) was added triphenylphosphine (1.39 g, 5.31 mmol) and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (acetone-hexane) to yield product 56 in 63% yield (0.41 g).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH:9]([C@@H:11]1[CH2:16][O:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][O:12]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:14]2[CH2:13][O:12][C@H:11]([C@H:9]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)[CH2:16][O:15]2)=[CH:18][CH:19]=1
Reactant: COc1ccc([C@H]2CO[C@H](C=O)CO2)cc1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CO[C@H]([C@@H]2CO[C@@H](c3ccc(OC)cc3)CO2)OC1

Procedure:
A mixture of 1.2 g. 2-propylpropan-1,3-diol, 2.2 g. trans-5-formyl-2-p-methoxyphenyl-1,4-dioxane (obtainable by reaction of 1,1-ethylenedioxypropan-2,3-diol with p-methoxystyrene oxide and hydrolysis), 0.01 g. p-toluene sulphonic acid and 15 ml. toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated. One obtains trans-2-p-methoxyphenyl-5-(trans-5-propyl-1,3-dioxan-2-yl)-1,4-dioxane.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][CH:13]2OCC[O:14]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.ClCCl.CC(C)=O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][CH:13]=[O:14])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCC(CCC2OCCO2)C1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)C1CCCC(CCC=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
2-[2-(3-tert-butylcyclohexyl)ethyl]-1,3-dioxolane (62 g, 0.22 mol, gc purity of 87%) and dichloromethane/acetone in a 4:1 ratio (3.7 L) were charged into a 5 L three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. Iron (III) chloride hexahydrate (212.3 g, 0.78 mol, 3.5 eq) was added to the reaction at ambient temperature. The reaction mixture was then stirred at ambient temperature for 4 h and subsequently quenched, at 5-10° C., with the addition of a saturated aqueous NaHCO3 (500 mL). The organic phase was then washed with brine (500 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled via a Vigreux column (0.5 mBar, 82-85° C.), to give colourless oil (34.7 g, gc purity 79%). The oil was chromatographed on a silica gel column with 2% EtOAc in hexane as elution agent giving 3-(3-tert-butylcyclohexyl)propanal (17.8 g, gc purity>98%, ratio cis:trans 75:25; yield 40%).
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([F:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:16](C1CCN(B(O)O)CC1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.[F-].[K+]>[F:13][C:10]1[N:11]=[CH:12][C:7]2[NH:6][C:5]3[N:14]=[CH:15][C:2]([C:20]4[CH:19]=[CH:18][C:17]([CH2:16][N:11]5[CH2:12][CH2:7][CH2:8][CH2:9][CH2:10]5)=[CH:22][CH:21]=4)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Fc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: OB(O)N1CCC(Cc2ccccc2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-6-fluoro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg, 0.38 mmol), 4-benzylpiperidine boronic acid (123 mg, 0.56 mmol) and 1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (31 mg, 0.038 mmol) in acetonitrile (1.5 mL) and 2N aqueous potassium fluoride solution (1.5 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was then heated under microwave irradiation at 150° C. for 30 minutes, allowed to cool to ambient temperature and diluted with water (3 mL). The resultant precipitate was collected by filtration, washed with water (5 mL) and ethyl acetate (10 mL). The resultant solid residue was purified by flash chromatography (silica, 4 g column, ISCO, 0-20% methanol in DCM) to afford the title compound as an off white solid (90 mg, 67%). 1H NMR (DMSO-D6, 300 MHz): 12.27 (s, 1H), 9.00 (d, J=2.3 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 3.48 (s, 2H), 2.42-2.29 (m, 4H), 1.54-1.47 (m, 4H), 1.44-1.34 (m, 2H). LCMS (Method A): RT=5.87 min, M+H+=361.
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][CH2:27][CH2:28][C:29](Cl)=[O:30])[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][CH2:27][CH2:28][C:29]([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:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCc1ccccc1)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.5 h
Yield: 19.5 %

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., 0.73 g of 4-phenylbutyryl chloride and, over 5 minutes, a solution of 0.4 g of triethylamine in 2 ml of anhydrous dimethylformamide. After stirring for 1 hour 30 minutes at the same temperature and then for 1 hour at 20° C., the insoluble product formed is isolated by filtration and washed twice with 3 ml in total of dimethylformamide. The filtrate and 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 with 3 ml of acetone 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 with 0.5 ml of methanol and dried under reduced pressure (5 mmHg; 0.65 kPa) at 60° C. 0.15 g of 10-(4-phenylbutyramido)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 2.92 (mt, 2H: --CH2 --); 2.28 (t, J=7.5 Hz, 2H: --CH2 --Ar); 2.62 (t, J=7.5 Hz, 2H: --CO--CH2 --); 6.18 (d, J=8.5 Hz, 1H: --CH-- 10); from 7.10 to 7.55 (mt, 7H: --H of the phenyl-- --H7 and --H 8); 7.50 and 7.87 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 7.55 and 7.60 (2s, 1H each; --H of the imidazole); 8.53 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.47 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]#[N:28].[NH4+].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:36]1[CH2:35][CH2:34][CH:33]([O:32][C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:23])[CH2:38][CH2:37]1
Reactant: N#Cc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (1.00 g, 5.00 mmol) in DCM (10.0 mL) at 0° C. was added DIPEA (2.62 mL, 15.00 mmol) and 3-fluoro-4-(piperidin-4-yloxy)benzonitrile hydrochloride (1.283 g, 5.00 mmol). The reaction mixture was stirred for 30 min, warming gradually to room temperature. The reaction mixture was treated with saturated aqueous NH4Cl. The organic layer containing yellow solid was collected and concentrated under reduced pressure. The solid was filtered, washing with water, and was lyophilized overnight to give the title compound as a yellow solid (1.325 g, 69%). ESI-MS m/z [M+H]+ 384.3.