Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:18](=[O:22])/[CH:19]=[CH:20]/[CH3:21])=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)Cl
Reactant: NCCc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-fluorophenyl)ethylamine (13.25 mL, 100 mmol) and triethylamine (14.6 mL, 105 mmol) in dichloromethane (375 mL) was stirred on an ice bath. A solution of crotonyl chloride (10.65 mL, 100 mmol) in dichloromethane (25 mL) was added dropwise over 15 minutes. The cooling bath was removed and the solution was stirred at room temperature for 2 hours. It was then washed twice with 1.0 N aqueous hydrochloric acid, then twice with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and concentrated under vacuum to provide a yellowish solid (20.78 g, quantitative). Recrystallization from toluene provided white needles (15.5 g, 75%), mp 121-123° C. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.85 (dq, J=15, 7 Hz, 1H), 5.74 (dd, J=15, 1 Hz, 1H), 5.49 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 1.85 (dd, J=7, 2 Hz, 3H). Mass spec (ES+) m/z 249.0 (M+H+acetonitrile+, 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCc1ccccc1
Product: O=C(Cl)CCCCCc1ccccc1
Yield: 93.8 %

Procedure:
6-Phenylhexanoic acid (2.5 g, 13 mmol) was treated with thionyl chloride (3.0 ml, 41.1 mmol) and stirred under reflux for 3 h. The mixture was evaporated under reduced pressure to remove thionyl chloride and then distilled at 92-95° C./0.1 mbar to give the product as a colourless oil (2.57 g, 94%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCOCC1
Product: N#Cc1c(OC2CCOCC2)cccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and tetrahydro-2H-pyran-4-ol in 100% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.69 (m, 2H), 2.03 (m, 2H), 3.56 (m, 2H), 3.87 (m, 2H), 4.98 (sept, J=3.8 Hz, 1H), 7.90 (m, 3H).
Reaction SMILES: Cl[C:2]1(Cl)[C:5](=[O:6])[CH2:4][CH:3]1[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[NH4+].CO>CCOCC.[Zn]>[O:6]=[C:5]1[CH2:2][CH:3]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: CCOC(=O)CCC1CC(=O)C1(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)CCC1CC(=O)C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of ethyl 3-(2,2-dichloro-3-oxocyclobutyl)propanoate (10.49 g, 43.87 mmol) and ammonium chloride (12 g, 220 mmol) in methanol (310 mL, 7600 mmol) was treated in small portions with zinc powder (14 g, 220 mmol). The reaction mixture was heated at reflux for 3 h after which time GC indicated the reaction was complete. The reaction mixture was cooled to room temperature and was filtered through Celite, washing the pad with Et2O. The filtrate was concentrated in vacuo to afford pale yellow solution. The solution was diluted with 200 mL Et2O and washed with 100 mL water. The separated aqueous layer was back extracted with 100 mL Et2O and the combined organic phase was washed with 100 mL 1:1 water/brine, 50 mL water, and 150 mL saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (4.49 g, 60%) as a pale yellow oil which was of sufficient purity for use in the next step: GC purity >95% (ret. time, 4.24 min).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Yield: 110.6 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (632 mg, 2.07 mmol, Eq: 1.00) in EtOH (25.0 ml) and ethyl acetate (10 ml) was combined with palladium on carbon (66.1 mg, 62.1 μmol, Eq: 0.03). The mixture was evacuated twice with hydrogen and then stirred with a hydrogen-filled balloon for 22 h. The hydrogen was replaced with nitrogen. The solution was filtered through celite. The celite was washed several times with EtOAc. Concentrated in vacuo to give tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (635 mg, quantitative yield). LC/MS-ESI observed [M+H]+ 278.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.C(C1CN([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C1)=O>C1COCC1>[C:49]([O:48][C:46]([N:16]1[CH2:15][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)=[C:2]3[Cl:1])[OH:13])[CH2:19]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 12: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.08 mL, 2.69 mmol) was added dropwise. The color of the solution became a dark opaque reddish-brown color. After 2 minutes, a THF solution of tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 minutes, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 minutes at which time the mixture was quenched with aqueous NH4Cl solution. The contents were diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a yellow foam. The crude material was chromatographed on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31](Br)[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[K+]>CO>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([OH:37])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(Br)cnc12
Agent: [K+]
Solvent: CO
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(O)cnc12
Yield: 74.4 %

Procedure:
tert-Butyl[(1R,2R)-2-({[4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-5-ethylthiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (0.151 g, 0.258 mmol) was dissolved in methanol (1.29 mL) and KOH (14.5 mg, 0.258 mmol) was added. The reaction was heated to 65° C. until conversion to the alcohol was complete. The reaction was then concentrated under reduced pressure. The remaining residue was mixed with dichloromethane, washed with saturated ammonium chloride (aq) twice and brine once. The organic layer was mixed with water and extracted 3× with dichloromethane. The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.100 g, 0.192 mmol). LRMS (APCI) calc'd for (C24H29F2N5O4S) [M+H]+, 522.2. found 522.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[S:15][CH:16]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Yield: 100.7 %

Procedure:
Following General Procedure A, the title compound (588 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol), tert-butyl [4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57 mmol) and K2CO3 (1.08 g, 3.45 mmol) in DMF (10 ml).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[O:12]=[C:8]1[CH:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][CH2:11][N:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCN1c1cccnc1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCN(c2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.9 %

Procedure:
To a stirred solution of 349 (1.48 g, 9.1 mmol) in anhydrous THF (25 ml) at −78° C. under nitrogen was slowly added a solution of LDA (mono THF, 13.4 mL, 20.1 mmol, 1.5 M in cyclohexane). After 45 min, methyl chloroformate (776 μL, 10.0 mmol) was added. The mixture was warmed to room temperature over 2 h, and then stirred overnight. Then, the reaction mixture was quenched by addition of sat. ammonium chloride and extracted with AcOEt. After separation, the organic layer was successively washed with sat. NH4Cl, water, and brine. The aqueous phase was extracted twice with AcOEt. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 5/95) to afford title compound 350 (520 mg, 26% yield) as a pale yellow sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.86 (d, J=2.5 Hz, 1H), 8.38 (dd, J=4.7, 1.4 Hz, 1H), 8.12-8.06 (m, 1H), 7.44 (dd, J=8.4, 4.7 Hz, 1H), 3.99-3.84 (m, 2H), 3.81 (t, J=8.8 Hz, 1H), 3.70 (s, 3H), 2.48-2.29 (m, 2H). MS (m/z): 221.0 (M+H)+..
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1.[Na].C([OH:15])C>N>[OH:15][CH:9]([C:6]1[CH2:5][CH:4]=[C:3]([O:2][CH3:1])[CH2:8][CH:7]=1)[CH3:10]
Reactant: COc1ccc(CCO)cc1
Reactant: CCO
Agent: N
Agent: [Na]
Product: COC1=CCC(C(C)O)=CC1

Procedure:
A solution of 40 g of 2-(4-methoxyphenyl)ethanol in 80 ml of ethanol and 800 ml of ammonia reduced with 30.4 g of sodium to yield 27.4 g, bp 87°-89° (0.7 mm), identified by nmr.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:19])([CH3:23])[CH3:22]
Reactant: OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and N,N-diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10° C. under N2. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was added dropwise over 2 h, maintaining a temperature of 10-15° C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83%) as a pale, straw-colored oil. Exact Mass calculated for C9H17NO3: 187.1. Found: LCMS m/z=188.2 (M+H+), 210.3 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.3 Hz, 6H), 1.47 (m, 2H), 1.86 (m, 2H), 3.08 (m, 2H), 3.86 (m, 3H), 4.90 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[O:32][CH:33]=[CH:34][CH:35]=1.[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.CO>[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: BrCCCCCCOCCCCCCc1ccco1
Agent: O=C(O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(O)CNCCCCCCOCCCCCCc2ccco2)ccc1O
Yield: 70.5 %

Procedure:
A solution of N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]methanesulphonamide (0.95 g), 2-[6-[(6-bromohexyl)oxy]hexyl]furan (0.84 g) and DEA (0.54 ml) in DMF (20 ml) was heated at 90° for 5 h, then evaporated in vacuo. The residue was purified by FCC with System A (39:10:1) eluant to afford a product which was dissolved in methanol (6 ml) and treated with benzoic acid (21 mg). The solvent was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a beige solid (75 mg), t.l.c. (System A 39:10:1) Rf 0.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[C:31]([CH3:37])([CH3:36])[C:32](C#N)=[O:33]>C1COCC1.CC([O-])(C)C.[K+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:29][C:31]([CH3:37])([CH3:36])[C:32](=[O:33])[C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: COc1ccc(C(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
To a room temperature, stirred solution of 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (100 mg, 0.26 mmol) in THF (5 mL), t-BuOK (1.0 mL, 1.0 N solution in THF) was added under an inert atmosphere and the resulting mixture was stirred for 30 min. 2-Bromo-2-methylpropanoyl cyanide (90 mg, 0.5 mmol) was then added to the reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10-15% ethyl acetate in hexanes) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (10 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[CH:11]([OH:13])[CH3:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[C:36]4[CH:37]=[N:38][C:39]([N+:42]([O-:44])=[O:43])=[C:40](O)[C:35]=4[O:34][CH:33]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[CH:11]([O:13][C:40]1[C:35]2[O:34][CH:33]=[C:32]([C:30]3[CH:29]=[N:28][N:27]([CH:24]4[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]4)[CH:31]=3)[C:36]=2[CH:37]=[N:38][C:39]=1[N+:42]([O-:44])=[O:43])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3coc4c(O)c([N+](=O)[O-])ncc34)cn2)CC1
Reactant: CC(O)c1c(Cl)c(F)cc(F)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1c([N+](=O)[O-])ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl
Temperature: 40 °C

Procedure:
1-(2,6-Dichloro-3,5-difluorophenyl)ethanol (133 mg, 0.586 mmol), 4-[4-(7-Hydroxy-6-nitrofuro[3,2-c]pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol), PPh3 (410 mg, 1.60 mmol) and THF (20 mL) was added to a dry round bottom flask. Diisopropyl azodicarboxylate (320 mg, 1.60 mmol) was added and the reaction mixture was heated at 40° C. More DIAD (320 mg, 1.60 mmol) was then added and the reaction mixture was heated at 40° C. for 2 h. Purification by flash column chromatography using 10%→40% EtOAc in hexanes afforded the title compound as a yellow solid. MS (ES+): m/z 581.88/583.80 (100/80) [MH+−isobutene]. HPLC: tR=4.29 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:7]3[C:6](=[O:12])[C:5]4[CH:4]=[N:3][N:2]=[CH:1][C:10]=4[C:9](=[O:11])[C:8]=3[N:22]=[N:21]2)=[CH:23][CH:24]=1
Reactant: O=C1C=CC(=O)c2cnncc21
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc3c2C(=O)c2cnncc2C3=O)cc1
Yield: 62 %

Procedure:
333 mg (2.07 mmol) of phthalazin-5,8-dione (1.00 g, 6.20 mmol) and 4-methoxybenzyl azide were dissolved in 60 ml of ethyl acetate, and then refluxed overnight. The solvent was removed under reduced pressure and residue was separated and purified by using column chromatography (ethyl acetate). 415 mg of brown powder was obtained and the yield was 62%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:24])[CH:4]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: O=[N+]([O-])c1cc(CCCCCCc2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(CCCCCCc2ccc(O)c(N)c2)ccc1O
Yield: 96 %

Procedure:
A solution of 7.0 g of 1,6-bis(4-hydroxy-3-nitrophenyl)hexane of Example 4 in ethyl acetate:methanol (3:1) and 400 mg of 5% palladium on carbon was hydrogenated on a Parr hydrogenation apparatus for 3 hours. After filtration and removal of solvent, 5.6 g of off-white solid was obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9])#[N:2]>CO.N.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN

Procedure:
tert-butyl 5-cyano-4,6-dimethylpyridin-2-ylcarbamate (8 g) was hydrogenated by means of raney-nickel (18.9 g) in MeOH/NH3 aq. 10% (100 ml). The reaction mixture was filtered through hyflo, washed with MeOH and evaporated under reduced pressure. The crude was solved in EA (100 ml) and heptane 80 (ml) was added. The solution was partly evaporated to a volume of approx. 80 ml. The precipitated solid was filtrated to afford the title compound. HPLC/MS (Method F): RtF=0.82 min, [M+H]+=252.3.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH:38]([OH:40])[CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:39][CH:38]([OH:40])[CH2:37]5)[CH2:32][CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: OC1CN(C2CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(O)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.157 g, 0.40 mmol), 1-piperidin-4-ylazetidin-3-ol (0.075 g, 0.48 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.17 g, 0.80 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 20:80) to give 554 as a white solid (0.145 g, 68%). LCMS (Method I): RT=2.20 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.27-7.20 (m, 2 H); 4.27-4.19 (m, 4 H); 3.80 (s, 3 H); 3.77 (t, J=4.7 Hz, 4 H); 3.74 (s, 2 H); 3.44 (t, J=7.1 Hz, 2 H); 3.26 (q, J=7.4 Hz, 3 H); 2.78-2.70 (m, 2 H); 2.62 (t, J=7.1 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.99-1.90 (m, 1 H); 1.60 (d, J=11.0 Hz, 2 H); 1.33 (t, J=7.4 Hz, 3 H); 1.21-1.10 (m, 2 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1ccc(Br)cc1
Product: Fc1ccc(-c2ccccc2)cc1
Yield: 93 %

Procedure:
From 4-fluoro-bromobenzene and phenyl boronic acid, yield 93%; mp 73-75° C. (lit.,9 73-75° C.); IR: 1599, 1519, 1487 and 1196; 1H NMR (400 MHz; CDCl3): 7.56-7.53 (4H, m), 7.43 (2H, d, J 7.8), 7.34 (1H, t, J 8) and 7.15-7.1 (2H, m); rr/z (EI) 172 (70%, M+), 119 (30) and 69 (100) (Found: M+, 172.068. C12H9F requires M, 172.068).