Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CC#N.Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:17][C:16]([OH:19])=[O:18]
Reactant: CC(=O)O
Reactant: N#CCc1ccccc1OC(F)(F)F
Agent: Cl
Product: O=C(O)Cc1ccccc1OC(F)(F)F

Procedure:
2-Trifluoromethoxyphenylacetonitrile (0.49 g, 2.6 mmol) from Step 3 above was refluxed for 3 h in a 1:1 mixture of acetic acid and concentrated aqueous HCl. The solvents were removed under reduced pressure. The residue was partitioned between EtOAc (75 mL) and water (2×25 mL). The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure to give 2-trifluoromethoxyphenylacetic acid as an amorphous solid (HPLC retention time=6.8 min (method A)).
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH:3]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:39]([N:49]([CH3:63])[C@H:50]([C:60](O)=[O:61])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:39]([N:49]([CH3:63])[C@H:50]([C:60]([NH:1][CH:2]([CH3:21])[CH:3]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[O:61])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: CC(N)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C[C@@H](C(=O)NC(C)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)N(C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a solution of amine 110 (20 mg, 0.062 mmol) in CH2Cl2 (1 mL), cooled to 0° C., NMM (7 μL, 0.069 mmol) and HOBt (25 mg, 0.18 mmol) were added. The solution was stirred at 0° C. for 15 minutes, and a solution of N-Cbz-N,O-dimethyltyrosine (21) (21 mg, 0.062 mmol) in CH2Cl2 (1 mL) was added. Finally a solution of DCC (14.2 mg, 0.069 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred 16 h at room temperature and filtered to remove the precipitate. The filtrate was diluted with CH2Cl2 (10 mL) and washed with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL) and NaCl (10 mL, sat), dried (Na2SO4), filtered, and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/3) to yield 111 (26 mg, 70%) as a white foam. Rf 0.36 (AcOEt/Hexanes 1/3). [α]D20=−40.1 (c=0.5, CHCl3). 1H-NMR (500 MHz, CDCl3): 0.09 (s, 6H), 0.95 (s, 9H), 1.14-1.17 (m, 3H), 1.43 (s, 9H), 2.86 (s, 3H), 3.29-3.32 (m, 1H), 3.42-3.48 (m, 1H), 3.60-3.68 (m, 2H), 3.82 (s, 3H), 4.17-4.18 (m, 1H), 4.87-4.89 (m, 1H), 4.95-4.96 (m, 1H), 5.02-5.14 (m, 2H), 5.21-5.22 (m, 2H), 6.34-6.37 (m, 1H), 6.79-6.83 (m, 2H), 6.98-7.00 (m, 1H), 7.01-7.17 (m, 2H), 7.20-7.36 (m, 5H). 13C-NMR (125 MHz, CDCl3): −5.5, 17.9, 18.2, 25.8, 28.3, 33.2, 44.5, 55.12, 62.6, 67.3, 57.1, 66.1, 113.8, 127.5, 127.9, 128.4, 129.8, 158.2, 171.5. IR (neat) 3328.5, 2930.3, 2856.3, 2361.0, 2346.6, 2249.0, 1708.8, 1513.7, 1452.5, 1449.5. HRMS m/z cald for C34H53N5O7Na (M+Na): 666.3550 found 666.3571.
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:11]([NH2:13])=O.C[O-].[Na+].Cl>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:13][CH:11]=[N:1][C:2]=1[CH2:9][CH3:10]
Reactant: NC=O
Reactant: CCC(N)=C(Cl)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl
Reaction time: 10 h
Yield: 87 %

Procedure:
Two dropping funnels are used for simultaneous dropwise addition of a solution of 35.5 g (0.2 mol) of methyl 3-amino-2-chloro-2-pentenoate and 31.5 g (0.7 mol) of formamide in 150 ml of methanol with stirring to 90.3 ml of a 30% strength sodium methylate solution in methanol at room temperature. The mixture is heated slowly to the reflux temperature and left at this for 10 h. After the mixture has cooled, dry HCl gas is passed through the solution until the pH is 3. Evaporation of the solvent is followed by extraction with butanone, drying and evaporation in a rotary evaporator. Yield: 87% [HPLC]
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[CH:9][C:10]([F:18])=[C:11]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:12]=1.[N+:19]([C:22]1[C:23]([CH:32]=[O:33])=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)([O-:21])=[O:20]>C1COCC1>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:11]1[CH:12]=[C:7]([CH:32]([C:23]2[C:22]([N+:19]([O-:21])=[O:20])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[OH:33])[CH:8]=[CH:9][C:10]=1[F:18]
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Fc1ccc(Br)cc1C1OCCO1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccc(F)c(C3OCCO3)c2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
Magnesium (983 mg, 40.5 mmol) was suspended in anhydrous THF (30 ml). 1,2-dibromoethane (0.17 ml, 2.02 mmol) was added and the solution was stirred at room temperature for 20 min. 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane 417 (3.2 g, 12.95 mmol) was added dropwise and the mixture was heated at 40° C. for 2 h. The mixture was allowed to cool to room temperature. The Grignard reagent (0.43M; 28.6 ml) was added to a suspension of 8-nitroquinoline-7-carbaldehyde 204 (2.5 g, 12.4 mmol) in dry THF (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 min. The mixture was quenched with sat. NH4Cl (10 ml) and the aqueous phase was extracted with EtOAc (20 ml). The organic phase was washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (50:50) as the eluent to give the title compound (3.39 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CC#N>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:21]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h

Procedure:
To (S)-2-(2-chloro-5-nitro-phenoxymethyl)-pyrrolidine (4.82 g, 18.77 mmol) in 167 mL CH3CN at RT was added 37% aqueous formaldehyde (7.58 mL) then NaCNBH3 (1.887 g, 30.03 mmol). The reaction was stirred for 1 h, as the reaction pH was adjusted every 10 min to about 7 by adding small amounts of HOAc. The reaction was concentrated to small aqueous volume and dissolved in 2 N NaOH (aq) and Et2O. The layers were separated, and the organic layer was washed twice with 2 N NaOH then extracted twice with 1 N HCl (aq). The combined acidic aqueous layers were basified to pH>12 with solid NaOH and extracted 3 times with EtOAc. The EtOAc layers were washed once with 2 N NaOH and then once with mix of brine and 2 N NaOH, combined, dried over Na2SO4, filtered, and concentrated to dryness, to yield the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Br:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Br:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)c(Br)n(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 525 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCCCCCCCCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCCCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,10-dibromodecane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,10-dibromodecane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a pale yellow solid. Yield: 1.32 g (65%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.40 (m, 14H), 1.76 (tt, J=7.0, 7.0 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.79 (t, J=7.0 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 8.95 (s, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].C(O/[CH:17]=[CH:18]/[C:19](=O)[C:20]([F:23])([F:22])[F:21])C.N12CCN(CC1)CC2>COCCO.Cl.C(OCC)(=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:12][CH:11]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Product: N#Cc1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 7.3 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (2 g, 11.2 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.26 g, 13.4 mmol) in dimethyleneglycol monomethylether (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.26 g, 11.2 mmol), and the mixture was stirred at 120° C. for 6 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give a white solid. The white solid was washed with ethyl acetate and collected by filtration to give the title compound (230 mg, 7.2%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:37]([Cu])#[N:38].N#N>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:37]#[N:38])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 160 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (200 mg, 0.36 mmol) and CuCN (110 mg, 1.08 mmol) in DMF (10 mL) was purged with N2 for three times. The resulting mixture was stirred at 160° C. overnight. After cooling to r.t., the reaction mixture was concentrated to obtain the crude product which was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate in petroleum ether) to afford (R)-tert-butyl 3-(4-amino-6-cyano-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (101) (117 mg, 65% yield) as a yellow solid. LC-MS (ESI): m/z (M+1) 497.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:17]([C:18]3[C:19](=O)[NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:10]3[N:11]=[C:12]([CH3:16])[N:13]([CH2:14][CH3:15])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:27]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:17]([C:18]3[C:19](=[S:37])[NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:10]3[N:11]=[C:12]([CH3:16])[N:13]([CH2:14][CH3:15])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:27]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: CCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (i) (0.065 g) and Lawesson's reagent (0.343 g) in 1,4-dioxane (5 ml) was heated at reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. Purification was by chromatography eluting with 0.2% 880 ammonia, 4% methanol in dichloromethane to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:18])([CH3:17])[CH2:5]/[C:6](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)/[CH:7]=[O:8].O>[OH-].[Na+]>[Cl:16][C:13]1[CH:12]=[CH:11][C:10](/[CH:9]=[C:6](\[CH2:7][OH:8])/[CH2:5][C:4]([CH3:3])([CH3:17])[CH3:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C/C(C=O)=C/c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
2.1 g of sodium borohydride, dissolved in a little 10% strength sodium hydroxide solution, are added to a solution of 47.3 g of Z-2-(2,2-dimethylpropyl)-3-(4-chlorophenyl)-propenal. After the reaction mixture has been stirred for 18 hours at room temperature, 200 ml of water are added to the solution and the resulting emulsion is extracted by shaking with methylene chloride. The organic phase isolated is then dried over sodium sulfate and evaporated down. 45.8 g (96%) of Z-1-(4-chlorophenyl)-2-hydroxymethyl-4,4-dimethylpent-1-ene are obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:12])[CH3:11]>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:12]
Reactant: CCO
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 25 °C

Procedure:
A mixture of 22.2 g of glyoxylic acid ethyl ester ethyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 90 g of ethanol and 7.5 g of 8% strength ethanolic sulfuric acid was heated under reflux for 4 hours. Thereafter, the reaction had ended and the reaction mixture was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed three times with ethanol and dried in vacuo at 70° C. 24.5 g, that is to say 80% of theory, of allantoin acid ethyl ester were obtained by this reaction.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)O1.[NH2:25][C:26]1[C:31]([F:32])=[C:30](Cl)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38].C(#N)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:25][C:26]1[C:31]([F:32])=[C:30]([C:15]2[CH:23]=[CH:22][C:18]3=[N:19][O:20][N:21]=[C:17]3[CH:16]=2)[N:29]=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:27]=1[Cl:38]
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc3nonc3c2)c(F)c(N)c1Cl
Temperature: 85 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol) and sodium carbonate (210 mg, 2.0 mmol) were sequentially added to a stirred mixture of ˜60% 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (900 mg, 2.2 mmol) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (480 mg, 2.0 mmol, 1.0 equiv) in a 1:1 mixture of water:acetonitrile (6.8 mL) at 23° C. The resulting brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (3×80 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the title compound as a tan powder (370 mg, 57% yield).
Reaction SMILES: [CH:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:18](OCC)C>>[CH:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1c[nH]nc1-c1cccnc1
Reactant: CCOCC
Product: CCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH2NH2.H2O were combined in diethylene glycol (10 ml) and warmed to reflux for 1 hour under N2. The mixture was cooled, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH3/MeOH) and subsequent purification by flash chromatography (ethyl acetate) afforded 3-(4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of 46A). Yield 0.18 g (86%). (TLC diethyl ether Rf 0.18). 3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47A, using the methodology described for the conversion of 21 A to 22A (see Scheme 3). Yield: 50% (amorphous). LCMS (method A); Rt: 2.30 min, ([M+H]+=246). 1H-NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 6.22 (bd, J=16 Hz, 1H), 6.03-5.98 (bs, 1H), 5.98-5.88 (m, 1H), 3.26-3.21 (m, 2H), 2.63 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 2.19-2.11 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15]CC3C=CC=CC=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c(OC)noc12
Reaction time: 3 h

Procedure:
A solution of 3-methoxy-6-benzyloxy-7-propyl benz-(4,5)-isoxazole (181 mg) in ethyl acetate (4 mL) was treated with 10% palladium on carbon catalyst (25 mg). The mixture was shaken under a hydrogen atmosphere (40 psi) for 3 hours. The mixture was filtered through Celite and concentrated to a solid. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 50 °C
Yield: 95 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.6 g, 8.48 mmol) in 20 mL of ethanol was added 20 mL of commercial solution of hydrogen peroxide (30%) and 1.8 mL of aqueous solution of sodium hydroxide (6.0 N). The suspension was heated to 50° C. for 20 min. The reaction mixture was cooled down and neutralized with 6.0 N aqueous HCl. Further precipitation was observed upon addition of water (20 mL). The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven at 40° C. (2.6 g, 95% yield) 1H NMR (CDCl3) δ 8.2 (s, 1H), 8.0 (d, 1H), 7.7 (br s, 1H), 7.6 (d, 1H), 6.4 (br s, 1H), 5.7 (dd, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 2.5 (m, 1H), 2.0 (m, 2H), 1.7 (m, 3H); ES-MS (m/z) 276 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[N:25][N:24]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=5)=[N:25][N:24]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Reactant: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(N)n4)cc3)c3ccccc23)c1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine and 1-chloro-4-(4-methyl-2-thienyl)phthalazine was added tBuOH. The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine as an off-white solid. MS m/z=504 [M+H]+. Calc'd for C28H21N7OS: 503.58.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 105.6 %

Procedure:
A suspension of (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 20.3 mmol) and palladium on carbon (1.0 g, 10%, wet, Degussa, E101 NE/W) in a 4:1 mixture of THF and EtOH (150 ml) was stirred under a hydrogen atmosphere (2 balloons) at 50° C. for 18 h. The reaction mixture was cooled to 25° C. and was filtered through Celite. The Celite was washed with THF (1×20 ml), and the combined filtrate and washings were concentrated under reduced pressure to give (R)-3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.81 g, 99%) as a brown foam. LCMS (Method G, ESI): RT=0.83 min, m+H=458.3. This material was used in the next step below without additional purification or characterization.