Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:3][CH:4]2[CH2:8][CH2:7][O:6][CH2:5]2)[C:11]=1[C:12]#[N:13]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(C#N)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.83 g, 21 mmol) was added portionwise to 3-hydroxytetrahydrofuran (1.82 g, 21 mmol) in tetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere. The suspension was warmed to room temperature and was stirred for 1 hour. The mixture formed was added over 30 minutes to 2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.5 g, 21 mmol) in tetrahydrofuran (50 ml) and the resulting solution was held at room temperature for 16 hours. Water (75 ml) was added and the aqueous mixture was extracted with ethyl acetate (3×200 ml) The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The material obtained was dried under vacuum to give the title compound as a brown solid (5.1 g).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:32]([C:34]1[C@@H:39]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:38]2[N:48]=[C:49]([NH:51][CH2:52][C:53](O)=[O:54])[N:50]=[C:37]2[N:36]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)[C:35]=1[CH3:66])#[N:33].N.O1CCOCC1>CN(C=O)C>[C:32]([C:34]1[C@@H:39]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:38]2[N:48]=[C:49]([NH:51][CH2:52][C:53]([NH2:2])=[O:54])[N:50]=[C:37]2[N:36]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[CH:57]=2)[C:35]=1[CH3:66])#[N:33]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(N)=O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., HATU (25 mg, 66 μmol, 3 eq.) and triethylamine (11 mg, 110 μmol, 5 eq.) were added to a solution of N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycine (10.5 mg, 22 μmol) in DMF (1 ml). After the reaction mixture has thawed to RT, it was once more cooled to 0° C., and a 0.5 M solution of ammonia in dioxane (0.44 ml, 219 μmol, 10 eq.) was then added. The mixture was stirred for 2 h, during which time it gradually warmed to RT. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.2 mg, 88% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([OH:14])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22].[OH-].[K+]>CC(C)=O.C(O)C.O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:21][CH3:22])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc(O)c1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OC)c1OC
Reaction time: 24 h

Procedure:
Combine 3,4-dimethoxy-5-hydroxybenzoic acid (1.0 g, 5.0 mmol), potassium carbonate (4.2 g, 30.2 mmol), and ethyl iodide (3.9 g, 25.2 mmol) in acetone (50 mL). Heat to reflux. After 24 hours, cool, add methanol (25 mL) and water (5 mL) After 18 hours, concentrate in vacuo to give a residue. Combine the residue and ethanol (50 mL) and potassium hydroxide (0.56 g, 10 mmol). After 18 hours, concentrate in vacuo to give a residue. Partition the residue between ethyl acetate and a 1 M aqueous solution of hydrochloric acid. Extract the aqueous layer three times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Triturate the residue to give a solid. Collect the solid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[N:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH2:17]1.[Na].[O-]CCCC.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:5]([NH:8][C:21]2[N:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: N#CC1=NC=CN(Br)C1
Reactant: Nc1cc(N2CCOCC2)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)c(Cl)cn2)cn1
Temperature: 140 °C
Yield: 31.6 %

Procedure:
5-Chloro-4-morpholinopyridin-2-amine (68 mg, 0.31 mmol), 4-bromo-cyanopyrazine (30 mg, 0.20 mmol), sodium Pert-butoxide (45 mg, 0.47 mmol), Pd(OAc)2 (3 mg, 0.01 mmol) and BINAP (0.030 g, 0.05 mmol) were mixed under argon atmosphere before addition of mixture of DMF in toluene (2:1, 0.7 mL). The reaction mixture was heated to 140° C. by microwave irradiation for 20 minutes. The reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Flash chromoatography on silica, eluting with ethyl acetate-hexane (1:1) gave 5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (20 mg, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]3[C:21]=2/[CH:22]=[CH:23]/[O:24]CC)=[CH:5][CH:4]=1)#[N:2]>C1COCC1.O.[Hg](OC(C)=O)OC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]3[C:21]=2[CH2:22][CH:23]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCO/C=C/c1c(-c2ccc(C#N)cc2)nc2cccc(C(=O)OC)n12
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(CC=O)n12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A stirred solution of (A4) in a mixture of THF/H2O 9:1 (0.2 M) was treated with Hg(OAc)2 (1.5 eq.). After the reaction mixture was stirred at 50° C. for 3 h, freshly prepared sat. aq. KI was added and stirring was continued at RT for 10 min. Then, the reaction mixture was extracted with EtOAc, washed with sat. aq. Na2S2O4 and dried (Na2SO4). Evaporation of the solvent gave methyl 2-(4-cyanophenyl)-3-(2-oxoethyl)imidazo[1,2-a]pyridine-5-carboxylate which was used in the next step without further purification. MS (ES+) C18H13N3O3 requires: 319, found: 320 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([F:35])[CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][C:30]=2[F:35])=[N:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(Cl)cc1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-chloro-2-fluorophenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.7 Hz), 8.10 (1H, d, J=2.7 Hz), 7.97–7.94 (3H, m), 7.42–7.39 (2H, m), 7.31–7.21 (3H, m), 5.37 (1H, quint, J=7.0 Hz), 1.61–1.58 (12H, m); MS (ESI) m/z 505 (M+H)+, 503 (M−H)−.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Reactant: BrCc1ccccc1
Product: CC(C)(CCCN1CCCC(OCc2ccccc2)C1)S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and benzyl bromide.
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:20]1[CH:21]=[C:22]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:23]=[N:24][C:25]=1[C:26]#[N:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:26]([C:25]1[N:24]=[CH:23][C:22]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:21][C:20]=1[NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[N:11]=1)#[N:27]
Reactant: Nc1cccc(-n2nccn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-n3nccn3)n2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Dioxane (1.06 mL), 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (51 mg, 0.32 mmol) and cesium carbonate (311 mg, 0.955 mmol) were added to tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (94 mg, 0.32 mmol) in a scintillation vial. The vial was purged and flushed with argon three times before Pd2 dba3 (29 mg, 0.032 mmol) and Xantphos (28 mg, 0.048 mmol) were added. The vial was purged and flushed 3 times with argon before the vial was sealed and heated to 80° C. After 16 hours, the reaction mixture was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-70% acetone in hexanes, linear gradient) to afford tert-butyl {(1S,2R)-2-[(6-cyano-5-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate. The isolated solids were dissolved in DCM (1 mL) and TFA (1 mL), and stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL). To this solution was added sodium hydroxide (4.0 M in water, 0.1 mL, 0.4 mmol) and hydrogen peroxide (30 wt % in water, 0.050 mL, 0.49 mmol). The reaction mixture was stirred at room temperature until complete conversion of the nitrile intermediate was observed by LCMS. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C19H24N9O [M+H]+ 394. found 394. 1H NMR (500 MHz, CD3OD) δ 9.20 (s, 1H), 8.07 (s, 2H), 7.83 (t, J=8.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.38 (s, 1H), 3.75-3.67 (m, 1H), 2.01-1.66 (m, 6), 1.66-1.51 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19](/[CH:21]=[C:7]1\[CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3][C:2]\1=[O:1])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of tert-butyl 4-oxocyclohexylcarbamate (10 g, 0.046 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL) was heated at 100° C. for 15 hours. 1,1-dimethoxy-N,N-dimethylmethanamine was then removed under reduced pressure. The crude desired product, (E)-tert-butyl 3-((dimethylamino)methylene)-4-oxocyclohexylcarbamate obtained as an oil was used in the next reaction without any purification. LCMS [M+H}: 269.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=[N:5]1>C(O)(=O)C>[Br:1][CH2:17][C:16]([C:7]1[CH:6]=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cnn(C)c1-c1ccc(C)cc1
Solvent: CC(=O)O
Product: Cc1ccc(-c2c(C(=O)CBr)cnn2C)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Bromine (97%, 0.104 mL, 1.97 mmol) was added to a solution of 1-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (420 mg, 1.96 mmol) in glacial acetic acid (10 mL), and the reaction mixture was vigorously stirred for 2 hours at 80° C. After removal of solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue, which was purified via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) to afford the product as a colorless oil. Yield: 353 mg, 1.20 mmol, 61%. LCMS m/z 293.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.71 (s, 3H), 3.97 (s, 2H), 7.31 (br AB quartet, JAB=8 Hz, ΔvAB=23 Hz, 4H), 8.05 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][C:16]#[N:17].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[C:1]1([CH2:7][CH2:8][O:12][CH2:11][CH2:10][O:9][CH2:14][CH2:15][C:16]#[N:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CC2OCCO2)cc1
Reactant: N#CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CCCOCCOCCc1ccccc1
Yield: 90 %

Procedure:
A mixture of 3-(2-phenylethoxy)ethanol (8.0 g, prepared from 2-phenylmethyl 1,3-dioxolane according to the general method in Can. J. Chem., 1974, 52, 888), 3-bromopropanenitrile (5.6 ml), sodium hydroxide (50 g) and tetrabutylammonium chloride (0.5 g) in dichloromethane (100 ml) and water (100 ml) was stirred at room temperature for 72 hours. The mixture was diluted with water and the organic layer separated. The aqueous layer was extracted with a further portion of dichloromethane. The combined organic extracts were washed with dilute aqueous hydrochloric acid and water, dried (MgSO4) and evaporated under reduced pressure to yield the crude product. This material was purified by flash chromatography over silica using 1:1 ether:petroleum ether (bp 60°-80°) as eluant to give the subtitled compound as an oil (9.84 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[NH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:24]([O:26][CH:27]=[CH:28][CH2:29][CH3:30])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:24]([O:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC=COC(=O)Cl
Reactant: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Product: C=CCCOC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C

Procedure:
Compound 4g was prepared by the same method for preparation of 4b, using pure compound 4 (0.200 g, 585 mmol) and butenyl chloroformate as starting materials to yield compound 4g as a white color solid (98 mg, 38%). 1H NMR (300 MHz, CDCl3) δ 12.46 (s, 1H), 9.22 (s, 1H), 7.56–7.53 (m, 2H), 7.30–7.26 (dd, J=8.6 and 2.4 Hz, 1H), 5.85–5.72 (m, 1H), 5.20–5.13 (m, 2H), 4.29 (t, J=6.9 Hz, 2H), 4.16 (m, 1H), 2.47 (q, J=6.8 Hz, 2H), 1.24 (d, J=6.6 Hz, 6H); 13C NMR: δ170.76, 168.08, 159.19, 155.88, 153.96, 132.63, 132.53, 131.26, 130.40, 128.61, 125.65, 118.32, 66.60, 45.23, 32.74, 22.27; MS m/z 440 (M+), 388, 338, 269, 245, 180, 159.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[CH3:62][S:63]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][O:10][S:63]([CH3:62])(=[O:65])=[O:64])[CH:8]=1)(=[O:65])=[O:64]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (71 mg, 0.091 mmol) in anhydrous dichloromethane (1.4 mL) was added triethylamine (0.038 mL, 0.272 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate. MS (m/z), found 960.2 (M+Na)+. To a mixture of methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (69 mg, 0.074 mmol) and compound 8 (54.1 mg, 0.184 mmol) in anhydrous DMF (0.8 mL) was added potassium carbonate (50.8 mg, 0.368 mmol). The reaction was allowed to stir for 18 hours at room temperature. The reaction was quenched with water and extracted twice with dichloromethane. The remaining aqueous layer was extracted twice with 50% MeOH/CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 265e (23 mg, 23%). MS (m/z), found 1375.4 (M+Na+H2O)+, 1393.4 (M+Na+2H2O)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:4].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:30]([N:29]([CH2:28][C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[F:25])[C:16](=[O:18])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1)[CH3:31]
Reactant: CCNCc1ccccc1F
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
(4-{2-[2-(Methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.200 mg, 0.605 mmol) was dissolved in DMF and cooled on an ice-bath N-(2-Fluorobenzyl) ethanamine (0.102 g, 0.666 mmol), TBTU (0.214 g, 0.666 mmol) and DIPEA (0.22 ml, 1.271 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. EtOAc was added and the organic phase was washed with two portions of 20 ml NaCO3 (sat). The organic layer was dried with MgSO4 and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with acetonitrile/buffer 60/40 and then increasing the acetonitrile concentration to 100% acetonitrile in 25 min, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M), column KR-100-7-C8, 50*500, flow 80 ml/min). 145 mg of the desired product was obtained after freeze drying (yield 71.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>>[C:8]1(=[O:13])[N:1]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Yield: 88.5 %

Procedure:
2 g of gamma-aminobutyric acid is reacted with an equimolar amount (2.87 g) of phthalic anhydride by dry melting at 150° C. The reaction product is crystallized from ethanol/water (1/2) so yielding 4 g of gamma-phthalimidobutyric acid with melting point 120°-123° C. and 88% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=2)=[N:4][N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(NS(C1C=NC=C(C2C3C(=C(C4C=CC=CC=4)C=CC=3)C(NCC3C=CC=CN=3)=NN=2)C=1)(=O)=O)(C)(C)C>>[NH2:24][C:20]1[CH:19]=[C:18]([C:5]2[C:6]3[C:11](=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=[CH:8][CH:7]=3)[C:2]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][N:4]=2)[CH:23]=[N:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: Nc1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Agent: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Product: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Yield: 31 %

Procedure:
4-(5-Aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (0.300 g, 30.9% yield, white solid) was prepared from 5-(4-chloro-5-phenylphthalazin-1-yl)pyridin-3-amine (0.800 g, 2.40 mmol) and benzylamine (10.0 mL, 92.0 mmol) by the methods described for the preparation of N-(tert-butyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide in Example 1. The residue was purified by combiflash (REDISEP®, silica gel, 12 g, 8% MeOH/CHCl3). The resulting residue was further purified by preparative HPLC (Condition 21 as described in general methods). LCMS (Condition 5): retention time 2.03 min, [M+1]=404.6. HPLC (Condition 28): retention time=5.47 min, purity 97.63%. 1H NMR (400 MHz, DMSO-d6) δ 4.49 (d, J=5.2 Hz, 2 H), 4.99 (t, J=5.2 Hz, 1 H), 5.52 (s, 2 H), 7.01-7.03 (m, 2 H), 7.15-7.28 (m, 4 H), 7.43-7.50 (m, 5 H), 7.66 (dd, J=2.0 Hz, J=6.4 Hz, 1 H), 7.85-7.90 (m, 2 H), 7.94 (d, J=2.0 Hz, 1 H), 8.09 (d, J=2.0 Hz, 1 H).