Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][C:77](O)=[O:78].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:77](=[O:78])[CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: COCCOCCOCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCOCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), [(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]acetic acid (0.016 mL, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% trifluoroacetic acid) to give the title compound (0.027 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 9.39 (s, 1H), 8.97 (t, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.42-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.31 (s, 2H), 7.09 (d, 1H), 4.53 (d, 2H), 4.02 (s, 2H), 3.61-3.66 (m, 2H), 3.56-3.60 (m, 2H), 3.53 (dd, 2H), 3.38-3.44 (m, 2H), 3.19 (s, 3H). ES MS: m/z 629 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19](Cl)=[O:20].OC1C(C)=CC(C(OC)=O)=C(C)C=1>>[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:20]
Reactant: Cc1cc(C(=O)Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Reactant: COC(=O)C(C)(C)c1ccc(C)c(N)c1
Agent: COC(=O)c1cc(C)c(O)cc1C
Product: Cc1ccc(C(C)(C)C(=O)O)cc1NC(=O)c1cc(C)c(OC[C@@H]2CN(C)c3ccccc3O2)cc1C
Yield: 66.2 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using methyl 2-(3-amino-4-methylphenyl)-2-methylpropanoate (132 mg)(the compound prepared by the same procedures as Example 16) and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (210 mg)(the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,5-dimethylbenzoate.), the title compound (202 mg) having the following physical data was obtained.
Reaction SMILES: CO[C:3]([C:5]1([CH2:10][CH2:11][CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:12][CH2:11][CH2:10][C:5]4([CH2:9][CH2:8][CH2:7][CH2:6]4)[C:3]3=[O:4])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: COC(=O)C1(CCC=O)CCCC1
Product: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCCC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(3-oxo-propyl)-cyclopentanecarboxylic acid methyl ester (Intermediate 7) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][C:16]1[C:21]([I:22])=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=1[C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:15][C:16]1[C:21]([I:22])=[C:20]([O:23][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][C:17]=1[C:24](=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(=O)c1ccc(O)c(I)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccc(OCc2ccccc2)c(I)c1OCc1ccccc1
Yield: 95.9 %

Procedure:
Add benzyl bromide (17.63 g, 103.1 mmol, 12.3 mL) and cesium carbonate (30.53 g, 93.7 mmol) to a solution of 1-(2,4-dihydroxy-3-iodo-phenyl)-3-methyl-butan-1-one (15.00 g, 46.9 mmol) in anhydrous dimethylformamide (120 mL) at room temperature under Argon gas. Stir the reaction at room temperature overnight. Filter the mixture and concentrate the filtrate under reduced pressure to an oil. Partition the oil between ether and water. Separate the organic layer and extract the aqueous layer with ether (2×). Combine the organic layers, wash with brine, dry over sodium sulfate, filter and concentrate to provide a redish oil (22.5 g, 45 mmol, 96% yield). MS (m/z): 501 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:33]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-methoxy-benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[C:14](=[O:32])[N:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:12]2=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)[C:14](=[O:32])[N:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:12]2=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 3.5 g of 1,1-dimethylethyl 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 1.5 and 25 ml of TFA in 50 ml of DCM is stirred at AT for 2 h 00. The mixture is neutralized with K2CO3. It is filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in DCM and washed with a saturated NaHCO3 solution and then with an 8% NaOH solution. The solution is dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure to give 2.67 g of the expected product.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]2[C:82]3[C:81]([F:84])([F:83])[CH2:80][CH2:79][C:78]([F:86])([F:85])[C:77]=3[C:76]([CH:87]([F:89])[F:88])=[N:75]2)[CH2:62][C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=2)=[N:52][C:53]([NH:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)=[N:54][CH:55]=1>>[CH:58]1([CH2:57][NH:56][C:53]2[N:52]=[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]3[C:82]4[C:81]([F:83])([F:84])[CH2:80][CH2:79][C:78]([F:85])([F:86])[C:77]=4[C:76]([CH:87]([F:89])[F:88])=[N:75]3)[CH2:62][C:63]3[CH:64]=[C:65]([F:70])[CH:66]=[C:67]([F:69])[CH:68]=3)[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=2)[CH2:59][CH2:60]1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCC2CC2)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCC3CC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (13B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 13A. 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=7.7 Hz, 1H), 7.73 (s, 1H), 7.24-7.02 (m, 2H), 6.90 (dd, J=10.7, 8.6 Hz, 1H), 6.65-6.24 (m, 2H), 6.13 (d, J=6.1 Hz, 2H), 4.91 (m, 1H), 4.83-4.62 (m, 2H), 3.09 (m, 2H), 2.71 (ddd, J=20.2, 13.3, 7.4 Hz, 2H), 2.37-2.06 (m, 4H), 0.88 (m, 1H), 0.47-0.16 (m, 2H), 0.02 (q, J=5.1 Hz, 2H). MS (m/z) 726.30 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][C@H:21]([CH3:25])[CH2:20]4)=[C:15]([CH3:26])[CH:14]=3)[N:11]=1)[C:8](=[O:27])[NH:7][CH:6]=[CH:5]2.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CO.O>[CH3:26][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[N:11]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=3)[CH:3]=[C:4]3[C:9]=2[C:8](=[O:27])[NH:7][CH:6]=[CH:5]3)[CH:18]=[CH:17][C:16]=1[N:19]1[CH2:24][CH2:23][O:22][C@H:21]([CH3:25])[CH2:20]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(Nc2nc(Cl)cc3cc[nH]c(=O)c23)ccc1N1CCO[C@H](C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc3cc[nH]c(=O)c3c(Nc3ccc(N4CCO[C@H](C)C4)c(C)c3)n2)cn1
Temperature: 90 °C

Procedure:
A mixture of (R)-6-chloro-8-(3-methyl-4-(2-methylmorpholino)phenylamino)-2,7-naphthyridin-1(2H)-one (770 mg, 2.0 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.8 g, 3.65 mmol), Pd(PPh3)4 (200.0 mg, 0.173 mmol) and Na2CO3 (1.0 g, 9.45 mmol) in a mixed solvent of dioxane (16.0 mL) and H2O (4.0 mL) was purged with N2, heated at 90° C. for 16 hours, evaporated to result in a residue which was subjected to chromatography with gradient mixed solvents from DCM/MeOH/28% aqueous NH4OH (49:10:1) to (19:10:1) afforded a product which was then recrystallized in toluene to afford the title compound. 1H NMR (DMSO-d6) δ 1.12 (d, J=6.4 Hz, 3H, CH3), 2.31 (s, 3H, CH3), 2.42 (m, 1H), 2.55 (s, 3H, CH3), 2.70 (m, 1H), 2.85-2.95 (2H), 3.65-3.73 (2H), 3.85 (m, 1H), 6.53 (d, J=7.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.48 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.74 (dd, J=8.0, 2.4 Hz, 1H), 8.35 (dd, J=8.8, 2.4 Hz, 1H), 9.20 (s, 1H), 11.77 (br s, 1H, NH), 11.92 (br s, 1H, NH); ESI-MS ink 442.2 (MH+); Anal. Calcd for C26H27N5O2: C, 70.73; H, 6.16; N, 15.86. Found: C, 70.73; H, 6.13; N, 15.83.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH:6]=[CH2:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[C:29]1([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)C>[CH:6]([O:5][C:3](=[O:4])[CH:2]=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:43][CH:42]=1)=[CH2:7]
Reactant: C=COC(=O)CI
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=COC(=O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 6 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottom flask equipped with a nitrogen inlet-outlet, magnetic stirrer and addition funnel was charged with vinyl iodoacetate (5.6 g, 26 mmol) and triphenylphosphine (6.9 g, 26 mmol) in 50 mL anhydrous tetrahydrofuran. The reaction mixture was blanketed with nitrogen and allowed to stir for 16 h and then cooled to 6° C. on an ice-water bath. Sodium hydride (1.0 g, 25 mmol) was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for 4 h, 4-diphenylaminobenzaldehyde (5.4 g, 20 mmol) dissolved in 40 mL anhydrous THF was added dropwise to the stirring reaction mixture over 30 minutes. After stirring at room temperature for five days, the reaction mixture was diluted with 50 mL diethyl ether and transferred to a separatory funnel. An additional 300 mL diethyl ether was added to the separatory funnel and the combined ether solution was washed three times with 100 mL water and one time with 100 mL saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated on a rotary evaporator. The residue was further dried on a high vacuum line to yield the crude product as a brown oil. After purification by flash column chromatography (silica gel; 3:7 dichloromethane:hexanes) 5.5 g of the pure product was obtained as a light yellow oil. The product yield was 81%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[I:17]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([I:17])[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12

Procedure:
A suspension of 4-chloro-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (2.44 g, 10.6 mmol) and N-iodosuccinimide (3.58 g, 15.9 mmol) in acetonitrile (106 mL) was heated at reflux for 1 d. The yellow solid was collected by filtration whilst warm to provide a mixture of the title compound and starting material (9:1, 4 g).
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22]COC)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].[ClH:26]>CO>[ClH:26].[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([OH:22])=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1coc(C(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2-isopropyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole (1.00 g) in methanol (12 mL) was added concentrated hydrochloric acid (0.52 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether to give 4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.95 g, yield 92%) as orange crystals. melting point: 205-209° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[C:10]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[OH-].[Na+].Cl>O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[C:10]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1ccncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccccc1)c1ccncc12
Yield: 86.1 %

Procedure:
methyl 5-phenylbenzo[c][2,6]naphthyridine-8-carboxylate (147 mg, 0.468 mmol) was reacted with EtOH (3 ml) and 6 N NaOH (1 ml) at 60° C. for 2 hours. Water was added and the mixture acidified using 6N HCl. The solid was filtered and washed with water. The material was triturated in AcOEt/hexanes, filtered and dried to afford 5-phenylbenzo[c][2,6]naphthyridine-8-carboxylic acid as an off-white solid (121 mg, 86% yield). LCMS (ES): >95% pure, m/z 301[M+1]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O.S(Cl)(Cl)=O>>[Cl:14][C:2]1[N:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2nccnc12
Solvent: O=S(Cl)Cl
Product: Clc1ncc2nccnc2n1

Procedure:
Reaction of pteridin-4(3H)-one IV′ with chlorinating agents such as phosphorous oxychloride or thionyl chloride affords chloro-pteridine V′. Suitable solvent for this reaction includes methylene chloride chloroform or toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26]I.[H-].[Na+].Cl>C1COCC1.[NH4+].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[CH2:12][CH2:13][O:14][CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCCC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To a solution of 3-(3',4'-dimethoxyphenyl)-3-phthalimido-1-propanol (1.02 grams, 2.99 mmol) and methyl iodide (0.37 mL, 5.94 mmol) in THF (10 mL) at room temperature, was added NaH (358 mg, 60%, 8.95 mmol). The mixture was stirred at room temperature for 45 minutes, and then was refluxed for 2 h. To the cooled mixture was added a few drops of NH4Cl, then HCl (1N, 25 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel 100 grams, 1:5 EtOAc:hexane) gave 3-(3',4'-dimethoxyphenyl)-1-methoxy-3-phthalimidopropane as a white solid, (750 mg, 71% yield): mp, 91.5°-92.5° C.; 1H NMR (CDCl3)δ2.50-2.59 (m, 1H, CHH), 2.70-2.86 (m, 1H, CHH), 3.27 (s, 3H, CH3), 3.39 (t, J=6 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 3.88 (s, 3H, CH3), 5.49 (dd, J=6.8, 9.2 Hz, 1H, NCH), 6.81 (d, J=8 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.67-7.72 (m, 2H, Ar), 7.77-7.83 (m, 2H, Ar); 13C NMR (CDCl3)δ31.29, 51.93, 55.80, 58.69, 69.64, 110.84, 115.56, 120.62, 123.12, 131.90, 1332.03, 133.84, 148.58, 148.81, 168.38; Anal Calcd for C20H21NO5 : C, 67.59; H, 5.96; N, 3.94. Found: C, 67.54; H, 5.97; N, 3.84.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:29]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:30])=[O:31])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of (5-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester (4.0 g, 10.3 mmol), 2-(tert-butylaminosulfonyl)-phenyl boronic acid (5.3 g; 20.6 mmol), PdCl2 dppf (1.7 g, 0.20 mmol) and 1M Na2CO3 solution (83 mL, 82.7 mmol) in 1,2-dimethoxyethane was heated to 90° C. for 12 h under inert atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc: hexanes, 3:7) to afford the title compound as a yellow viscous oil (5.4 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.14 (m, 1H), 7.88 (m, 1H), 7.43-7.69 (m, 6H), 7.19 (m, 1H), 7.28 (m, 1H), 1.52 (s, 9H), 1.48 (s, 9H), 1.06 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H37N3O6S: 520.65 (M+H), Found 520.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:22][CH2:21][CH2:20][NH2:23])=[N:14][CH:13]=1
Reactant: NCCN
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(N)c1
Product: COc1ccc(NC(=O)c2ccc(NCCN)nc2)c(N)c1
Yield: 48 %

Procedure:
N-(2-Amino-4-methoxyphenyl)-6-chloronicotinamide (277 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (144 mg, 48% yield) as a brown solid. LC-MS (m/z) 302 (M+1).
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=[O:19].[Li+]>CO>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:19])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Agent: [Li+]
Solvent: CO
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
0.5 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 1.5 g of polyethyleneoxyglycol (molecular weight: 600) and 0.5 g of lithium trifluoromethane sulfonate salt. The mixture was dropped on an ion-conducting glass electrode and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled to room temperature and immersed in methanol and dried. A thin membrane of styrene-maleic acid polyethyleneoxy ester copolymer of an excellent adhesive strength and mechanical strength was prepared. The ion conductivity of the polymer thin membrane prepared as above was 7×10-7S/cm at room temperature.