Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28].[I:29]Cl.OS([O-])=O.[Na+].C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([I:29])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(I)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 96.1 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,2-difluoro-7-(trimethylsilyl)benzo[d][1,3]dioxol-4-yl)-5-fluoropicolinate (400 mg, 0.92 mmol) in 1,2-dichloroethane (5 mL) was treated with iodine monochloride (900 mg, 5.5 mmol) and stirred for 20 h at 20° C. The mixture was combined with 10 wt % NaHSO3 solution (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL), and the combined organic phases were washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (430 mg, 96%): mp 156-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 5.02 (s, 2H), 3.99 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.22, −137.49; ESIMS m/z 487 ([M+H]+), 485 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:20])=[O:4].B(Br)(Br)Br>ClCCl>[F:21][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:20])=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)C(C)Cc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.383 g, 1.01 mmol) in dichloromethane (30 mL) was treated with BBr3 (2.35 mL of a 1.0M solution in CH2Cl2, 2.35 mmol) and stirred overnight while warming to 20 C. The excess BBr3 is quenched with water, and the resulting mixture was diluted with ether (100 mL), washed with saturated aqueous Na2CO3 (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.302 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.22 (m, 1H), 6.77 (m, 1H), 5.34 (s, 1H), 4.35 (m, 1H), 3.62 (m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), 2.69 (m, 1H), 1.31 (m, 3 H), 1.22 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:6]
Reactant: CN(C)CCN
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCN(C)C
Yield: 88 %

Procedure:
The procedure of Example 9 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.3 ml of N,N-dimethylethylene diamine were used as starting materials. 6.5 g (yield 88%) of the title compound was obtained as a pale yellow oil.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)C(C)C)C.S(=O)(=O)(O)O.[NH2:39][C:40]1[CH:41]=[N:42][N:43]([CH3:46])[C:44]=1[NH2:45]>C(Cl)Cl>[NH2:45][C:44]1[N:43]([CH3:46])[N:42]=[CH:41][C:40]=1[NH:39][C:1]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (1.94 g) in methylene chloride (20 ml) was added tert-butyl N-(3-aminopropyl)carbamate (2.30 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added N-ethyldiisopropylamine (2.56 g) and 4,5-diamino-1-methylpyrazole sulfuric acid salt, (2.10 g), and the mixture was stirred at 30° C. for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 6% methanol/chloroform to give 5-amino-4-(3-{3-[(tert-butoxycarbonyl)amino]propyl}ureido)-1-methylpyrazole (1.75 g) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Yield: 104 %

Procedure:
8-Benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (10 mg, 0.02 mmol), K2CO3 (12 mg, 0.09 mmol) and iodomethane (2 μL, 0.03 mmol) in DMF (0.1 mL) was stirred for 1 hour. The mixture was diluted with ethyl acetate (5 mL), washed with water (2 mL) and brine (2 mL), dried over magnesium sulfate, filtered and evaporated to give methyl 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylate (10 mg, 100%). ESI-MS m/z calc. 480.6. found 481.5 (M+1)+; Retention time: 1.82 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[C:5]([C:8]#[N:9])[S:6][CH:7]=1.Cl.[NH2:13]O.[CH3:15][C:16]([O:18]C(C)=O)=[O:17]>C(Cl)Cl.C(O)(=O)C.[Pd]>[C:16]([OH:18])(=[O:17])[CH3:15].[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[C:5]([C:8](=[NH:13])[NH2:9])[S:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1nc(C(F)(F)F)cs1
Reactant: NO
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: N=C(N)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of 4-(trifluoromethyl)thiazole-2-carbonitrile (0.9 g, 5 mmol) and TEA (1.1 mL, 7.5 mmol) in DCM (20 mL) was added hydroxylamine hydrochloride (0.35 g, 5 mmol), then the mixture was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=10/1) to give the crude product as a white solid. To the white solid in acetic acid (25 mL) were added Ac2O (0.32 mL, 3.33 mmol) and Pd—C (10%, 0.2 g), then the mixture was stirred at 25° C. for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then the residue was crystallized from EtOAc (2 mL) and ether (10 mL) to give the title compound as a white solid (0.74 g, 58%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].CCOC(C)=O>C1COCC1>[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH:15][C:33](=[O:35])[CH3:34])[CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccn2nc(C)c(-c3nc(-c4ccccc4)c(-c4nc[nH]n4)s3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i) and TEA (0.75 mL) in THF (10 mL), was added acetic anhydride (0.5 mL, 5.3 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (50 mL) and EtOAc (50 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether, and dried to give the title compound (33 mg, 35%) as a white solid.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[F:43][C:30]([F:29])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccccc1OC(F)(F)F)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-(Trifluoromethoxy)benzenesulfonyl chloride (26 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.0 mg). MS m/z 413 [M+H]+.
Reaction SMILES: N[C@H]([C:8]([OH:10])=[O:9])CCC(=O)N.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[C@H:13]([CH2:15]C)[CH3:14].N1CCC[C@H]1C(O)=O.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)[CH2:38][C:39]1[C:47]2C(=CC=CC=2)N[CH:40]=1.C(S)CS>>[C:8]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH:13]([CH3:14])[CH3:15])([O:10][C:39]([CH3:47])([CH3:40])[CH3:38])=[O:9]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Agent: SCCS
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
A larger excess of 6 to 8 equivalents is used in the coupling of steps (h) and (m) with the tert-butoxycarbonyl-protected amino acids aparagine, glutamine, isoleucine, proline, and threonine. In the cycles following addition of a tryptophane residue, 2% 1,2-ethanedithiol (FLUKA) is added to the deprotection steps (a) and (b) in order to prevent the oxidation of the indole ring. Dehydration of the carboxamide function of glutamine is minimized by preforming the 1-hydroxybenzotriazole ester (0°, 15 min) before addition to the resin in step (h).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=C(C#N)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1.[OH-:15].[Na+].[CH3:17][CH2:18][OH:19]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:17]([C:18]([OH:15])=[O:19])[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1
Reactant: CCO
Reactant: [OH-]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1
Agent: [Na+]
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (50 mg, 0.3 mmol) in EtOH (2 mL) was treated with 10N NaOH (0.5 ml) and stirred at 90° C. for 2 hrs. The reaction mixture was purified by prep-HPLC to afford the title compound (22 mg, 40%) as light pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.72 (3H, s), 7.57 (1H, d, J=5 Hz), 7.72 (1H, s), 7.76 (1H, s), 8.28 (1H, s), 8.63 (1H, d, J=4.9 Hz). [M+H] Calc'd for C10H9N3O2, 204. Found, 204.
Reaction SMILES: O.O.O.O.O.[O-:6][Si:7]([O-:9])=[O:8].[Na+:10].[Na+].[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>>[Si:7]([OH:13])([OH:9])([OH:6])[OH:8].[S:12]([O-:16])([O-:15])(=[O:14])=[O:13].[Na+:10].[Na+:10]
Reactant: O=S(=O)(O)O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: O[Si](O)(O)O
Reaction time: 1.5 h

Procedure:
About 150 parts by weight of sodium metasilicate pentahydrate are slowly added to about 75 parts by weight of concentrated sulfuric acid while agitating and keeping the temperature below 100° C. The reaction takes place under ambient pressure, and the reaction is complete in 1 to 2 hours, thereby producing a white granular silicic acid compound and sodium sulfate. The mixture is washed with water then filtered to remove the salt and water, thereby recovering the silicic acid compound. The silicic acid compound is air dried at 25° to 75° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][NH:3]1.[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(N)(=O)=O)[C@@H](C)CN1
Yield: 35.5 %

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (2 g) in dioxane (100 ml) was added sulfamide (2.5 g) and the reaction mixture was then heated at reflux in dioxane (100 ml) for 72 h. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected, dried and reduced in vacuo to give (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide as a white solid (1.2 g). A mixture of (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide (0.38 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and, 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), 0.4 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 4 h. The reaction mixture was then reduced in vacuo and the residue partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give a yellow solid. This residue was then purified by prep HPLC to give the title compound as a white solid. Yield: 9 mg
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4'-Hydroxybiphenyl-4-carboxylic acid (3.5 g) and triethylamine (2.4 g) were dissolved in dichloromethane (30 ml). Undecanoyl chloride (4.3 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added thereto, and the organic layer was separated in a separating funnel. The solvent was removed by evaporation, and the residue was dried after washing with n-hexane to give the titled compound (5 g).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCC.CC=CCCCCC>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH3:11].[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: CC=CCCCCC
Product: CC=CCCCCCCCC(=O)OC
Product: CCCCCC=CCCCCCCCC(=O)OC
Reaction time: 17 h

Procedure:
Reaction was carried out in the same manner as in Example 1, except that a mixture of 1 ml of methyl oleate and 1 ml of 2-octene was used in place of 1 ml of the methyl oleate, the reaction temperature was 70°C., and the reaction time was 17 hours. There were obtained methyl 9-undecenoate in a yield of about 5% and methyl 9-pentadecenoate in a yield of about 7% (estimated from the chromatogram). Besides, metathesis products were obtained independently from methyl oleate and 2-octene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:68]([NH:75][CH2:76][CH2:77][CH2:78][NH2:79])([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:79][CH2:78][CH2:77][CH2:76][NH:75][C:68](=[O:69])[O:70][C:71]([CH3:72])([CH3:73])[CH3:74])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (400 mg, 0.86 mmol), HATU (380 mg, 1.0 mmol) and N,N-diisopropylethylamine (244 mg, 1.9 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1,3-propanediamine (174 mg, 1.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 500 mg, 94%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=1>CO.[Pt](=O)=O>[NH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([CH:8]2[C:9]3=[N:10][NH:11][C:12](=[O:20])[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:18]=43)[NH:19][CH:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:22]1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2c1cccnc1
Agent: O=[Pt]=O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2C1CCCNC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 3.3 %

Procedure:
A suspension of 8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol) and platinum (IV) oxide (60 mg) in methanol (20 mL) was purged in 20 atm hydrogen and stirred at 50° C. for 24 hr. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (4 mg, yield: 4%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ 1.19-1.32 (m, 2H), 1.60-1.65 (m, 2H), 1.94-1.97 (d, J=10.0 Hz, 1H), 2.31-2.43 (m, 2H), 2.82-2.85 (d, J=12.4 Hz, 1H), 3.02-3.05 (d, J=12 Hz, 1H), 3.29-3.32 (dd, J1=2.8 Hz, J2=8.4 Hz, 1H), 4.25-4.26 (d, J=2.8 Hz, 1H), 7.02-7.05 (dd, J1=0.8 Hz, J2=8.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.40-7.53 (m, 3H), 8.25-8.29 (m, 2H); LC-MS (ESI) m/z: 348(M+1)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]([NH:19][C:20]([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])[CH3:18])=[CH:13][CH:12]=1.[CH:30]1[C:34]2[C:35](Cl)=[N:36][CH:37]=[N:38][C:33]=2[NH:32][CH:31]=1>CC(N(C)C)=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]([NH:19][C:20]([C:22]2([C:28]#[N:29])[CH2:23][CH2:24][N:25]([C:35]3[C:34]4[CH:30]=[CH:31][NH:32][C:33]=4[N:38]=[CH:37][N:36]=3)[CH2:26][CH2:27]2)=[O:21])[CH3:18])=[CH:15][CH:16]=1
Reactant: C[C@@H](NC(=O)C1(C#N)CCNCC1)c1ccc(Cl)cc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)C1(C#N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
DIPEA (1.101 mL, 6.17 mmol) was added to (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (Intermediate 44) (720 mg, 2.47 mmol) and 6-chloro-7-deazapurine (379 mg, 2.47 mmol) in DMA (50 mL) at 25° C. The resulting solution was stirred at 90° C. for 3 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyano-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (46.2%) as an orange solid. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1OC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(C(=O)Nc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3ccc(O)cc3)ncnc2n1
Yield: 75 %

Procedure:
The product of Example 39A was reacted with the product of Example 9B using the procedure of Example 37D substituting the product of Example 39A for the product of Example 37C and substituting the product of Example 9B for Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (32 mg, 75%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 6.75 (d, J=8.82 Hz, 2 H) 6.82-6.98 (m, 3 H) 7.20-7.38 (m, 2 H) 7.54 (d, J=8.46 Hz, 1 H) 7.69-7.81 (m, 1 H) 7.87 (dd, J=8.64, 2.02 Hz, 1 H) 8.10 (s, 1 H) 8.19 (d, J=1.84 Hz, 1 H) 8.61 (s, 1 H) 8.78 (d, J=8.46 Hz, 1 H) 9.39 (s, 1 H) 10.01 (s, 1 H) 10.32 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.