Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([NH:17][S:18]([CH:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])(=[O:20])=[O:19])[N:10]=1.IC.Cl>O1CCCC1.CCOCC.O>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([NH:17][S:18]([C:21]([CH3:1])([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])(=[O:20])=[O:19])[N:10]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Temperature: 5 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
Potassium t-butoxide (5.3 g) was added with stirring and cooling to the product of Example 1 (7.5 g) in dry tetrahydrofuran (120 ml). The mixture was stirred for 41/2 hours at room temperature, and was then cooled to 5° C., when iodomethane (3.2 g) in dry tetrahydrofuran (10 ml) was added dropwise. Stirring was continued at room temperature for 24 hours, and the intermittently for 7 days. The solvent was run off under vacuum, and the residue was stirred with ice, water and ether while being acidified to pH=1 with hydrochloric acid. The ether solution was separated, the aqueous layer being extracted twice more with ether, and the combined ether extracts were washed with water (twice), dried over magnesium sulfate, and run down under vacuum to give the desired product (7.1 g) in am impure form. Purification by flash chromatography on silica gel, eluting with dichloromethane and ethyl acetate (9:1), followed by preparative HPLC gave 0.4 g of the pure desired product, mp 124°-127° C.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][N:10]=1.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:34]=[N+:35]=[N-:36])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Reaction time: 3 h
Yield: 99 %

Procedure:
Into ethyl acetate was suspended 1.91 g of 6-(trifluoromethyl)nicotinic acid, and then 1.52 g of triethylamine and 3.03 g of DPPA were added thereto, followed by 3 hours of stirring. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and saturated saline and the solvent was removed by evaporation to obtain 2.0 g of 6-(trifluoromethyl)nicotinyl azide as a solid. The resulting acid azide was dissolved into 20 ml of toluene and the solution was heated and refluxed to convert the acid azide into 5-isocyanato-2-(trifluoromethyl)pyridine. Thereafter, 1 ml of methanol was added thereto at room temperature, followed by 1 hour of stirring. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation to obtain 1.2 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of 6.43 g (49 mmol) 3chloropropylamine and 13.6 ml (98 mmol) triethylamine in 220 ml methylene chloride was cooled by an ice bath and 9 g (48.5 mmol) 4-nitrobenzoyl chloride were added fractionwise. After one hour stirring at room temperature the organic phase was washed twice with water, dried over MgSO4 and concentrated in vacuo to afford 10.68 g (91%) of beige crystals. 1H NMR was consistent with the desired structure.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2n1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 3, 100 mg, 0.35 mmol) in methylene chloride (2 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.26 mL, 0.52 mmol) and then stirred at 0° C. for 30 min. The resulting reaction mixture was then treated with a solution of 2-aminoquinoline (75 mg, 0.52 mmol) and pyridine (0.14 mL, 1.74 mmol) in tetrahydrofuran (5 mL), and the reaction mixture was allowed to warm to 25° C. The reaction was then stirred at 25° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-quinolin-2-yl-propionamide (93 mg, 65%) as an oil: EI-HRMS m/e calcd for C23H22Cl2N2O (M+) 412.1109, found 412.1123.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Li])CCC.[B:17]([O:26][CH:27]([CH3:29])C)([O:22][CH:23](C)C)OC(C)C.C(Cl)(=O)C.C(O)CCO>C(OCC)C.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]2[O:22][CH2:23][CH2:29][CH2:27][O:26]2)=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: COc1c(Cl)ccc(Br)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: OCCCO
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(B2OCCCO2)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 144.2 %

Procedure:
To a solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4 g, 0.043 mol) in diethyl ether (150 mL) at −78° C. was slowly added n-butyl lithium (2.5M, 19.0 mL, 0.0475 mol), and the solution was stirred for thirty minutes. A solution of triisopropyl borate (12.0 g, 0.064 mL) in THF (25 mL) was slowly added and the solution warmed to 0° C. Acetyl chloride (10.0 g, 0.13 mol) was added. After stirring for one hour the solution was concentrated and the solid residue was partitioned between ethyl acetate (150 mL) and 1N sodium hydroxide (50 mL). Ice was added to the aqueous phase that was subsequently acidified with sufficient concentrated hydrochloric acid to obtain a pH of 2. The heterogeneous mixture was extracted with ethyl acetate (2×150 mL) and the combined organic phases were dried and concentrated. The resulting solid was slurried in toluene, propane-1,3-diol (6.6 g, 0.09 mol) was added, and the resulting mixture was heated under reflux to remove water via a Dean-Stark trap. After two hours, the mixture was allowed to cool and was concentrated under vacuum. The resulting oil was dissolved in methylene chloride (50 mL), washed with water (25 mL), dried, and concentrated to give 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (6.4 g, 0.062 mol): 1H NMR (CDCl3): δ 7.15 (m, 1H), 6.95 (dd, 1H), 4.05 (t, 4H), 3.8 (s, 3H), 1.95 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[CH:17]([O-])([O-])OC>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:12][CH3:17])/[CH3:11])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: COC([O-])[O-]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CO/C(C)=C\C(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A mixture of 33 g of m-nitro-acetylacetanilide, 38.1 g of methyl orthoformate and 13 drops of 36° Be sulfuric acid was allowed to stand for 16 hours and after the addition of 40 drops of quinoline and 150 ml of toluene, the mixture was heated to 130° C. while distilling of the methanol formed as an azeotrope. The mixture was cooled and vacuum filtered and the recovered precipitate was crystallized from acetone to obtain 24 g of m-nitro-3-methoxy-crotonanilide melting at 187° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([C:8]1[CH:7]=[N:6][N:5]2[CH:30]=[C:2]([C:36]3[CH:37]=[N:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:12]1)(=[O:29])[NH2:28]
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(N[C@@H]4CN(C(=O)OCc5ccccc5)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1
Temperature: 95 °C
Reaction time: 0.03 h

Procedure:
A mixture of (+/−)-(cis)-benzyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylpyrrolidine-1-carboxylate (0.40 g, 0.847 mmol), (6-methoxypyridin-3-yl)boronic acid (0.168 g, 1.10 mmol), palladium acetate (9.51 mg, 0.042 mmol) and 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.040 g, 0.085 mmol) in dioxane (3.0 mL) was degassed by purging with argon for 3 min. Aqueous potassium phosphate (2.0 M) (1.27 mL, 2.54 mmol) was added and purging with argon was continued for 2 min. The reaction vial was sealed and heated at 95° C. for 3 h then the resulting mixture was cooled and concentrated to remove dioxane and the residue was taken up in EtOAc (300 mL). The resulting solution was washed with water, brine and dried over MgSO4, filtered and concentrated to afford a yellow solid as the crude product mixture. This material was purified by preparative chromatography using CH2Cl2/MeOH mixtures as the eluant and a 40 g silica cartridge. Fractions containing the major product were combined and concentrated to afford a bright yellow solid as the title compound. HPLC (method B) retntion time=3.65 min. LCMS (m+1)=501.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2cncc(Br)c2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 5-bromonicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.11 (s, 1H), 9.11 (d, J=2.1, 1H), 8.88 (d, J=1.8, 1H), 8.80 (d, J=9.3, 1H), 8.42 (t, J=2.1, 1H), 7.75 (d, J=2.7, 1H), 7.34-7.30 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[O:26])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.O.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.Cl[Pd]Cl.[Fe+2]>[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[C:5]4[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:23][CH2:22]1
Reactant: CC1c2c(nc(Cl)nc2N2CCOC[C@@H]2C)CS1(=O)=O
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1c2c(nc(-c3ccc(NC(=O)NC4CC4)cc3)nc2N2CCOC[C@@H]2C)CS1(=O)=O
Temperature: 80 °C
Yield: 20.8 %

Procedure:
To a solution of 2-chloro-5-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (100 mg, 0.3147 mmol) in DME/H2O (2 mL, 4/1, v/v) were added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (114.1 mg, 0.37 mmol) and sodium carbonate (100.1 mg, 0.94 mmol) The reaction was degassed twice and a catalytic amount of Pd(dppf)Cl2 (10 mg, 0.013 mmol) was added to the suspension. The mixture was heated at 80° C. for 3 h under a nitrogen atmosphere. The resulting mixture was cooled and H2O was added. The mixture was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, and then evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/ethyl acetate=20/1˜5/1) and preparative HPLC to provide the product as a white solid (30.0 mg, 21%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.ClCCl.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc(CO)o1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxymethylfuran-2-carboxylic acid (5.90 g), dry dichloromethane (100 ml), pyridine (6.71 ml), 4-dimethyl-aminopyridine (507 mg), and acetic anhydride (4.21 ml) was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and washed with 5M hydrochloric acid and brine (3 times), dried (MgSO4), and evaporated. The residue was re-evaporated twice from dry toluene to give the title acid as a solid (5.00 g); δH [(CD3)2CO) 2.05 (3 H, s), 5.11 (2 H, s), 6.62 (1 H, d, J 4 Hz), 7.17 (1 H, d, J 4 Hz) and 8.31 (1 H, br s).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 391.16 g/mol.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:8][CH3:9])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:3](=[O:10])[N:4]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[C:5]([S:8][CH3:9])=[N:6][N:7]=1
Reactant: N#Cc1ccccc1CBr
Reactant: CSc1nnc(C)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nnc(C)c(=O)n1Cc1ccccc1C#N
Temperature: 0 °C

Procedure:
To a solution of 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5, 1.546 g, 9.85 mmol) in dry DMF (10 mL) at 0° C. was added K2CO3 (1.36 g, 9.85 mmol) and 2-cyanobenzylbromide (2.316 g, 11.82 mmol). The mixture was heated at 0° C. for 16 h. The mixture was diluted with water, and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried over MgSO4, and concentrated. This was purified by column chromatography on silica gel, and eluted with 20% to 50% ethyl acetate in petroleum ether and 1:1:2 petroleum ether-dichloromethane-ethyl acetate to provide 2-((6-methyl-3-(methylthio)-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (6). MS: m/z, 273 (100%, M+1), 295 (60%, M+23).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:27]([CH2:28][C:29]5[C:30]([F:46])=[N:31][C:32]([NH:35][CH2:36][C:37]6[C:38]([O:44][CH3:45])=[N:39][CH:40]=[C:41]([F:43])[CH:42]=6)=[CH:33][CH:34]=5)=[CH:26][N:25](S(C5C=CC=CC=5)(=O)=O)[C:22]4=[N:23][CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OC(N1CCC(N2C=C(C3C=C4C(CC5C(F)=NC(NCC6C(OC)=NC=C(F)C=6)=CC=5)=CNC4=NC=3)C=N2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CO.ClCCl>[F:43][C:41]1[CH:42]=[C:37]([CH2:36][NH:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:27]3[C:21]4[C:22](=[N:23][CH:24]=[C:19]([C:17]5[CH:16]=[N:15][N:14]([CH:11]6[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]6)[CH:18]=5)[CH:20]=4)[NH:25][CH:26]=3)=[C:30]([F:46])[N:31]=2)[C:38]([O:44][CH3:45])=[N:39][CH:40]=1
Reactant: COc1ncc(F)cc1CNc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cc23)c(F)n1
Agent: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cc23)c(F)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)c(F)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
In a vial, 4-[4-(1-benzenesulfonyl-3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (170, 0.137 g, 0.178 mmol) was dissolved in a solution of potassium hydroxide (0.392 g, 6.99 mmol) in 7.0 mL of methanol and the reaction was heated at 50° C. for 3 hours. Aqueous 1 M citric acid was added, then the reaction was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. 4-[4-(3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (P-1702, 56 mg, 0.0888 mmol) was combined with this and 10 mL of dichloromethane and trifluoroacetic acid (0.50 mL, 6.5 mmol) were added, then stirred at room temperature for 2 hours. Aqueous saturated sodium bicarbonate was added to pH=8, then concentrated under vacuum and ethyl acetate and water were added. The organic layer was isolated and washed with aqueous saturated sodium bicarbonate, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a yellow solid (P-1703, 74 mg). MS (ESI) [M+H+]+=631.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC.CO.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>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH3:13])=[N:3][N:4]=[CH:5]2
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2nncc3cc(Cl)ccc23)c(C)c1

Procedure:
A mixture of 1,6-dichlorophthalazine (300 mg, 1507 μmol), 2,4-dimethylphenylboronic acid (249 mg, 1658 μmol), Pd(PPh3)2Cl2 (52.9 mg, 75.4 μmol, Strem), and sodium carbonate (479 mg, 4522 μmol) in DME:EtOH:H2O=7:2:3 (5 mL) was heated to 130° C. for 5 min in the Emrys Optimizer microwave. The mixture was diluted with MeOH and H2O and concentrated over SiO2. The residue was purified with flash chromatography (MeOH/CH2Cl2=0→2%) to afford the title compound. MS (ESI, pos. ion) m/z: 269 (M+1).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[N:6][N:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[N:8]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][N:7]6[N:6]=[N:5][C:4]([CH2:2][CH3:3])=[N:8]6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1nnn(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cn5nnc(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[(5-ethyl-2H-tetrazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (170 mg, compound B97), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (143 mg; compound C10) and COMU (167 mg) in DCM (3.0 ml) is added DIPEA (0.25 ml). The reaction mixture is stirred at RT for 1 h. Saturated aqueous sodium bicarbonate solution (2 ml) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc] and by preparative HPLC to yield the title compound as a solid.