Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.C1COCC1.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[NH2:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:48][C:43]4[N:44]=[CH:45][CH:46]=[CH:47][N:42]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.00 g, 8.47 mmol), and THF (85 ml). To this, was added pyrimidin-2-amine (1.208 g, 12.71 mmol) and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (18.63 ml, 18.63 mmol) was added dropwise and allowed to stir at 0° C. After 1 hour, the mixture was diluted with 1N aq. HCl (10 mL) and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 10-50% of a 3:1 EtOAc/EtOH solution in heptane) to give 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (3.54 g, 7.06 mmol, 83% yield) as an off white solid. m/z (ESI) 502.8 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[C:19]([NH:21][C:22]2[C:27]3=[CH:28][N:29]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:38])[N:30]=[C:26]3[C:25]([CH3:39])=[CH:24][N:23]=2)[N:18]=[CH:17][N:16]=1)(C)(C)C>C(Cl)Cl>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[N:29]1[CH:28]=[C:27]2[C:22]([NH:21][C:19]3[CH:20]=[C:15]([NH2:14])[N:16]=[CH:17][N:18]=3)=[N:23][CH:24]=[C:25]([CH3:39])[C:26]2=[N:30]1
Reactant: Cc1cnc(Nc2cc(NC(=O)OC(C)(C)C)ncn2)c2cn(-c3c(Cl)cccc3Cl)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2cc(N)ncn2)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C

Procedure:
TFA (1.5 mL) was slowly added to the crude mixture of {6-[2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamic acid tert-butyl ester and {6-[2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester in DCM (1.5 mL) at 0° C., under an atmosphere of nitrogen. The reaction mixture was stirred with warming to room temperature over 2 hours. The resultant mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether. The pale yellow solid formed was filtered and washed with diethyl ether to afford the crude title compound (30 mg). The filtrate was concentrated under reduced pressure to afford impure title compound as an yellow oil (220 mg). The two batches were separately dissolved in ethyl acetate, then combined and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude residue. This was purified by silica gel flash chromatography (0-10% methanol in DCM), then further purified by HPLC (gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)], to afford the title compound as a white powder (14 mg, 14% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.51 (d, J=0.9 Hz, 1H), 7.89-7.85 (m, 2H), 7.81-7.74 (m, 2H), 6.51 (br s, 1H), 2.45 (d, J=1.3 Hz, 3H). LCMS (Method B): RT=3.05 min, m/z: 386 [M+H+].
Reaction SMILES: [C:1]12([N:11]3[C:16]([CH2:17][CH:18]([CH:24]=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=[N:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC[O-].[Na+].[Cl:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.CCOC(C)=O.CCCCCC>CCO>[ClH:30].[ClH:30].[C:1]12([N:11]3[C:16]([CH2:17][C:18]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)([CH:24]=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=[N:13][CH2:12]3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)C(C=O)CC1=CC=NCN1C12CC3CC(CC(C3)C1)C2
Reactant: ClCc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(C=O)(CC1=CC=NCN1C12CC3CC(CC(C3)C1)C2)Cc1cccnc1
Product: Cl

Procedure:
The procedure described in Example 140B was followed with a solution of 3-N-adamantan-1-yl-3-oxo-2-pyrimidin4-ylmethyl-propanoic acid, ethyl ester [prepared as described in Example 144] (0.225 g, 0.629 mmol) in EtOH (3 mL), a 21% by weight solution of NaOEt in EtOH (0.306 mL, 0.818 mmol), and a solution of 3-chloromethylpyridine (0.088 g, 0.692 mmol) in EtOH (1 mL) except that the reaction was heated at 60° C. overnight (16 hours). After flash chromatography (75 to 100% EtOAc-hexane), the title compound, free base (0.119 g, 42%) was obtained as a yellow solid. A portion of the free base (0.039 g, 0.087 mmol) was treated with ethanolic HCl as described in Example 140C to give the dihydrochloride salt (0.030 g, 66%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:22]([O-])(=O)C.[Na+].C=O>>[N:21]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:22][C:2]2[NH:1][C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:12][CH2:11]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Reactant: c1cnc(N2CCNCC2)nc1
Agent: C=O
Agent: [Na+]
Product: c1cnc(N2CCN(Cc3cc4cccnc4[nH]3)CC2)nc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)pyrimidine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.42 (m, 4H) 3.68 (m, 4H) 4.05 (s, 2H) 5.59 (s, 1H) 6.60 (m, 1H) 7.08 (m, 2H) 7.37 (m, 2H 8.07 (m, 2H). (ESI) m/z 295 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25](N(OC)C)=[O:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:37][Mg]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25](=[O:26])[CH3:37])=[CH:14][CH:13]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Tert-butyl(2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.175 g, 0.355 mmol) was dissolved in tetrahydrofuran (5 mL) and a solution (0.15 mL, 0.43 mmol) of 3 M methyl magnesium bromide in diethyl ether was added dropwise under ice-cooling. This mixture was stirred at room temperature for 1 h and quenched with saturated aqueous ammonium chloride solution (5 mL). The whole was extracted with ethyl acetate (10 mL), and the organic layer was washed once each with 0.1 M aqueous citric acid solution (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl(6-acetyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.132 g, 83%) as a colorless powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21].[CH2:33]1[O:37][C:36]2[CH:38]=C(O)[CH:40]=[CH:41][C:35]=2[O:34]1.N1C=CN=C1>C1COCC1>[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][C:31]1[CH:40]=[CH:41][C:35]2[O:34][CH2:33][O:37][C:36]=2[CH:38]=1)=[O:29])(=[O:21])=[O:22]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Oc2ccc3c(c2)OCO3)c1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Carbonyldiimidazole (530 mg., 3.26 mmol.) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (Example 17) (1.0 g, 2.72 mmol) in dry THF (10 ml). The mixture was stirred at room temperature for 15 minutes. Sesamol (767 mg., 5.44 mmol) and imidazole (185 mg, 2.72 mmol) were added simultaneously. The resulting mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was evaporated. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered and the filtrate concentrated to give a yellow oil which was recrystalized from EtOAc/Et2O/Hexane. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]-thiophene-3-sulfonamide was obtained as a white powder (494 mg, 37% yield), m.p. 174-176° C.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21]Cl)=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@:7]2([CH2:14][C:15]3=[N:16][CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]3[CH2:21]2)[C:6]1=[O:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CCl)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N1C(=O)[C@]2(Cc3cc(Cl)cnc3C2)c2cccnc21
Temperature: -3.299999952316284 °C
Reaction time: 0.25 h

Procedure:
A solution of 57 (2.39 g, 6.56 mmol) in toluene (50 mL) was cooled to −2.5° C. under nitrogen atmosphere. Compound 61 (17 mg, 0.020 mmol) was charged, and the resulting solution was aged for about 15 min while cooled to −3.3° C. A pre-cooled (−1° C.). aqueous NaOH (26.2 mL, 0.3 N) was charged in over 4 min below −0.6° C. The reaction was aged at −1.3° C. for 3 h. The reaction was quenched with water (10 ml). The organic layer was washed with water (10 mL), concentrated, flushed with IPA to give crude product 58 (2.59 g, 94.4% ee, 83% wt by NMR against 1,3,5-trimethoxybenzene as an internal standard).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:1]([CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]2[CH2:24][CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]2=[O:21])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCNC(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
To tert-butyl 2-benzylpiperazine-1-carboxylate (0.052 g, 0.190 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.181 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol), and the reaction was stirred a room temperature. After stirring overnight, the reaction was concentrated, loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.) and eluted with a gradient of 5% to 100% ethyl acetate/hexanes. To the resulting product was added HCl (2.0 Min diethyl ether, 3.57 μl, 0.117 mmol), and the reaction was stirred at room temperature overnight. The reaction was centrifuged, and the solvent was decanted away from the solid. Diethyl ether (1 mL) was added, and the suspension was sonicated to give a fine suspension. The reaction was centrifuged, the solvent was decanted and the resulting solid dried to give the title compound as the hydrochloride salt. 1H NMR (300 MHz, pyridine-d5) δ ppm 7.05-7.50 (m, 15H), 4.65-4.80 (m, 2H), 4.25-4.55 (m, 2H), 3.95-4.15 (m, 2H), 3.40-3.75 (m, 5H), 2.95-3.27 (m, 2H), 2.75-2.85 (m, 2H); MS (DCI+) m/z 454.2 (M+H)+.
Reaction SMILES: CN(C)CCN.Cl.CN(C)[CH2:10][CH2:11][CH2:12]N=C=NCC.ON1[C:24]2C=CC=[CH:28][C:23]=2N=N1.O.[C:30]([C:33]1[CH:55]=[CH:54][C:36]2[NH:37][C:38](C3C4C5C(=CC=CC=5)C([NH-])C=4C=CC=3)=[N:39][C:35]=2[CH:34]=1)([OH:32])=[O:31]>N1C2N=CC=C(C(O)=O)C=2C=C1.CN(C)C=O>[CH:23]([O:31][CH:11]([CH3:10])[CH3:12])([CH3:28])[CH3:24].[NH:37]1[C:38]2[N:39]=[CH:35][CH:34]=[C:33]([C:30]([OH:32])=[O:31])[C:55]=2[CH:54]=[CH:36]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: [NH-]C1c2ccccc2-c2c(-c3nc4cc(C(=O)O)ccc4[nH]3)cccc21
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(O)c1ccnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 10 ml round-bottomed flask, dissolve 200 mg of [4-(5-carboxy-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-yl]amide of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid, obtained in Example 206, in 2.5 ml of dimethylformamide, then add successively 100 μl of N,N-dimethylethylenediamine, 79 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 28 mg of 1-hydroxybenzotriazole (HOBT), and then stir for 20 hours at room temperature. Bring the dimethylformamide to dryness, add water, and drain the precipitate that formed and then wash with water and then with a 10% saturated solution of sodium hydrogen carbonate and, finally, with water. The crude solid obtained is dried and then purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 then 9/1 by volume). After formation of a paste with diisopropyl ether, in this way we obtain 103 mg of 4-[5-(2-dimethylaminoethyl)aminocarbonyl-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-yl]amide of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid, in the form of an off-white powder with the following characteristics:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:22][C:17]=3[S:16][C:15]2=[N:28]C(=O)C(F)(F)F)(=O)=O)=CC=1.[CH3:36][S-:37].[Na+]>C(O)C>[NH:28]=[C:15]1[N:14]([CH2:13][CH2:12][CH2:11][S:37][CH3:36])[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:22][C:17]=2[S:16]1
Reactant: Cc1ccc(S(=O)(=O)OCCCn2c(=NC(=O)C(F)(F)F)sc3cc(OC(F)(F)F)ccc32)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Yield: 81.5 %

Procedure:
3-(2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)propyl p-toluenesulphonate (3.88 g) and sodium methanethiolate (1.03 g) in absolute ethanol (20 cc) are heated at 60° C. for 6 hours. After cooling to a temperature close to 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The oily residue is taken up in distilled water (50 cc) and the organic phase is extracted with ethyl ether (50 cc). After drying over magnesium sulphate and concentrating to dryness under reduced pressure, 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (1.88 g) is obtained, which is converted to the hydrochloride melting at 181° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16](C(OCC)=O)[N:15]([CH3:24])[C:14]3=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1.CN(C=O)C.C(#N)C.Cl>CO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:14](=[O:25])[N:15]([CH3:24])[NH:16][C:17]3=[O:18])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCOC(=O)n1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Yield: 90 %

Procedure:
Ethyl 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-3,5-dioxo-1,2,4-triazolidine-1-carboxylate (3.2 g, 8.8 mmol) was stirred in a (1/1) mixture of MeOH/1N aqueous NaOH (100 mL) at ambient temperature for 30 minutes. The mixture was acidified with aqueous 1N HCl (150 mL), extracted with ethyl acetate (3×, 100 mL), dried over sodium sulfate, filtered and concentrated to afford 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (2.3 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.44 (s, 3H), 3.05 (s, 3H), 5.17 (s, 2H), 7.94 (s, 1H), 8.13 (s, 1H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[CH2:9][N:8]([C:15]1[C:20]3[N:21]=[C:22]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)[N:23]=[C:24]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:19]=3[N:18]=[CH:17][N:16]=1)[CH2:7]C2>C(OCC)(=O)C.C1CCCCC1>[CH2:9]([N:8]([C:15]1[C:20]2[N:21]=[C:22]([N:31]3[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH2:36]3)[N:23]=[C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:19]=2[N:18]=[CH:17][N:16]=1)[CH3:7])[C:10]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1
Reactant: COc1cc2c(cc1OC)CN(c1ncnc3c(N4CCOCC4)nc(N4CCC(=O)CC4)nc13)CC2
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC(=O)CC3)nc12

Procedure:
8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-oxo-piperidin-1-yl) -4-morpholino-pyrimido[5,4-d]-pyrimidine Rf value: 0.09 (silica gel; ethyl acetate/cyclohexane =2:1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1C1C=CC=C2C=1C=NN2.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:26]=2[C:36]([F:39])([F:38])[F:37])O1.BrC1C=NC=CC=1C>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][C:26]=1[C:36]([F:37])([F:38])[F:39]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2C(F)(F)F)OC1(C)C
Reactant: Cc1ccncc1-c1cccc2[nH]ncc12
Agent: Cc1ccncc1Br
Product: Cc1ccncc1-c1ccc(NS(C)(=O)=O)cc1C(F)(F)F
Yield: 58 %

Procedure:
The compound of Example 240 was prepared by the procedure described for the preparation of Intermediate 1C using Intermediate 52 and 3-bromo-4-methylpyridine. The crude material was purified by reverse phase preparative HPLC using a PHENOMENEX® Luna 30×100 mm column with a linear gradient of Solvent A (10% methanol/90% water with 0.1% TFA) and Solvent B (90% methanol/10% water with 0.1% TFA) over 12 min with peak detection at 254 nM. Collected fractions were applied to a 1 g Waters OASIS® MCX cation exchange cartridge, which was washed with methanol and 2 M ammonia in methanol, to provide the title compound (43 mg, 58%) as a solid: HPLC Ret timed: 1.21 min. MS: m/z=331 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.42 (1 H, d, J=5.0 Hz), 8.24 (1 H, s), 7.70 (1 H, s), 7.60 (1 H, d, J=8.3 Hz), 7.24-7.49 (2 H, m), 3.09 (3 H, s), 2.12 (3 H, s); 19F NMR (CD3OD) δ ppm 60.8.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([C:23]#[C:24][CH:25]4[CH2:28][N:27]([C:29]([O:31]C(C)(C)C)=O)[CH2:26]4)=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].F[C:37](F)(F)[C:38](O)=O.Cl[CH2:44]Cl>>[CH:38]1([C:29]([N:27]2[CH2:26][CH:25]([C:24]#[C:23][C:17]3[CH:16]=[C:15]4[C:20]([C:21](=[O:22])[C:12]([C:9]5[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=5)=[CH:13][O:14]4)=[CH:19][CH:18]=3)[CH2:28]2)=[O:31])[CH2:37][CH2:44]1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(C#Cc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)C1
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CN(C(=O)C5CC5)C4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carboxylate (103 mgs, 0.209 mmol) in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL, 2.08 mmol) was added and stirred at room temperature. After 2 hours the reaction mixture was concentrated and the residue dried under reduced pressure. The crude material was dissolved in dichloromethane (3 mL) and diisopropylethylamine (0.2 mL) and cyclopropanecarbonyl chloride (0.1 mL) were added, and the mixture stirred at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure, and the residue dissolved in tetrahydrofuran (2 mL) and 7N ammonia in methanol (4 mL) was added, and the mixture was stirred for 14 hours. The reaction mixture was then concentrated and chromatographed (SiO2, 5% methanol/ethyl acetate) to provide N-(4-(7-((1-(cyclopropanecarbonyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:10]([CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[O:18])[C:9]2=[O:30])=[CH:4][CH:3]=1.[C:31](=[O:34])([O-])[O-:32].[K+].[K+].[C:37](=O)([O-])O.[Na+]>CN(C=O)C.C(O)C.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>[O:30]=[C:9]1[N:10]([CH2:16][C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C@@H:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([C:31]([O:32][CH3:37])=[O:34])=[N:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])O
Reactant: CC(C)[C@H]1CN(c2ccc(Br)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1ccc(N2C[C@H](C(C)C)N(CC(=O)Nc3cccc(C(F)(F)F)c3)C2=O)cn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-[(5S)-3-(6-bromopyridin-3-yl)-2-oxo-5-(propan-2-yl)imidazolidin-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (100 mg), potassium carbonate (43 mg), and Pd(PPh3)4 (24 mg) in DMF/ethanol (2:1, 2.1 mL) was stirred under atmosphere of carbon monoxide gas at 80° C. for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, the mixture was washed with ethyl acetate, and the organic layer was washed with water and brine. After concentration under reduced pressure, the residue was purified by preparative HPLC to afford methyl 5-[(4S)-2-oxo-3-(2-oxo-2-{[3-(trifluoromethyl)phenyl]amino]ethyl)-4-(propan-2-yl)imidazolidin-1-yl}pyridine-2-carboxylate (50 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cn1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NCc1ccc(OCc2ccccc2)cn1

Procedure:
2-(5-Benzyloxy-pyridin-2-ylmethyl)-isoindol-1,3-dione described in Preparation Example 184 (4.10 g, 11.9 mmol) was dissolved in ethanol (40 mL) and tetrahydrofuran (40 mL). Hydrazine monohydrate (5.77 mL, 119 mmol) was added to this solution at room temperature, and the solution was stirred under reflux for 50 minutes. The reaction solution was partitioned in water and ethyl acetate. This organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (2.8 g, quantitatively) was obtained as a pale yellow solid.