Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1>CS(C)=O>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]3)=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]3)[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a suspension of 7-amino-4-(4-isopropyl-piperazin-1-yl)-2-methyl-2,3-dihydro-isoindol-1-one (1.62 g, 5.6 mmol) and potassium carbonate (2.55 g, 8.7 mmol) in dimethylsulfoxide (30 mL), 2, 4, 5-trichloropyrimidine (970 μL, 8.4 mmol) is added and stirred at 70° C. for 4 hours. To the mixture is added 2,4,5-trichloropyrimidine (650 μL, 5.6 mmol) and the mixture is stirred at 70° C. for 6 hours. The mixture is cooled and then extracted twice with dichloromethane. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography to afford 7-(2,5-dichloro-pyrimidin-4-ylamino)-4-(4-isopropyl-piperazin-1-yl)-2-methyl-2,3-dihydro-isoindol-1-one (1.95 g) as yellow solids in 80% yield. Rf=0.26 (MeOH/AcOEt=1/4). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.13 (s, 3H), 1.14 (s, 3H), 2.87-2.69 (m, 5H), 3.18-3.08 (m, 4H), 3.22 (s, 3H), 4.40 (s, 2H), 7.20 (d, 1H), 8.20 (s, 1H), 8.66 (d, 1H), 11.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CO.C(Cl)Cl>[O:11]=[C:10]1[C:4]2[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc2c(c1)C(=O)CCCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 128A (1.63 g, 9.30 mmol) and K2CO3 (2.57 g, 18.60 mmol) in MeOH (10 ml) under nitrogen atmosphere was cooled to 0° C. The mixture was treated with benzyl chloroformate (1.726 ml, 12.09 mmol), raised to room temperature and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.75-1.90 (m, 4H), 2.67-2.75 (m, 2H), 2.84-2.92 (m, 2H), 4.70 (d, J=5.76 Hz, 2H), 6.72 (s, 1H), 7.16 (d, J=8.14 Hz, 1H), 7.36-7.39 (m, 5H), 7.49 (d, J=2.71 Hz, 1H), 7.70 (d, J=7.12 Hz, 1H). MS (M+NH4)+ m/z 327.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl.C(OCC)(=O)C>[Cl:24][CH2:25][C:26]([NH:18][NH:17][C:15]([C:14]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])=[C:10]([Cl:22])[C:11]2[N:12]([CH:19]=[CH:20][N:21]=2)[CH:13]=1)=[O:16])=[O:27]
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (100 mg, 0.25 mmol) of Step A, Example 35 was suspended in dichloromethane (2 mL) and 4-Me morpholine (0.040 mL, 0.36 mmol) was added. The mixture was cooled to 0° C. and then chloroacetyl chloride (0.029 mL, 0.36 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour under N2. Rinsed reaction mixture into a separatory funnel with a small amount of tetrahydrofuran and methanol and then diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (20:1 dichloromethane/methanol) to yield the desired product (64 mg, 54%) as a yellow solid. MS ESI (+) m/z 474, 476 (M+, Cl, Br pattern) detected.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.62 mL (22.73 mmol) of dimethylsulfoxide in 60 mL dry methylene chloride is cooled to -78° C. and 1.44 mL (16.53 mmol) oxalyl chloride is added dropwise. The mixture is stirred 0.5 hour at -78° C. and a solution of 1.0 g (3.31 mmol) of 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)octane in 15 mL dry methylene chloride is added and the mixture is stirred for 10 minutes at -78° C. The mixture is warmed to -60° C. and maintained for 15 minutes at that temperature. The reaction is quenched by the addition of 6.9 mL triethylamine. The cold bath is removed and the reaction allowed to warm to room temperature. The reaction mixture is extracted with 150 mL methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried, filtered, concentrated and chromatographed using 3:2 ethyl acetate, hexane to yield 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)octane; NMR (CDCl3): delta 2.6 (t,2H), 2.4 (t,4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH:10]1[C:14]2([CH2:16][CH2:15]2)[CH2:13][N:12](CC2C=CC=CC=2)[CH2:11]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH:10]1[C:14]2([CH2:15][CH2:16]2)[CH2:13][NH:12][CH2:11]1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC12CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C1CNCC12CC2

Procedure:
A solution of [1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethyl]carbamic acid tert-butyl ester (Example A4a, 1.47 g) in methanol (30 mL) in a Parr shaker is treated with 10% palladium on carbon (0.5 g) and hydrogen introduced (50 psi) for 24 hours. The reaction mixture is filtered through celite, washed with methanol, and the combined filtrate concentrated in vacuo to afford the title compound. MS CI: m/z 241 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][CH3:36].[I-].[K+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][O:35][CH3:36])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Yield: 19.3 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) in 2 mL of DMF, triethylamine is added (34 uL, 0.244 mmol) followed by 1-bromo-2-methoxyethane (36 uL, 0.256 mmol). A spatula tip of potassium iodide was added and the reaction heated at 60° C. for 48 hours. The reaction was cooled and then partitioned between EtOAc (50 mL) and water (25 mL). The organic layer was washed with water (5×15 mL) to remove DMF. The EtOAc layer was the dried with Na2SO4 and then concentrated to yield an off-white solid. The solid was recrystallized from EtOAc-hexanes to yield 11 mg (19%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.88 (s, 1 H), 7.80 (d 1 H), 7.58 (s, 1 H), 7.35 (m, 5 H), 7.15 (d, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.80 (m, 2H), 3.45 (t, 2H), 3.30-3.05 (m, 6 H), 2.70-2.50 (m, 2 H), 2.25 (m, 1 H), 1.97 (m, 1H); ES-MS m/z 468.2 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[F:18][C:19]1[C:24](F)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].O>CN(C)C=O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2([O:3][C:24]3[C:23]([F:26])=[C:22]([F:27])[C:21]([F:28])=[C:20]([F:29])[C:19]=3[F:18])[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C2(O)CCN(C)CC2)cc1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C2(Oc3c(F)c(F)c(F)c(F)c3F)CCN(C)CC2)cc1
Temperature: 85 °C

Procedure:
To a suspension of sodium hydride (2.2 g, 60% in oil) in 20 ml of dimethylformamide, was added a solution of 11.0 g of 4-hydroxy-4-(4-methylphenyl)-1-methylpiperidine in 50 ml of dimethylformamide. After heating to 85° C. for thirty minutes, the mixture was cooled with an ice-bath, and treated over a period of ten minutes with a solution of 7 ml of hexafluorobenzene in 20 ml of dimethylformamide. After stirring at ambient temperature for twenty hours, the mixture was poured into 200 ml water, stirred for five minutes, then extracted with ethyl acetate (2×). The organic layer was washed with water (2×), followed by a saturated solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichloromethane). The desired fractions were combined, and evaporated to yield 13 g of (4-(4-methylphenyl)-1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(F)c3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(F)c4)c3cnc21

Procedure:
1-Ethyl-5-(3-fluorobenzoyl)-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (2.85 g) was refluxed overnight in 50 ml of pyridine containing 3.0 g of hydroxylamine hydrochloride. The pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product thus obtained was filtered off and recrystallized from methanol to give 2.21 g of analytically pure product, mp 136°-137° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:6]1=2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.ClCCl.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2ccc([N+](=O)[O-])cc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (75 mg, 0.281 mmol) and palladium, 10 wt. % on activated carbon (29.9 mg, 0.028 mmol) in ethanol (5 mL) was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 90 minutes. During this time, the yellow color of the reaction dissipated. To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (160 mg, 0.561 mmol), and the resulting suspension was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and filtered to remove palladium. The organic filtrate was further diluted with water and saturated sodium carbonate (1:1). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 27 (61 mg, 62.8%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.37 (brs, 2H), 6.17 (s, 1H), 6.08 (d, J=7.8 Hz, 1H), 3.63-3.58 (m, 2H), 3.39-3.32 (m, 2H), 3.01-2.96 (m, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.10 (s, 6H); ESI-MS (m/z, %): 347 (MH+, 100), 276 (74); ESI-HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1349; HPLC purity: 95% by area.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37](OC2C=CC([N+]([O-])=O)=CC=2)=[O:38])[CH2:33][C:34]([NH2:36])=[O:35])=[O:30])=[CH:23][CH:22]=1>CN(C)C=O>[NH:31]([C:29]([O:28][CH2:27][C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1)=[O:30])[C@H:32]([C:37]([NH:1][C@H:2]([C:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:38])[CH2:33][C:34](=[O:35])[NH2:36]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.4 g of H-Phe-NHNH-BOC, 1.94 g of Z-Asn-ONP and 3 ml of dimethylformamide are stirred at room temperature until the mixture solidifies. After allowing to stand overnight, the material is triturated with ether, and the dipeptide derivative is filtered off and washed with ether until free of nitrophenol. The product begins to melt at 211°C with decomposition. Rf = 0.55 in chloroform-methanol (8:2) on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29].[Cl-].[NH4+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C
Yield: 39.6 %

Procedure:
To a 50 mL round bottom flask equipped with a stir bar was added 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (0.415 g, 1.03 mmol) and THF (12 mL). The reaction mixture was cooled to −78° C. To the stirred suspension was added vinylmagnesium bromide (5 mL, 1 M in THF, 5 mmol) in one portion. The solution was allowed to gradually warm to −30° C. over 1 h. Additional vinylmagnesium bromide (3 mL, 1 M in THF, 3 mmol) was added and the reaction mixture was further warmed to 0° C. over 1.5 h. The cold reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3×50 mL). The organic fractions were collected, washed with brine (3×25 mL) and concentrated. The resulting solid was further purified by flash chromatography, eluting with EtOAc:Hexane (0-100%) to give 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 40%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.43 (s, 1H), 7.77-7.75 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 6.06-5.98 (m, 1H) 5.42 (app d, 1H, J=5.5 Hz), 5.32 (app d, 1H, J=17.2 Hz), 5.16 (app d, 1H, J=10.2 Hz), 4.26 (s, 3H), 2.27 (s, 3H); ESMS (m/z): found, 429.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.II.[I:16](O)(O)(O)(O)(O)=O.S(=O)(=O)(O)O>O.C(O)(=O)C>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2oc3ccccc3c2c1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 77 %

Procedure:
In a 500-mL three-neck flask, a suspension of 8.4 g (50 mmol) of dibenzofuran, 6.2 g (25 mmol) of iodine, 5.7 g (25 mmol) of orthoperiodic acid, 150 mL of glacial acetic acid, 30 mL of water, and 500 μL of sulfuric acid was heated and stirred at 60° C. for 4.5 hours. After that, the mixture was stirred at room temperature for 16 hours. The generated precipitate was collected by filtration, and the resulting matter was dissolved in 150 mL of toluene and a toluene solution was made. This toluene solution was washed with water three times. After the washing, magnesium sulfate was added to the toluene solution to adsorb moisture. This mixture was filtered and the given filtrate was concentrated. After that, hexane was added, and the mixture was irradiated with ultrasonic waves to perform recrystallization, so that 11.3 g of white powder, which was the objective substance, was obtained in 77% yield. A synthetic scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:16]=[C:17]2[O:18][C:1](=[O:2])[NH:11][C:12]2=[N:13][CH:14]=1
Reactant: Nc1ncc(Cl)cc1O
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 25 °C
Yield: 85 %

Procedure:
Phosgene is introduced at 40°-50° C., after the addition of 20 parts of pyridine, into a solution of 10 parts of 2-amino-3-hydroxy-5-chloropyridine in 200 parts of chloroform, and stirring is maintained for one hour at room temperature; the chloroform and the pyridine are evaporated off in a water-jet vacuum, and ice-water is added to the residue. The precipitate is filtered off and dried at 40°-50° C. in vacuo. There are obtained 10 parts of 6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 184°-186° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14](F)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CCN(C(C)C)C(C)C.C(O)CCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccncc1
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3NCc3ccncc3)C2O)cc1
Temperature: 170 °C

Procedure:
A mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1-hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.11 g, 0.38 mmol, Step B) and 4-(aminomethyl)pyridine (0.070 mL, 0.68 mmol) in 0.70 mL of DIEA and 1.0 ml of BuOH was subjected to microwave heating at 170° C. for 17 min. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (0 to 5% of MeOH in CH2Cl2) to provide the titled compound as an off-white solid. MS (ES+): 389.1 (M+H)+. Calc'd for C23H24N4O2-388.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:34]([Mg]Cl)([CH3:37])([CH3:36])[CH3:35].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2ncc(C(O)C(C)(C)C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (95.0 mg, 0.213 mmol) was dissolved in THF (2.5 mL) and the flask was cooled in an ice water bath. Then, tert-butylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.60 mL, 0.60 mmol) was added via syringe, turning the reaction red. The reaction was stirred under nitrogen while being warmed to room temperature, and after 70 min the reaction was treated with MeOH (1.0 mL) and 5 N HCl (0.50 mL). The flask was fitted with a reflux condenser and put in a preheated oil bath (about 50° C.), and stirring was continued for 1 h. Then, the reaction was cooled to room temperature, diluted with MeOH, concentrated, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)-2,2-dimethylpropan-1-ol (45.9 mg, 97.4% purity, 52% yield). 1H NMR (d6-DMSO, 400 MHz) δ 12.62 (br s, 1H), 9.61 (s, 1H), 8.63 (s, 1H), 8.53 (d, J=2.74 Hz, 1H), 8.21-8.14 (m, 2H), 6.88 (d, J=9.0 Hz, 1H), 4.31 (s, 1H), 3.86 (s, 3H), 2.85 (s, 3H), 0.91 (s, 9H). m/z (ESI, pos. ion) 420 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH2:64])[CH:61]([CH3:63])[CH3:62]>CN(C=O)C>[CH2:60]([NH:64][C:24]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:15]=1[NH:14][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:13])[NH:21][CH:20]=[CH:19]2)=[O:25])[CH:61]([CH3:63])[CH3:62]
Reactant: CC(C)CN
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mol), HATU (38 mg, 0.1 mmol) and DIEA (35 μL, 0.2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, 66%). 1H-NMR (400 MHz, DMSO-d6) δ 12.66 (d, J=7.4 Hz, 1H), 12.42 (s, 1H), 11.21 (s, 1H), 8.81 (d, J=6.6 Hz, 1H), 8.47 (s, 1H), 8.36 (t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.72-7.71 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (m, 1H), 6.48 (m, 1H), 3.10 (t, J=6.2 Hz, 2H), 1.88 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); HPLC ret. time 2.73 min, 10-99% CH3CN, 5 min run; ESI-MS 403.3 m/z (MH+).