Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]#[N:7]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)c(F)c1

Procedure:
A solution of 4-chloro-3-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100° C. overnight. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS (APCI+) m/z 206 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN>>[NH2:3][CH:12]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(COc1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CC(C)(C)OC(=O)NCC(N)COc1ccc(F)cc1

Procedure:
1.97 g of rac-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(4-fluorophenoxy)propyl]-carbamate (4.75 mmol, 1 equivalent) were initially charged in 5 ml of 40% strength aqueous methylamine solution, and the mixture was reacted in a microwave at 100° C. for 2 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane/methanol gradient). This gave 900 mg (67% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][C:20]([CH3:29])([CH3:28])[CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[C:20]([CH3:29])([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1OC)CC(C)(C)NC2
Product: COc1cc2c(cc1OC)CC(C)(C)N(C(=O)c1cc3ncc(Cl)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11]CC)=O.Cl>N1C=CC=CC=1>[F:16][C:6]([F:5])([F:15])[C:7]1[O:14][CH:2]=[CH:3][C:8]=1[CH2:9][OH:11]
Reactant: O=CCCl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: OCc1ccoc1C(F)(F)F
Reaction time: 52 h

Procedure:
210 ml of chloroacetaldehyde were added over 30 minutes at 20° C. to 36.5 ml of ethyl 4,4,4-trifluoroacetoacetate in 600 ml of pyridine and the mixture was stirred for 52 hours. The reaction mixture was poured into 650 ml of concentrated hydrochloric acid and ice, stirred for 5 minutes and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain after chromatography on silica (eluent: 7/3 hexane/ethyl acetate), 43 g of the expected product.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[C:9]([C:11]1[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[O:18])[CH:14]=[CH:15][CH:16]=1)#[N:10].Cl.[NH2:35][OH:36].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>CCO.CC(O)=O>[NH2:10][C:9](=[N:35][OH:36])[C:11]1[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: CCOC(=O)CCc1cccc(CNC(=O)c2cccc(C#N)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCc1cccc(CNC(=O)c2cccc(C(N)=NO)c2)c1
Reaction time: 5 h
Yield: 110.4 %

Procedure:
A solution of the compound of Example 19 (0.491 g, 1.3 mmol), hydroxylamine hydrochloride (0.092 g, 1.3 mmol), and triethylamine (0.18 mL, 1.3 mmol) in absolute EtOH (10 mL) was heated to reflux (86°-90° C.). After 5 hours, TLC [1:1 EtOAc/hexane (10 mL) and 5 drops of AcOH] showed that starting material was still present. Additional hydroxylamine hydrochloride (0.038 g, 0.5 eq) and triethylamine (0.09 mL) was added. After 40 minutes, the TLC showed no difference. The reaction was concentrated in vacuo to give a pale yellow oil (0.53 g). The oil was purified by column chromatography [50 g silica gel, 3% MeOH/CH2 Cl2 (500 mL) followed by 10% MeOH/CH2Cl2 (150 mL)] and the desired product was collected in 85% yield (0.42 g). NMR was consistent with proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[C:30]1([CH2:36][N:37]2[CH2:42][CH2:41][C:40]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH2:39][CH2:38]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1.C(N(CC)CC)C>[C:17]1([S:14]([NH:13][C@@H:7]([CH2:8][CH2:9][C:10](=[O:11])[N:45]2[CH2:46][CH2:47][C:40]3([CH2:39][CH2:38][N:37]([CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:42][CH2:41]3)[CH2:43][CH2:44]2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NS(=O)(=O)c1ccccc1
Reactant: c1ccc(CN2CCC3(CCNCC3)CC2)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](CCC(=O)N1CCC2(CCN(Cc3ccccc3)CC2)CC1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6.82 g (19.86 mmol) of the intermediate from Step B in 20 ml dry THF containing 2.8 ml triethylamine was cooled to −10° C. 2.15 g (19.8 mmol) ethyl chloroformate were added dropwise, and the mixture was stirred for ten minutes, while a precipitate was formed spontaneously. A solution of 4.85 g (19.86 mmol) of the intermediate from Example 20, Step D in a mixture of 24 ml dry THF and 5.3 ml triethylamine was added quickly in small portions. It was warmed to room temperature, stirred over night, poured into water, and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure, and the title compound was obtained by chromatography on silica gel with dichloromethane/ethanol 93:7.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1nc2ccccc2[nH]1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-benzimidazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH:26][C:25]4=[O:33])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=[N:6][CH:5]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[N:9]=[C:8]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH:26][C:25]4=[O:33])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: [N-]=[N+]=Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1

Procedure:
The crude 1,3-dihydro-1-{1-[1-(6-azido-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one was hydrogenated under 1 atm. of hydrogen in 20 mL of ethanol over 0.05 g of 5% palladium on carbon. The catalyst was removed by filtration and the filtrate concentrated to dryness under reduced pressure. Preparative thin layer chromatography using 20% methanol/10% conc. NH4OH/70% chloroform gave 35 mg of 1,3-dihydro-1-{1-[1-(6-amino-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a solid: 1H NMR (400 MHz, CDCl3) 8.12 (s, 1H), 8.02 (s, 1H), 7.85 (br s, 1H), 7.19-7.04 (m, 4H), 4.95 (br s, 1H), 4.62 (br s, 1H), 4.2 (br s, 1H), 3.65 (br s, 1H), 3.6-3.2 (m, 4H), 3.15 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.45-2.25 (m, 2H), 2.1-1.8 (m, 4H). The dihydrochloride salt was precipitated from chloroform/methanol: Analysis calculated for C21H27N7O2.0.45 CHCl3.0.65 NH4Cl: C: 46.25, H: 5.54, N: 18.38 found C: 46.28, H: 5.92, N: 18.48.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[N:5]=[C:4]([O:10][CH2:11][C:12](OC)=[O:13])[C:3]=1[Cl:16].[CH3:17][CH:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[N:5]=[C:4]([O:10][CH2:11][C:12]([O:25][CH:18]([CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:13])[C:3]=1[Cl:16]
Reactant: COC(=O)COc1nc(F)c(Cl)c(N)c1Cl
Reactant: CCCCCCC(C)O
Product: CCCCCCC(C)OC(=O)COc1nc(F)c(Cl)c(N)c1Cl
Temperature: 130 °C

Procedure:
Methyl (4-amino-3,5-dichloro-6-fluoro-2--pyridinyloxy)acetate (1375 g of 98.0 percent assay, 5.02 moles) was combined with 1901 g (14.6 moles of 1-methylheptanol (2-octanol) in a 5 liter flask equipped with a stirrer, a 30 centimeter (cm) Vigreaux column and distillation head, and a thermometer. The solution was heated to about 130° C. at 10 kiloPascals (kPa) pressure to remove any water present in the system. A 1.3 g portion of tetrabutyl titanate catalyst was added and the mixture was heated at about 150° C. under 60 kPa pressure for 6 hours, distilling out the nethanol as it formed. The pressure was slowly reduced to about 3.3 kPa and the excess 1-methylheptanol was removed by distillation along with any other volatiles. The residue, which amounted to 1857 g, was the title compound. It was found to be 97.4 percent pure and to contain 0.2 percent unreacted methyl ester and 0.1 percent 1-methylheptanol. The yield was, accordingly, 98 7 percent of theory.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1

Procedure:
A stirred mixture of 2-fluoro-4-hydroxybenzoic acid (5 g) (G. W. Gray et al. Mol. Cryst. Liq. Cryst. 67, 1981, 1-24), 4-dimethylaminopyridine (0.010 g) and triethylamine (11 mL) in DCM (100 mL) was treated with acetic anhydride (6.35 mL). After 2 h the solution was evaporated and the residue redissolved in EtOAc, washed with 5% citric acid, water (3×), dried (Na2SO4) and evaporated to give the title compound as a white solid (4.92 g); APCI m/z 199.1 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[CH:8]2.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[CH:8]2
Reactant: OCc1cccc2cccc(O)c12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2cccc(O)c12

Procedure:
Prepared from the known (J. Chem. Soc., C, (1966) 523) 8-hydroxymethyl-1-naphthol by hydrogenolysis using 0.1 equiv. of 20% palladium hydroxide on carbon (Pearlmann's catalyst) in ethanol at 45 psi hydrogen for 4 hours in quantitative yield, M.P. 56°-59° C.
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:33])[C:8]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(O)C>[CH2:27]([O:26][C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][C:8]=1[C:7]([OH:33])=[O:6])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1cc(C(=O)OCC)c(OCCCCCC)cc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1cc(C(=O)O)c(OCCCCCC)cc1C(=O)O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 8.91 g (135 mmol) 85% aqueous KOH solution and 20 ml water is added to 16.3 g (38.57 mmol) 2,5-dihexoxyterephthalic acid diethyl ester in 20 ml ethanol and the whole is stirred for 2 hours at 90° C. The crude product precipitated by the dropwise addition of 12.5 ml conc. HCl with ice-cooling is filtered off, washed neutral with water and recrystallized from ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([NH2:24])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([NH:24][C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[N:15]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: Clc1cc(CN2CCCC2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(Nc3cc(CN4CCCC4)ccn3)ncc2c1
Temperature: 100 °C

Procedure:
2-Chloro-4-pyrrolidin-1-ylmethyl-pyridine (1 eq), isoquinoline-3-ylamine (1 eq), 2.0 eq. of caesium carbonate, 10% (mol) Xantphos and 10% (mol) of Pd2(dba)3 were mixed in toluene (3 ml). The reaction mixture was degassed for three times and then warmed to 100° C. overnight. The reaction mixture was cooled, concentrated and purified by column chromatography eluting 0-10% sat. NH3/MeOH and DCM to afford the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([Cl:16])=[O:15].N1C=CC=CC=1>O1CCCC1>[Cl:16][S:14]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[O:15]
Reactant: CC(C)OC(=O)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N(c1ccccc1)S(=O)Cl
Yield: 61.1 %

Procedure:
Eighteen grams isopropyl phenylcarbamate (~0.1 mol) and 14.0 g thionyl chloride (0.12 mol) were dissolved in 50 ml dry tetrahydrofuran and protected from moisture by a calcium chloride tube. Eight grams pyridine (0.1 mol) were added dropwise while the mixture was stirring at a water bath temperature (15°-20° C.). After the addition of pyridine was completed, the mixture was stirred for 12 hours at room temperature. Pyridine hydrochloride was filtered and the solvent was removed under vacuum. The concentrated residue was diluted with hexane and filtered. The hexane was removed under vacuum and the residue was distilled, giving 16.0 g of product distilling at 113-115/0.08 mm. NMR spectrum of the product in chloroform-d-TMS gave the following absorptions: δ7.6-7.2 (m, 5H, phenyl protons), δ5.5-4.9 (m, 1H, CH) and δ1.4-1.3 (d, 6H, C(CH3)2).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:37][CH2:38][CH2:39][CH3:40])=[C:16]([C:18]3[NH:19][C:20](=[O:36])[C:21]4[N:22]([C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=5)[CH:23]=[N:24][C:25]=4[N:26]=3)[CH:17]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]>C(O)(=O)C.O.[Fe]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:22]2[C:21]3[C:20](=[O:36])[NH:19][C:18]([C:16]4[CH:17]=[C:12]([S:9]([N:6]5[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]5)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=4[O:37][CH2:38][CH2:39][CH3:40])=[N:26][C:25]=3[N:24]=[CH:23]2)=[CH:28][CH:29]=1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2ncn(-c3ccc([N+](=O)[O-])cc3)c2c(=O)[nH]1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2ncn(-c3ccc(N)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
Iron powder (137 mg, 2.45 mmol) was added to a solution of 2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-(4-nitrophenyl)purin-6-one (Example 11; 110 mg, 0.19 mmol) in acetic acid (2.2 mL) and water (100 μL), and the reaction stirred vigorously at room temperature for 3 hours. The mixture was filtered through Celite®, washing well with ethyl acetate, and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, the layers separated, and the organic phase dried (MgSO4) and evaporated under reduced pressure to give the title compound (80 mg, 79%).
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[NH:15][C:16]([CH:18]1[C:26]([CH3:28])([CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[C:29](=[O:52])[C@@H:30]([NH:34]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH:31]([CH3:33])[CH3:32])=[O:17]>C(Cl)Cl>[NH2:34][CH:30]([CH:31]([CH3:33])[CH3:32])[C:29]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]([CH3:28])([CH3:27])[C@H:18]1[C:16]([NH:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])=[O:17])=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)C(N)C(=O)N1c2ccccc2C(C)(C)[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
Piperidine (0.1 mL, 1.01 mmol, Eq: 9.86) was added to a solution of (S)-(9H-fluoren-9-yl)methyl 1-(2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (71 mg, 102 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give (S)-1-(2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (32 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[CH3:21][N:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[C:24]([CH3:37])[C:23]1=[O:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.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]>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:26]2[CH:25]=[C:24]([CH3:37])[C:23](=[O:38])[N:22]([CH3:21])[CH:27]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Temperature: 70 °C
Yield: 35.6 %

Procedure:
A mixture of the title compound from step 3 (100 mg, 0.31 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (93 mg, 0.37 mmol), Pd(dppf)Cl2 (23 mg, 0.31 mmol) and K3PO4 (199 mg, 0.94 mmol) in dioxane/water (3 mL/0.5 mL) was N2 purged and heated at 70° C. for 12 h. Concentration under vacuum and silica gel chromatography (PE:EA=3:10:1) followed by prep-HPLC gave the title compound (45 mg, 35.4%). 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.25-7.24 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 3.68 (s, 3H), 3.38 (s, 3H), 2.25 (s, 3H). LCMS: 407.9 (M+1)+
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:52]([O:55][CH2:56][C:57]1[C:58]([N:72]2[CH2:83][CH2:82][N:81]3[C:74](=[CH:75][C:76]4[CH2:77][C:78]([CH3:85])([CH3:84])[CH2:79][C:80]=43)[C:73]2=[O:86])=[N:59][CH:60]=[CH:61][C:62]=1[C:63]1[CH:68]=[C:67](Br)[C:66](=[O:70])[N:65]([CH3:71])[CH:64]=1)(=[O:54])[CH3:53].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:52]([O:55][CH2:56][C:57]1[C:58]([N:72]2[CH2:83][CH2:82][N:81]3[C:74](=[CH:75][C:76]4[CH2:77][C:78]([CH3:85])([CH3:84])[CH2:79][C:80]=43)[C:73]2=[O:86])=[N:59][CH:60]=[CH:61][C:62]=1[C:63]1[CH:68]=[C:67]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:8][N:7]=2)[C:66](=[O:70])[N:65]([CH3:71])[CH:64]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Nc1cc(C2CC2)on1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)on3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 31.7 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-cyclopropylisoxazol-3-amine (80 mg, 0.65 mmol), XantPhos (29 mg, 0.050 mmol), Pd2dba3 (45 mg, 0.050 mmol), [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricy-clo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (350 mg, 0.65 mmol), Cs2CO3 (390 mg, 1.2 mmol), and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting mixture for 10 minutes, it was heated at reflux for 2 h. The mixture was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 311a (120 mg, 32%) as a brown solid. MS-ESI: [M+H]+ 583.2.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([Br:58])[CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[C:53]([Br:58])[CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Yield: 80 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a pale yellow solid (26 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J=2 Hz, 1H), 8.02 (dd, J=2 and 9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 7.45-7.31 (m, 7H), 7.17-7.12 (m, 2H), 2.44-2.34 (m, 2H), 2.17-2.07 (m, 2H), 2.05-1.95 (m, 1H), 1.71-1.61 (m, 1H). LCMS (Method F): RT=9.86 min, [M+H]+=446/448.