Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[OH:18].CCN(CC)CC.[B:26]([O-])([O-])[O-]>O1CCOCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([B:26]2[O:8][C:5]([CH3:7])([CH3:6])[C:2]([CH3:4])([CH3:3])[O:1]2)=[CH:13][C:12]=1[OH:18]
Reactant: COc1ccc(Br)cc1O
Reactant: CC(C)(O)C(C)(C)O
Reactant: [O-]B([O-])[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pinacol (11.29 g; 0.0955 mol) in dry dioxane (40 ml) was added dropwise, over an hour, to a solution of borane-methyl sulphide complex (9.0 ml; 10M; 0.090 mol) in dioxane (40 ml) and stirred at RT under N2. To his solution was added HB(pin) (22.0 ml; 0.152 mol) and 2-methoxy-5-bromophenol (19.63 g; 0.0967 mol) in dioxane (30 ml). This solution was allowed to stir overnight at room temperature before being added, dropwise, to the activated catalyst [PdCl2(dppf)CH2Cl2 (2.38 g; 2.91 mmol) and NEt3 (40.0 ml; 0.287 mol) in dry dioxane (450 ml) heated at 80° C. and allowed to cool to RT]. The reaction mixture was heated at 100° C. GC analysis after 18 hours showed the desired borate compound at 12.0 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](SC)[N:3]=1.[Mn]([O-])(=O)(=O)=O.[K+].[S:16](=[O:18])=[O:17].[C:19](O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1
Reactant: CC(=O)O
Reactant: O=S=O
Reactant: CSc1nccc(Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-chloro-2-methylthiopyrimidine (10.00 g, 62.3 mmol) in glacial acetic acid (50 ml) at 10°-15° C. was added a solution of potassium permanganate (12.50 g, 79.15 mmol) in water (100 ml). The reaction mixture was stirred overnight at room temperature, cooled to 5° C. and then treated with gaseous sulphur dioxide until the dark solution was decolourised. Water was added and the mixture extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and then water, and dried. Evaporation gave 4-chloro-2-methanesulphonylpyrimidine as a white solid (10.84 g), mp 91°-3° C. 4-Chloro-2-methanesulphonylpyrimidine (7.00 g, 36.33 mmol) was treated with sodium phenoxide [from phenol (3.41 g, 36.33 mmol) and sodium hydride (1.74 g, 39.97 mmol, 50% dispersion in oil)] in dry DMF (100 ml) at 0°-5° C. After 30 minutes, the starting material had been consumed (GC analysis). The reaction mixture was diluted with water and then extracted with ether (×2). The combined extracts were washed with 5% aqueous sodium hydroxide solution (×2) and brine, and then dried. Evaporation of the solvent gave a very pale yellow, mobile oil (5.35 g). Chromatography (eluent ether:n-hexane, 2:3) followed by crystallisation afforded 4-chloro-2-phenoxypyrimidine as a white solid (3.50 g, 84% pure by GC). Further chromatography yielded pure product (2.50 g, 33%), mp 59°-60° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl.CO.N>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:39](=[O:40])[NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is added to a solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5 ml of toluene, and the reaction mixture is stirred at 1000 for 2 hours. The white suspension is cooled and filtered. The tide compound is obtained as white crystals of melting point 245° (decomposition). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.76, FD-MS: M+ =546.
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.C(O)(=O)C.[Br:18]Br>O>[Br:18][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: c1ccc2c(c1)oc1ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2oc3ccccc3c2c1
Reaction time: 20 h
Yield: 30.3 %

Procedure:
150 grams (892 mmol) of dibenzofuran and 1 L of acetic acid were loaded into a flask. The air in the flask was replaced with nitrogen, and then the contents were dissolved under heat. 188 grams (1.18 mol) of bromine were dropped to the solution while the flask was sometimes cooled with water. After that, the mixture was stirred for 20 hours under air cooling. The precipitated crystal was separated by filtration, and was then sequentially washed with acetic acid and water. The washed crystal was dried under reduced pressure. The resultant crystal was purified by distillation under reduced pressure, and was then repeatedly recrystallized with methanol several times. Thus, 66.8 g of 2-bromodibenzofuran were obtained (in 31% yield). The resultant was identified as Intermediate 2-3 by FD-MS analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.O.[Mn]([O-])(=O)(=O)=[O:27].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:27])=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2cc(C=O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(-n2cc(C(=O)O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(3-methoxyphenyl)-3-(2-nitrophenyl)-1H-pyrazole-4-carbaldehyde (1.00 g), water (2 ml) and pyridine (2 ml) was added portionwise potassium permanganate (538 mg). After stirring for 1 hour, the precipitated manganese oxide was filtered off through Celite, the Celite layer was washed with 1N aqueous sodium hydroxide solution. The filtrate and washings were combined, washed with ethyl acetate. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was solidified by adding hexane. The solid was collected by filtration and washed with hexane to obtain the target compound (676 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5](F)=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[N:8][C:6]=2[CH:7]=1
Reactant: Oc1ccccc1C=Nc1cc(Br)c(F)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc2c(cc1Br)N=Cc1ccccc1O2
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 115.6 %

Procedure:
To a solution of 2-[[(5-bromo-2,4-difluorophenyl)imino]methyl]phenol (14.5 g, 46.5 mmol) in DMSO (0.43 L), K2CO3 (12.8 g, 71.8 mmol) and 18-Crown-6 (145 mg, 0.55 mmol) were added. The resulting mixture was stirred at 140° C. for 2.5 h and then allowed to cool to ambient temperature. Water (0.6 L) was added and the product was collected by filtration, washed with water and dried under reduced pressure to yield the title compound (15.7 g, 100%) which was used without further purification. 1H-NMR (400 MHz, CDCl3) 6.93-6.96 (d, J=8.2, 1H), 7.10-7.14 (d, J=8.2, 1H), 7.23-7.28 (m, 1H), 7.34-7.37 (m, 1H), 7.46-7.51 (m, 1H), 7.55-7.57 (d, J=7.8, 1H), 8.47 (s, 1H). (m/z)=292+294 (M+H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1.[O:19]1[C:23]([NH2:24])=[CH:22][CH:21]=[N:20]1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:14]#[N:15])=[C:16]([CH3:17])[NH:24][C:23]4[O:19][N:20]=[CH:21][C:22]3=4)[CH:10]=2)[NH:5][N:4]=1
Reactant: COc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Reactant: Nc1ccno1
Product: COc1n[nH]c2ccc(C3C(C#N)=C(C)Nc4oncc43)cc12

Procedure:
43 mg (0.178 mmol) (2E)-2-[(3-methoxy-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 8A) were treated with 1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 3 mg (5% of th.) of the racemic title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C@@H:12]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH3:22]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:20]([O:18][CH2:17][C@@H:14]1[CH2:15][CH2:16][C@H:12]([C:10]2[O:9][N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:11]=2)[CH2:13]1)[CH2:21][CH3:22]
Reactant: OC[C@H]1CC[C@@H](c2nc(-c3ccncc3)no2)C1
Reactant: CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CCCOC[C@@H]1CC[C@H](c2nc(-c3ccncc3)no2)C1

Procedure:
cis-[3-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclopentyl]methanol (Preparation 5) was reacted with 1-bromopropane in the presence of tetrabutylammonium iodide, using a similar procedure to that described in Example 106, to afford the title compound: RT=3.69 min, m/z (ES+)=288.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.[CH3:20][O-:21].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:21][CH3:20])[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(Cl)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 18 using 2,4,6-trichloro-5-nitropyrimidine (Intermediate 37), 5-methyl-1H-pyrazol-3-amine and sodium methoxide as the starting materials. LCMS: 285 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([Cl:23])=[O:22]>O1CCOCC1>[ClH:23].[F:29][C:18]([F:17])([F:30])[C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3C(F)(F)F)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.19 g, 0.87 mmol), 2-trifluoromethyl-4-fluoro-benzoyl chloride (0.395 g, 1.74 mmol), and 1,4-Dioxane (50 mL). Stir and heat the mixture at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia/methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.241 g, 68%). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.031 g, 0.59 mmol). Concentrate and dry under vacuum to obtain the title compound. HRMS Obs. m/z 410.1490, Calc. 410.1491; m.p. 145-150° C.
Reaction SMILES: [I-].[CH:2]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:16]1COCC1>>[CH:2]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: C1CCOC1
Agent: [I-]
Product: C=C(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspension of methylbiphenylphosphonium iodide in dry THF cooled at 0° C. was added NaNH2. After stirring for 15 h at ambient temperature, cyclohexylphenyl ketone Was added. The reaction mixture was stirred for 8 h at ambient temperature and then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed (brine), dried (Na2SO4) and concentrated. Silica gel column chromatography of the crude product using petroleum ether:EtOAc (49:1) as eluent gave α-cyclohexylstyrene as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[CH:4]=1.C(O[BH-](O[C:35](=[O:37])[CH3:36])OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+].O1[CH2:52][CH2:51][CH2:50][CH2:49]1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:49][CH:50]3[CH2:36][CH2:35][O:37][CH2:52][CH2:51]3)[CH2:11][CH2:10]2)=[C:5]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(CC3CCOCC3)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg, 0.030 mmol) produced in Example (85c) in tetrahydrofuran (1 mL) were added tetrahydropyranyl-4-carbaldehyde (5.2 mg, 0.045 mmol), sodium triacetoxyborohydride (13 mg, 0.061 mmol) and acetic acid (1.8 mg, 0.030 mmol) in that order, followed by stirring for 60 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl] -4-(tetrahydropyran-4-ylmethyl)piperazine.
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:18]([CH2:21][O:22]CC(OC)OC)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])[CH3:10])[CH2:2][CH3:3].[CH3:32]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(O)C>[CH3:32][O:16][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=1[CH2:11][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:29][CH2:30][CH3:31])[CH2:1][CH2:2][CH3:3])[CH3:10]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(COCC(OC)OC)cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CO)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
The compound (263.3 mg) obtained in Example 102-3 was dissolved in ethanol (6 ml). The reaction solution was added with WSCI hydrochloride (147.5 mg) and HOBt (104.9 mg) and the whole was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in 2-methyl-2-propanol (6 ml). The reaction solution was added with pyridinium p-toluenesulfonate (35.2 mg) and the whole was refluxed under heating for 2 days. After that, the solution was added with 1 mol/l hydrochloric acid (4 ml) and stirred at 90° C. for 30 minutes. After having been cooled to room temperature, the reaction solution was subjected to extraction with chloroform. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to thereby adjust to pH 13, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (hexane/ethyl acetate) thereby obtaining the subject compound (83.5 mg) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:34][C:35](Cl)=[O:36].[NH4+:38].[OH-]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:35](=[O:36])[CH2:34][NH2:38])=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Reactant: O=C(Cl)CBr
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A −40° C. solution of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (70 mg, 0.16 mmol) in THF (20 mL) was treated with a solution of bromoacetyl chloride (25 mg, 0.16 mmol) in THF (1 mL). After 5 min a 27% aqueous NH4OH solution was added and the reaction mixture was stirred at rt overnight. The resulting slurry was filtered and the solid washed with Et2O to obtain 2-fluoro-6-[(2-{[1-glycyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a grey solid (67 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.07-3.19 (m, 2H), 3.44, (s, 2H), 3.78 (s, 3H), 3.97-4.10 (m, 2H), 6.23, (s, 1H), 6.82-7.04 (m, 3H), 7.27-7.41 (m, 1H), 7.60 (s, 1H), 8.02 (s, 1H), 8.10 (s, 1H), 8.51 (d, J=7.61 Hz, 1H), 8.67 (s, 1H), 10.53 (s, 1H), 11.33 (s, 1H) a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=491.26.
Reaction SMILES: C(O)(=O)C.[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][C:9](=[O:14])[CH2:8][C:7]1([CH3:16])[CH3:15].C(#N)C.OO.[CH2:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH:22]1([O:5][N:6]2[C:11]([CH3:12])([CH3:13])[CH2:10][C:9](=[O:14])[CH2:8][C:7]2([CH3:16])[CH3:15])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: OO
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Temperature: 50 °C
Yield: 66 %

Procedure:
A solution of 0.369 g (1.86 mmol) of ferrous chloride tetrahydrate and 0.327 g (5.45 mmol) of glacial acetic acid in 6 ml of water is added to a mixture of 10.97 g (64.4 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 100 ml of acetonitrile, and 65 ml of cyclohexane that is heated to 50° C. A solution of 18.21 g (268 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture dropwise over 5.25 hours as the reaction temperature is brought to and maintained at 60-62° C. A total of 0.227 g of ferrous chloride tetrahydrate, 0.267 g of glacial acid, and 5 ml of water is added to the reaction mixture in 3 portions during the peroxide addition. Work up according to the procedure of Example 44 affords 10.83 g (66% yield) of the title compound, a white solid, mp 32-36. GC assay is 98.5%.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH2:7][C@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[OH:1][CH:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH2:7][C@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: O=C1OCC[C@@H]1Cc1ccccc1OCC1CO1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CO
Product: O=C1OCC[C@@H]1Cc1ccccc1OCC(O)CN1CCC(c2ccc3ccccc3c2)CC1
Yield: 46.8 %

Procedure:
(2S)-α-(2′-(2,3-Epoxypropan-1-yloxy)benzyl)-γ-butyrolactone (1.5 g) and 4-(naphthalen-2-yl)piperidine (1.5 g) were dissolved in methanol (50 ml) and the reaction mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the obtained oil was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([O:29][CH3:30])=[CH:24][N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=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.[Cu]I>[Cl:21][C:22]1[N:27]=[C:26]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:25]([O:29][CH3:30])=[CH:24][N:23]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1OC
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.35 g, 2.0 mmol) in DMF (3 mL) and Et3N (0.70 mL, 5.0 mmol) was added to a mixture of 2,4-dichloro-5-methoxypyrimidine (0.30 g, 1.7 mmol), PdCl2(PPh3)2 (0.12 g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) and PPh3 (0.044 g, 0.17 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (50 mL). The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-25% EtOAc in hexanes) to give the title compound A98 as a pale yellow solid (0.38 g, 72%); 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (dd, J=7.6, 1.0 Hz, 1H), 7.46-7.29 (m, 3H), 4.03 (s, 3H), 3.99 (s, 2H), 3.71 (s, 3H). LCMS-A: rt 5.92 min; m/z 317.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=[O:13].S(=O)(=O)(O)O.[Br:20]Br>>[Br:20][C:6]1[C:7]2[C:12]3[C:3]([C:2](=[O:13])[C:1](=[O:14])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: O=C1C(=O)c2ccc(Br)c3cccc1c23

Procedure:
In the second route, the raw material acenaphthenequinone and the solvent concentrated sulfuric acid are added into liquid bromine and refluxed for 2 hours to obtain 5-bromoacenaphthylene-1,2-dione. The resulting bromoacenaphthene reacts with alcohol, thioalcohol, phenol, thiophenol, ester or amide to obtain the corresponding substituted acenaphthenequinone iv, as follows: