Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.CCO>[OH:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C=Cc2ncccc2OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(CCc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
Methyl 4-[2-(3-benzyloxy-2-pyridyl)ethenyl]benzoate (2.0 g, 5.8 nnol) was partially dissolved in EtOAc (20 ml) and EtOH (10 ml). The reaction vessel was flushed with argon, palladium-on-carbon (0.2 g, 10%) was added and the reaction was flushed with argon followed by hydrogen. The reaction was stirred at ambient temperature for 18 hours, filtered and evaporated to give methyl 4-[2-(3-hydroxy-2-pyridyl)ethyl]benzoate as a pale orange solid (1.3 g, 90%) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]#[N:12])=[N:7][C:8]=1[CH2:9]Br.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1=[N:7][C:6]([C:11]#[N:12])=[CH:5][CH:4]=[C:3]1[CH2:2]2
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: N#Cc1ccc(CBr)c(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(C#N)nc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 5,6-bis(bromomethyl)pyridine-2-carbonitrile from Step C (1.80 g, 6.21 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.64 g, 6.21 mmol, described in Intermediate 2) in DMF (207 mL) was added cesium carbonate (6.07 g, 18.6 mmol), portionwise, over 5 min. After 18 h, the mixture was partitioned between CH2Cl2 (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (200 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 10:90, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+].Cl.[C:38]([NH:46][C@H:47]1[CH2:51][NH:50][C@H:49]([C:52]([O:54][CH3:55])=[O:53])[CH2:48]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH3:55][O:54][C:52]([C@@H:49]1[CH2:48][C@@H:47]([NH:46][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:51][N:50]1[C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:53]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of BOC-Gly-OH (28.13 g, 0.1606 mol) and 1-hydroxybenzotriazole (0.1686 mol, 25.64 g; contains 11.12 wt % H2O) in THF (1.3 L) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1686 mol, 32.328 g) (Flask A). The mixture was stirred at ambient temperature for 4 h, then the stirring was stopped and the oily residue was allowed to settle. In a separate flask (Flask B), NaOH (0.1606 mol; 32 mL of 5N solution) was added to a suspension of (2S,4R)-methyl 4-benzamidopyrrolidine-2-carboxylate hydrochloride (0.1606 mol, 45.73 g) in THF (0.52 L) over 15 min. The mixture was stirred at ambient temperature for 10 min, during which time the solids mostly dissolved. The solution of HOBt ester prepared in Flask A was added to Flask B at ambient temperature over 15 min, leaving the oily residue behind. The residue in Flask A was washed with 250 mL of THF, and the THF solution was decanted from the heavy oil and added to the mixture in Flask B. The reaction mixture was stirred at ambient temperature for 40 min. Water (500 mL) was added, and the mixture was concentrated under vacuum to remove THF (˜550 mL residual volume). EtOAc (500 mL) was added, followed by brine (300 mL). The phases were separated and the aqueous phase was extracted with 2×300 mL of EtOAc. The combined organic fraction was washed with 2×250 mL of 1N HCl, 2×250 mL of sat. NaHCO3 solution, and 150 mL of brine, then dried over MgSO4, and concentrated to afford 48.31 g of (2S,4R)methyl-4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylate as a foamy solid (74% yield).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])#[C:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:7]2[C:6]([CH:1]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under an argon atmosphere. 2.7 g (10 mmol) 2-pent-1-ynyl-phenylamine were added to 2.3 g (20 mmol) potassium tert.butoxide in 50 mL of N-methyl-2-pyrrolidinone and the mixture was stirred overnight at RT. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic phase was dried and evaporated down. The residue was purified on silica gel.
Reaction SMILES: CN1C(=O)CCC1.Cl[C:9]1[CH:14]=[N:13][C:12]([Cl:15])=[CH:11][N:10]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:15][C:12]1[CH:11]=[N:10][C:9]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To an NMP (7.5 ml) solution of 1.51 g of 2,5-dichloropyrazine were added 2.00 g of 1-(t-butoxycarbonyl)piperazine and 2.00 g of potassium carbonate, followed by 1 hour of stirring under heating at 100° C. The mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2.73 g of 2-chloro-5-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine. Using this compound, 2-chloro-5-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazine was obtained in a similar manner to Example 14 as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.CC(C)([O-])C.[K+].[N:19](OC(C)(C)C)=[O:20]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[N:19][OH:20])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cn1)CCCC2
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cn1)CCCC2=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A solution of 3-methoxy-5,6,7,8-tetrahydroisoquinoline (1.40 g, 8.59 mmol) in THF (20 ml) was added to a solution of potassium tert-butoxide (1.92 g, 17.18 mmol) in THF (25 ml) and the resulting mixture was stirred at room temperature for 18 h, then cooled to 0° and tert-butyl nitrite (3.05 ml, 2.65 g, 27.77 mmol) added dropwise. After stirring for 18 h at room temperature brine was added and the mixture extracted three times with ethyl acetate. The combined organic phase was dried (MgSO4) and concentrated to afford the title compound (1.50 g) as a flesh coloured solid m.p. 175-178° MS (ES+) 193 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]Br)[CH:13]=2)[N:8](C(=O)C)[C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2].[CH3:25][NH:26][CH3:27]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:26]([CH3:27])[CH3:25])[CH:13]=2)[NH:8][C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Reactant: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of (1-acetyl-5-bromomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (378 mg, 0.93 mmol) in THF (16.0 mL) is added a 33% solution of dimethylamine in ethanol (8.0 mL). The resulting reaction mixture is stirred for 15 h at room temperature, followed by removal of the volatiles in vacuo. The residue is purified by flash column chromatography (silica gel, CH2Cl2/MeOH 9:1) to afford the title compound as a yellow solid (303 mg, 0.92 mmol, 99%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.31 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 2.64 (s, 6H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 329 (M(C16H19F3N2O2)+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][NH:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][N:10]=[C:11]([Cl:21])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(Cl)=NNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 20 °C
Yield: 63.6 %

Procedure:
A suspension of 1-(4,5-dichloro-2-nitrophenyl)-2-trimethylacetyl-hydrazine (739 g.) and phosphorus pentachloride (517 g.) in carbon tetrachloride (4.8 liters) is heated until the evolution of gas ceases, the reaction mixture being taken progressively to the reflux temperature. To the solution obtained there is added, after cooling to 20°C., a solution of phenol in carbon tetrachloride (3.36 liters) containing 2.36 moles of phenol per liter. The reaction mixture is then heated at the reflux temperature until the evolution of gas finishes. It is then cooled to 20°C., filtered and the resulting solution is concentrated under reduced pressure (20 mm. Hg.) at 60°C. The residue is purified by chromatography on "Kieselgel", elution being effected with a mixture of heptane and diethyl ether (9.5 - 0.5 by volume). After recrystallisation from isopropanol and then heptane, there is obtained 1-(4,5-dichloro-2-nitrophenyl-hydrazono)-1-chloro-2,2-dimethylpropane (498 g.) melting at 99° - 100°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C.Cl>CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][NH2:11]
Reactant: COC[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC[C@@H]1CCCN1CCN

Procedure:
A solution of (S)-tert-butyl 2-(2-(methoxymethyl)pyrrolidin-1-yl)ethylcarbamate (step 1) (1.89 g, 7.32 mmol) and in MeOH (5 ml) and treated with 2M HCl in MeOH (10 equivalents) at room temperature over the weekend. The solvent was removed in vacuo to afford the title compound;
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][C@H:10]([N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH3:25])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:34])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)CO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxy-4,4-dimethylpentan-2-yl(methyl)carbamate (1.23 g, 3.27 mmol) in THF (20 mL) were added pyridine (0.79 mL) and acetyl chloride (0.386 g, 4.91 mmol). The reaction mixture was stirred at RT overnight and filtered. The filtrate was concentrated to give (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentyl acetate (1.36 g, crude), which was used without further purification. LRMS (M-Boc+H+) m/z 318.2
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C=O)C>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([O:16][CH2:27][C:28]#[N:29])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCCl
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2

Procedure:
A stirred mixture of 2-cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone (2.9 g., 0.1 mole), potassium carbonate (15.2 g., 0.11 mole) and chloroacetonitrile (7.5 g., 0.10 mole) in DMF (100 ml.) is heated at 55°-60° C. for two hours and poured into water. The 2-cyclopentyl-6-cyanomethoxy-7,8-dichloro-1-tetralone that separates is collected and dried.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[OH-].[NH4+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:1][C:11]1[C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[N:9][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Reactant: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=NCC(F)(F)F)Nc1nn(CCCCO)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution (2.75 ml.) of bromine (80 mg.) in chloroform was added to a solution of 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (140 mg.) in HOAc (2 ml.). After stirring at room temperature for 1 hour the mixture was basified with 6 N aqueous ammonium hydroxide and then extracted with EtOAc (6×10 ml.). The combined extracts were dried (MgSO4) and evaporated to dryness in vacuo to give 4-bromo-1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (145 mg., 82%) having the following n.m.r. spectrum in d6DMSO: 7.7 (s, 1H); 4.2 (br t, 2H); 3.9 (t, 2H); 3.3 (t, 2H); 1.5 (br m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]C)[N:10]=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[N:10]=[C:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C=C1N=C(C)N(Cc2ccccc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=NC(=Cc2ccccc2O)C(=O)N1Cc1ccccc1
Temperature: -40 °C
Yield: 86.6 %

Procedure:
3-Benzyl-3,5-dihydro-5-(2′-methoxybenzylidene)-2-methylimidazol-4-one (1.38 g) was dissolved in dichloromethane (20 ml) and boron tribromide (1.3 ml) was added dropwise while stirring the mixture at −40° C. Thereafter, the mixture was stirred under ice-cooling for 1 hr, poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-benzyl-3,5-dihydro-5-(2′-hydroxybenzylidene)-2-methylimidazol-4-one (1.14 g) as red crystals. The crystals and (S)-glycidyl nosylate (1 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.1 g) was added. The mixture was heated at 50° C. for 2 hr, poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (1.05 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (10 ml) and refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.25 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:17])=[CH:8][C:9]=2[NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[N:4]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:3]=1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:17])=[CH:8][C:9]=2[NH:11][CH:12]([CH2:13][O:14][CH3:29])[CH2:15][CH3:16])[N:4]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:3]=1
Reactant: CI
Reactant: CCC(CO)Nc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(COC)Nc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Reaction time: 0.05 h

Procedure:
A solution of 2-[3,6dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-butan-1-ol (69 mg, 0.196 mmol) in 1 ml of dry tetrahydrofuran was treated with 60% sodium hydride oil (28 mg, 0.7 mmol). After stirring for 3 minutes, methyliodide (0.3 ml) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was quenched with water and extracted with ether. The organic layer was washed with water, dried and concentrated to give 61 mg of crude material. The residue was purified through silica gel column chromatography using chloroform as eluent to give 43 mg of the title compound in yellow glass form. 1H NMR (CDCl3): 6.91 (s, 2H), 6.00 (s, 1H), 5.05 (d, 1H), 3.4-3.6 (m, 2h), 3.41 (s, 3H), 2.66 (s, 3H), 2.28 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.6-1.8 (m, 2H), 1.05 (t, 3H), ppm; IR (CHCl3) 2920, 1586 cm−1; High MS calc. 366.2413, found 3.66.24516. The glass form was converted to the corresponding HCl salt form as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:12]=[C:13]1[CH2:18][CH2:17][C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:19]#[N:20])[CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2([OH:12])[CH2:18][CH2:17][C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:19]#[N:20])[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: COc1ccc([Mg]Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1F
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 15 ml of 3-fluoro-4-methoxyphenylmagnesium bromide solution (0.5 M in THF) were dissolved in 15 ml of dry THF in a dried two-necked flask equipped with a reflux condenser, and subsequently 1.5 g of 4-oxo-1-phenylcyclohexanecarbonitrile in the form of a suspension in 10 ml of THF were slowly added dropwise at room temperature. A precipitate was formed in the course of this. The reaction solution was heated under reflux for 2 h, subsequently added to ice water, treated with saturated ammonium chloride solution and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified chromatographically (HEP/EA 2:1) on silica gel. 950 mg of the title compound were obtained as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: NCCc1ccccn1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNCCc4ccccn4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 70.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 2-(2-aminoethyl)pyridine (0.239 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)-5-[(2-(pyridin-2-yl)ethyl)aminomethyl]indol-2-yl)isoindolinone (85.7 mg, yield 71%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1.[C:22](=[O:24])=[O:23].[Cl-].[NH4+].Cl>C1COCC1.CCOC(C)=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][C:22]([OH:24])=[O:23])=[CH:11][C:12]=1[C:18]([F:19])([F:20])[F:21])#[N:15]
Reactant: O=C=O
Reactant: Cc1ccc(C#N)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(=O)O)cc1C(F)(F)F
Temperature: -78 °C
Yield: 88 %

Procedure:
Lithium diisopropylamide (13.8 mL, 24.8 mmol, 1.8M in THF) was added to 4-methyl-2-(trifluoromethyl)benzonitrile (2.30 g, 12.4 mmol) in THF (20 mL) at −78° C. and stirred for minutes at −78° C. Excess solid carbon dioxide was added then the mixture was stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride (10.5 mL) and EtOAc (20 mL) were added then the aqueous layer was acidified with HCl acid solution (1 M). This was extracted with EtOAc (3×15 mL) and the combined organic phases were dried over sodium sulphate and evaporated in vacuo to afford the title compound as a brown oil in 88% yield, 2.52 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH3:11].[CH3:13][N:14](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][C:5]=1[CH3:11]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C#N)cc1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid methyl ester (108 g, 471 mmol) in N,N-dimethylformamide (41) under a nitrogen atmosphere was added zinc (II) cyanide (88.5 g, 753.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (65 g, 56.60 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and saturated aqueous ammonium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 4-cyano-2-methylbenzoic acid methyl ester (73 g, 89% yield). 1H NMR (400 MHz, CDCl3): 7.78 (d, 1H), 7.52 (m, 2H), 3.92 (s, 3H), 2.62 (s, 3H).