Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[N:24](C5CCCCO5)[CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2].BrC1C(C)=NC(C2N=CN(C3CCCCO3)N=2)=CC=1.C(N1C2=NC([Sn](C)(C)C)=CN=C2NCC1=O)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>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].CN(C)C=O>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[NH:24][CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: [Pd]
Agent: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 100 °C
Yield: 66.7 %

Procedure:
1-Isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. To a flask was added 3-Bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.446 g, 1.380 mmol), 1-isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.490 g, 1.380 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.139 g, 0.152 mmol), tri-o-tolylphosphine (0.092 g, 0.304 mmol), triethylamine (0.577 mL, 4.14 mmol) and N,N-dimethylformamide (3 mL). Nitrogen gas was bubbled through the reaction mixture for 5 min and the mixture was heated to 100° C. for 1 h. After cooling to rt, the reaction mixture was filtered through Celite, rinsed with methanol and concentrated to dryness. The resulting residue was purified by silica gel flash column chromatography (0-80% ethyl acetate in hexanes, followed by 0-10% methanol in dichloromethane) to yield the desired product (0.40 g, 0.921 mmol, 66.7% yield). MS (ESI) m/z 435.5 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O>C(O)C.Cl.[Pd]>[NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1c([N+](=O)[O-])ccc2[nH]nnc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1N
Yield: 117.3 %

Procedure:
A suspension of 4-amino-5-nitrobenzotriazole (0.72 g, 4 mmol) in 100 ml of ethanol and 1 ml of conc. hydrochloric acid was hydrogenated at atmospheric pressure and room temperature for 6 h in the presence of 100 mg of 5% palladium-on-charcoal. The mixture was filtered and the catalyst was washed with about 50 ml of water. The combined filtrate was evaporated to dryness giving 0.70 g of the 4,5-diamino-benzotriazole as an hydrochloride. A solution of the crude diamino compound in 40 ml of 4M hydrochloric acid was refluxed with oxalic acid dihydrate (0.50 g, 4 mmol) for 3 h. The mixture was cooled on ice, and pH was adjusted to 5-6 with 2N sodium hydroxide. The precipitate was filtered off and washed with water and ethanol. It was then dissolved in 10 ml of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. After adjustment to pH 6-7 with 4M hydrochloric acid the reprecipitated product was isolated, washed with water and ethanol, and dried at 10 0° C. affording 0.12 g (15%) of pure title compound; m.p.>300° C.; IR (KBr): 3200-2000, 1670 cm-1 ; 1H-NMR (DMSO-d6): 6.9 (broad s, 3H, NH+2OH); 7.03 (d,J=8 Hz, 1H, ArH); 7.43 (d,J=8 Hz,1H, ArH).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[N:17][C:16]([OH:19])=[CH:15][N:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](OS(C)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:19][C:16]2[CH:15]=[N:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 96.7 %

Procedure:
Cesium carbonate (372 mg) was added to a DMF solution (2 ml) of 2-bromo-5-hydroxypyrazine (100 mg) and 1-t-butoxycarbonyl-4-(methanesulfonyloxy)piperidine (192 mg), and stirred at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate=1:11) to obtain the entitled compound (198 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])([O-])=O.C(O)C.C(O)(=O)C.[H][H]>[Fe].[Rh].O>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Fe]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 78.8 %

Procedure:
In a 500 ml Parr hydrogenation reactor were placed 8.50 g (0.0457 mole) of 2,4-dinitrofluorobenzene, 1.0 g (0.018 mole) of powdered iron, 0.15 g of 5% rhodium on alumina, 100 ml of ethanol, 100 ml of acetic acid, and 5 ml of water. The reaction was stopped after 140 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was concentrated under reduced pressure, and water was added to the residue. Filtration yielded 5.62 g of crude 2-fluoro-5-nitroaniline. Analysis of the nmr spectrum of the product showed it to be >90% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: C([SiH](CC)CC)C.O=[C:9]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11]>C(O)(C(F)(F)F)=O>[NH:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:15]1
Reactant: COC(=O)C(=O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1c[nH]c2ncccc12
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a mixture of triethylsilane (9.95 g, 85.78 mmol) in TFA (25 mL) was added portionwise methyl oxo(1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (5.0 g, 24.48 mmol). After a period of 18 h at 50° C., the solvent was evaporated and saturated NaHCO3 was added followed by DCM. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash with 10% ethyl acetate in hexane to 100% ethyl acetate to provide 3.5 g of the title compound.
Reaction SMILES: COC([C:5]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=O.[I-].[Li+]>CN(C)C=O>[CH2:23]([O:22][C:20]([CH2:19][CH:5]1[CH:9]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC1(C(=O)OC)C(=O)CCC1CSc1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)CCC1CSc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
The resulting 1-(ethoxycarbonylmethyl)-2-oxo-5-phenylthiomethylcyclopentane carboxylic acid methyl ester (640 mg; 1.83 mmol) was dissolved in dimethylformamide (20 ml) and was admixed with anhydrous lithium iodide (250 mg; 1.85 mmol). The mixture was refluxed with vigorous stirring for 5 hours and was cooled to room temperature. The reaction product was extracted by adding ether (50 ml) and dilute hydrochloric acid (50 ml) to the reaction mixture. The ether extract was washed with a saturated sodium chloride solution and was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(ethoxycarbonylmethyl)-3-phenylthiomethyl cyclopentanone (420 mg) as an oily product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[S:11]1[CH:15]=[C:14]([CH2:16][C:17]#[N:18])[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]1=2.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[S:11]1[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]1=2
Reactant: N#CCc1csc2ccccc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: NCCc1csc2ccccc12
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
Lithium aluminium hydride (1.16 g, 30.3 mmol) was suspended in dry diethyl ether (100 ml). Anhydrous aluminium chloride (4.04 g, 30.3 mmol) was introduced into this suspension under argon. After five minutes, a solution of benzo[b]thiophene-3-acetonitrile (5.25 g, 30.3 mmol) in dry diethyl ether (70 ml) was added. When the addition was complete, the mixture was heated under reflux for four days. Lithium aluminium hydride (930 mg) and aluminium chloride (500 mg) were added again to the reaction mixture and the mixture was heated under reflux for a further eight hours. For working up, it was neutralized with an aqueous solution of potassium sodium tartrate (80 ml, 20 wt. %). When the evolution of gas had ended, the phases were separated and the cloudy aqueous phase was filtered off with suction over a glass frit. The residue on the frit was washed with ethyl acetate and the clear aqueous phase was extracted with ethyl acetate (3×50 ml). The organic phases were dried over sodium sulfate and filtered and the filtrate was concentrated. Crude benzo[b]thiophen-3-ylethylamine (3.7 g) was obtained as a red-brown oil. Treatment with methanolic hydrochloric acid gave a tacky hydrochloride, which was immediately converted back into the free base. 794 mg (15%) benzo[b]thiophen-3-yl-ethylamine were obtained as a yellow oil, which was employed for the further synthesis.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].O>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Yield: 85.8 %

Procedure:
After dissolving 2,4-difluoroaniline (10 ml, 98.21 mmol) in tetrahydrofuran (200 ml), pyridine (8.7 ml, 108.33 mmol) was added at room temperature and the mixture was stirred. It was then cooled on ice, phenyl chloroformate (13.6 ml, 108.33 mmol) was added dropwise over 15 minutes, and the mixture was then stirred at room temperature for 24 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The obtained crystals were suspended in ethanol and diluted with hexane, and then the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (21.00 g, 84.26 mmol, 85.80%) as light violet crystals.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=4)[N:20]=3)=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[Cl:32][C:30]1[CH:31]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]4)=[N:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH:27]=[C:28]([Cl:34])[C:29]=1[Cl:33]
Reactant: C=CCOC(=O)N1CCN(c2ccc(-c3ccnc(Nc4cc(Cl)c(Cl)c(Cl)c4)n3)cn2)CC1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Clc1cc(Nc2nccc(-c3ccc(N4CCNCC4)nc3)n2)cc(Cl)c1Cl
Yield: 41.7 %

Procedure:
A solution of 4-(2-(4-allyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-N-(3,4,5-trichlorophenyl)-2-pyrimidineamine (170 mg,0.33 mmol) in dichloromethane and DMF (3 ml,1:1 mixture) was stirred with acetic acid (1 ml), dichloro-bis(triphenylphosphine)palladium (II) (15 mg) and tri-n-butyltin hydride at room temperature for 5 min. The reaction was added to a saturated aqueous NaHCO3 solution, which was extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane and then subjected to column chromatography (silica gel with 1% ammonium hydroxide-8% methanol-dichloromethane) to give the title compound (60 mg) as an off-white solid m.p. 208-211°. δH(d6 DMSO) 10.03(1H, s), 8.91 (1H, d, J 2.5 Hz), 8.51 (1H, d, J 5.4 Hz), 8.22 (1H, dd, J 9.1, 2.5 Hz),8.16 (2H, s), 7.43 (1H, d, J 5.4 Hz), 3.56 (4H, m) and 2.78 (4H, m).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC(Cl)C>[CH3:14][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:25]2[N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:22])=[O:23])[CH:28]=[CH:27][CH:26]=2)=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
Under nitrogen atmosphere, to a suspension of aluminum chloride (4.62 g) in dichloroethane (50 mL) was added a solution of p-toluoyl chloride (4.91 g) in dichloroethane (5 mL) at room temperature over a period of 10 minutes. After stirring for 30 minutes, to the mixture was added a solution of 1-benzenesulfonyl-1H-pyrrole (6.00 g) in dichloroethane (10 mL) over a period of 10 minutes. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was poured into ice water, and the aqueous layer was extracted twice with methylene chloride. The organic layers were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give (1-benzenesulfonyl-1H-pyrrol-2-yl) (4- methyl-phenyl) ketone (9.9 g, 100%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:24][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:14]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-benzenesulfonyl-1H-pyrrole (283.9 g) in methylene chloride (1.0 L) were added p-toluoyl chloride (318 g) and boron trifluodie ether complex (350 g), and the mixture was allowed to stand at room temperature for 7 days. The reaction solution was washed twice with IN hydrochloric acid (750 mL), washed with 1N aqueous sodium hydroxide solution (750 mL) and a saturated brine (100 mL), dried, and filtered. The filtrate was concentrated to about a half volume thereof under atmospheric pressure, and thereto was added hexane (500 mL). The mixture was further concentrated, and methylene chloride was evaporated off. The resultant was cooled to 10° C., and the precipitated crystals were collected by filtration, washed with hexane and toluene, and dried to give (1-benzenesulfonyl-1H-pyrrol-2-yl) (4-methylphenyl) ketone (315 g, 71%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]([CH3:50])[C:25]([C:27]1[N:44]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:30]2[N:31]=[C:32]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=3)[N:33]=[CH:34][C:29]=2[CH:28]=1)=[O:26].C1COCC1.[OH-].[Na+]>ClCCl.C(O)(C)(C)C.CCOCC>[CH3:23][N:24]([CH3:50])[C:25]([C:27]1[N:44]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:30]2[N:31]=[C:32]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][N:37]=3)[N:33]=[CH:34][C:29]=2[CH:28]=1)=[O:26]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(CO)cn3)nc2n1C1CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A suspension of Dess-Martin periodinane (0.435 g, 1.06 mmol) in dichloromethane (5 ml) and tert-BuOH (0.1 ml) is stirred at rt. for 15 minutes. To this mixture is added a solution of 7-cyclopentyl-2-(5-hydroxymethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.3 g, 0.79 mmol) in dichloromethane:THF (5 ml:7 ml) over 5 minutes. The reaction is stirred at it for 1 h after which ether (50 ml) and NaOH 1M (25 ml) are added. The mixture stirred vigorously for 10 minutes and then the phases are separated. The aqueous layer is back-extracted with ether (25 ml). The combined organic fractions are ished with water, brine, dried (MgSO4) filtered and the solvent evaporated to give 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a white solid (0.244 g, 82%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](=[O:15])[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4]([OH:15])=[CH:3][CH:2]=1
Reactant: O=C1CCNc2cc3ccccc3cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Oc1ccnc2cc3ccccc3cc12
Temperature: 25 °C

Procedure:
To 1 g of 2,3-Dihydrobenzo[g]quinolin-4(1H)-one (5) (5.07 mmol) in 20 mL of toluene (0.25 M) under a nitrogen atmosphere was added 1.5 g of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 1.3 equivalents). The reaction mixture was heated to reflux and monitored by TLC until completion (approximately 2 h). After cooling to rt, the mixture was concentrated in vacuo then filtered through a silica plug using 10% methanol in methylene chloride to afford crude phenol (6). Subsequently, the crude phenol was directly subjected to the halogenation conditions of step 2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Reactant: BrC1c2ccccc2C1Br
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (about 37 mmol) of 1,2-dibromobenzocyclobutene (contaminated with a little 2-bromo-1-iodobenocyclobutene) and 100 ml of xylene are kept under reflux for 16 hours, using a water separator. The mixture is cooled and the precipitate is filtered off and washed with xylene. Yield 5.82 g (71%); melting point 253°-254° C. The procedure in Examples 58 to 61 is analogous.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:8]([NH:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21]2)[S:15][CH3:16])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([SiH2:5][O:6][C:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:8]([NH:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21]2)[S:15][CH3:16])([CH3:11])[CH:9]=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(CO)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
N-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-2-hydroxy-1-methyl-ethyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (1.90 g) from Stage 2 above in dichloromethane (55 ml) was treated with Dess-Martin periodinane (1.615 g). The reaction mixture was stirred at room temperature for 1 h30 and then treated with saturated aqueous NaHCO3 and saturated aqueous sodium thiosulphate. The organic layer was washed thrice with saturated aqueous NaHCO3. The organic phase was separated, dried over sodium sulphate, filtered and evaporated to yield 1.694 g of N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-1-methyl-2-oxo-ethyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide which was used as such in Stage 4 described below.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1>ClCCl>[CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)c1cccc(C(O)c2cccnc2)c1
Solvent: ClCCl
Product: COC(OC)c1cccc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 19 parts of α[3-(dimethoxymethyl)phenyl]-3-pyridinemethanol, 36 parts of activated mangenese (IV) oxide and 280 parts of dichloromethane was stirred over weekend at room temperature. The reaction mixture was filtered over silica gel and the filtrate was filtered again over diatomaceous earth and silica gel. The filtrate was evaporated and the residue was distilled in vacuo. The desired fraction was collected, yielding 15.7 parts (82%) of [3-(dimethoxymethyl)phenyl](3-pyridinyl)methanone (intermediate 6).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:21]=[O:22].C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]([C:20]2[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=2)[OH:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc(OCc3ccccc3)c2)c1
Yield: 82.1 %

Procedure:
1-Benzyloxy-3-bromobenzene (10.56 g, 40.13 mmol), 3,5-dimethoxybenzaldehyde (7.34 g, 44.14 mmol), and n-butyl lithium (17.66 ml, 44.14 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (3-Benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82%): 1HNMR (CDCl3) 7.43-7.21 (m, 6H, Ar), 7.04-6.85 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.72 (d, J=3 Hz, 1H, CHOH), 5.04 (s, 2H, CH2), 3.76 (s, 6H, 2OCH3), 2.21 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.