Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[S:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH:18]([CH2:35][CH2:34][CH3:38])[C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[S:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Yield: 96.2 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g; 0.246 mmol), LHMDS 1N in THF (0.280 mL; 0.280 mmol), 1-iodopropane (0.040 mL; 0.410 mmol) in DMF (3.5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.087 g (96%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[C:5]2[N:14]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][C:4]=2[CH:3]=1.[CH3:37][N:38](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH3:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:14]2[C:5]3[C:6]([C:8]4[CH:13]=[N:12][CH:11]=[CH:10][N:9]=4)=[N:7][C:2]([C:37]#[N:38])=[CH:3][C:4]=3[N:16]=[C:15]2[N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32]1
Reactant: CN(C)C=O
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cnccn4)c32)CC1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cnccn4)c32)CC1
Temperature: 140 °C

Procedure:
To a sealable tube were added 6-chloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine (250 mg, 0.497 mmol) and Zn(CN)2 (46 mg, 0.397 mmol). DMF (4 mL) was added, and the mixture was purged with nitrogen for 5 minutes. Pd(dppf)Cl2 dichloromethane complex (20.2 mg, 0.024 mmol) was added, and the mixture was degassed with nitrogen again for 5 minutes. The tube was sealed and heated to 140° C. for 2.5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column using 30-45% ethyl acetate/petroleum ether as eluent to afford 3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-4-(pyrazin-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calc'd. for C29H31N7O [M+H]+ 494. found 494.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1[Cl:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(#N)C>[Br:35][C:20]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][N:15]2[C:16]([Cl:17])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:12]([CH3:27])=[N:13][C:14]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (800 mg, 2.063 mmol) in acetonitrile (20 mL) was added NBS (367 mg, 2.063 mmol). The reaction mixture was stirred at r.t. for 1 h. The solvent was evaported and the residue was purified by silica gel chromatography to afford (920 mg, 96%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.09 (dd, J=8.1, 1.4 Hz, 2H), 7.61-7.39 (m, 3H), 5.65 (s, 1H), 3.73 (s, 3H), 2.73 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [OH:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]1=[O:13].COCCOC.[F:20][C:21]([F:27])([F:26])[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:21]([F:27])([F:26])[S:22]([O:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]1=[O:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=c1oc2ccccc2c(=O)n1O
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c(=O)n1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
3-Trifluoromethanesulfonyloxy-1,3-benzoxazine-2,4-dione was prepared by the following procedure. To a dried flask with a stirrer, under nitrogen, were added 3-hydroxy-1,3-benzoxazine-2,4-dione (3.35 g, 18.7 mmol) (U.S. Pat. 2,714,105) and 100 mL of dried DME. The mixture was held at -15°, and trifluoromethanesulfonyl chloride (2.00 mL, 18.7 mmol) followed by triethylamine (3.00 mL, 22 mmol) were added dropwise by syringe. After warming to room temperature, the reaction mixture was diluted with 200 mL of methylene chloride and washed successively with water, 2 percent aqueous sodium bicarbonate, and water, and then dried. Evaporation of the solvent gave 5.13 g of white solid: mp 73°-76°. Recrystallization from methylene chloride-hexane gave 3.60 g (62%) of 3-trifluoromethanesulfonyloxy-1,3-benzoxazine-2,4-dione: mp 74°-76°; uv (CH3CN) 237 (11,100), and 289 nm (2180); ir (KBr) 1800 (s), 1742 (vs), 1612 (m), 1465 (s), 1448 (s), 1342 (m), 1228 (vs), 1126 (m), 1090 (m); mass spectrum 310.9686 (calcd for C9H4NO6F3S: 310.9701); 217,0098 (calcd for C9H4O3F3 : 217.0112); 120.0200 (calcd for C7H4O2 : 120.0211). A second crop of product, 0.70 g, raised the overall yield to 73.9%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:38][CH:37]=3)=[N:33]2)=[CH:28][CH:27]=1.[OH:48][C:49]1[N:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(O)C.[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:42]1([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:32]3[N:31]=[CH:30][C:29]4=[CH:28][CH:27]=[C:26]([C:52]5[CH:51]=[CH:50][C:49]([OH:48])=[N:54][CH:53]=5)[N:34]4[N:33]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: OB(O)c1ccc(O)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.2 %

Procedure:
Palladium Acetate (0.018 g, 0.000080 mol) and Triphenylphosphine (0.026 g, 0.00010 mol) were dissolved in Tetrahydrofuran (1.2 mL, 0.015 mol) and the mixture was allowed to stir at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.150 g, 0.000401 mol) was then added and the reaction was again allowed to stir for 10 minutes. 6-hydroxy-3-pyridine boronic acid (0.111 g, 0.000802 mol) was added followed by 0.9 M of Sodium carbonate in water (1 mL, 0.0009 mol) and Ethanol (1.2 mL, 0.021 mol). The reaction mixture was then heated at 80° C. and was allowed to stir overnight. The reaction mixture was poured over saturated sodium chloride, and organics were extracted with ethyl acetate. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Gilson prep HPLC to afford 8.16 mg of 5-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyridin-2-ol as a lyophilized powder. (M+H)=389.7. 1H NMR (400 MHz, DMSO, d6) δ 9.27 (s, 1H), 8.89 (s, 1H), 8.42 (m, 1H), 8.13 (dd, 1H, J=2.60, 7.00 Hz), 7.58 (d, 2H, J=8.92 Hz), 7.06 (m, 3H), 6.90 (d, 1H, J=4.76 Hz), 6.52 (d, 1H, J=9.61 Hz), 3.77 (m, 4H), 3.11 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C@@H:8]2[NH:15]C(=O)OC(C)(C)C)([CH3:3])[CH3:2].Cl>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C@@H:8]2[NH2:15])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)OC(C)(C)C)CCO2
Agent: Cl
Solvent: CO
Product: CC(C)Oc1ccc2c(c1)[C@@H](N)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of tert-butyl (4S)-6-isopropoxy-3,4-dihydro-2H-chromen-4-ylcarbamate (340 mg, 1.11 mmol) in methanol (2 mL) was added hydrochloric acid (2 mL, 4 N in 1,4-dioxane, 8 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was diluted with methylene chloride (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×50 mL). The combined extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide (4S)-6-isopropoxychroman-4-amine (240 mg, 99% crude yield): 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J=2.7 Hz, 1H), 6.90-6.86 (m, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.55-4.46 (m, 2H), 4.24-4.17 (m, 2H), 2.40-2.31 (m, 1H), 2.18-2.08 (m, 1H), 1.28 (d, J=6.0 Hz, 6H). This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)c(-c2cc(C=O)c(C)o2)c1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-fluoro-5-methoxyphenylboronic acid (1.4 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.5 g, 93%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 51 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 1-bromodecane under conditions described in Example 58 gave 5-(decyloxy)-2-hydroxybenzoic acid methyl ester (51% yield, mp 40°-43°).
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])[CH3:5].Cl[CH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]2[CH:29]=1>CN(C)C=O>[C:4]([NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17][CH2:19][C:20]3[N:21]=[C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]4[CH:29]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])[CH3:5]
Reactant: Cc1ccn2cc(CCl)nc2c1
Reactant: CC(=O)Nc1nc2ccc(O)cc2o1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(OCc3cn4ccc(C)cc4n3)cc2o1
Temperature: 50 °C
Reaction time: 17 h
Yield: 10.1 %

Procedure:
Methanolic sodium methoxide (28 wt. %, 1.25 g) was added to a solution of 2-acetamido-6-hydroxybenzoxazole (1.25 g) and 2-chloromethyl-7-methylimidazo[1,2-a]pyridine (1.41 g) in N,N-dimethylformamide (25 ml). After the mixture was stirred at 50° C. for 17 hours, the solvent was evaporated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (62.5 g) by eluting with chloroform-methanol (50:1, V/V), and the product obtained was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-acetamido-6-[(7-methylimidazo[1,2-a]pyridin-2-yl)methoxy]benzoxazole (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24]C3CCCCO3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:43][C:16]([C:18]3[S:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (366 mg) in acetic acid (3.1 mL) was added ammonium acetate (773 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 39%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 481 (MH+).
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[H][H]>CO.[C].[Pd]>[CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2]
Reactant: [H][H]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: [Pd]
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C
Yield: 96.2 %

Procedure:
10% palladium carbon (20 mg) was added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.5 mg, 0.106 mmol) in methanol (4 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for four hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the target compound (48.8 mg, 96%).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>CO>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3cc(C=Cc4ccccc4)ccc3c21
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3cc(CCc4ccccc4)ccc3c21

Procedure:
A modification of the method described in Example 123 was used to reduce 1-(2-methylpropyl)-7-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.5 mmol). The reaction was carried out in methanol (100 mL) for seven days. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 1-(2-methylpropyl)-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 172–173° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[CH:24]=[CH:25][C:26](Br)=[CH:27][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([N:16]1[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[N:13]=[C:12]1[CH:8]([NH2:7])[CH:9]([CH3:10])[CH3:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester in DCM (2 ml), was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give the free amine product.
Reaction SMILES: [CH:1]1([C:6]2[N:14](COCC[Si](C)(C)C)[C:13]3[C:12](=[O:23])[N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:10]([O:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:23])[N:11]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:10]([O:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ncccc1Oc1nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c(=O)n1CC(C)C
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1nc2nc(C3CCCC3)[nH]c2c(=O)n1CC(C)C
Temperature: 85 °C
Yield: 12.7 %

Procedure:
A mixture of 8-cyclopentyl-1-isobutyl-2-(2-methyl-pyridin-3-yloxy)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.11 g, 0.214 mmol), 2N HCl (2.5 ml), ethanol (2.5 ml) was heated at 85° C. for 4 hours. The mixture was cooled and the solvent was evaporated. The residue was diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography to provide 8-Cyclopentyl-1-isobutyl-2-(2-methyl-pyridin-3-yloxy)-1,7-dihydro-purin-6-one (0.01 g) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([C:19]([CH3:21])=[CH2:20])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:19]([CH3:20])[CH3:21])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: C=C(C)c1cc(OC)cc2c1cc1n2CCC1CC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(OC)cc12
Reaction time: 0.75 h

Procedure:
To the compound of Step 1 (200 mg, 0.67 mmol) in EtOH (20 mL) was added Pd/C 10% (100 mg). The mixture was hydrogenated with a Parr hydrogenator at 50 psi for 45 minutes the filtered on a pad of celite. The filtrate was evaporated to dryness and used as such in the next step (170 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1)=[O:31]
Reactant: Nc1ncc(Br)nc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N)c(-c2ccc(OC(F)(F)F)cc2)n1
Yield: 73 %

Procedure:
To a solution of 10.20 g (0.029 mol) 5-bromo-3-(4-trifluoromethoxy-phenyl)-pyrazin-2-ylamine in 100 ml methanol and 40 ml ethyl acetate was added 0.500 g (0.0006 mol) PdCl2 dppf CH2Cl2 ([1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct, Cas Registry No. [95464-05-4]) and 8.113 ml (5.9 g, 0.058 mol) triethylamine and the mixture was stirred at 110° C. under 70 bar carbon monoxide pressure for 4 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with a gradient of 100% heptane to 100% ethyl acetate to yield 6.800 g (73% yield) of the title compound as off white crystalline solid. MS (ISP) (M+H+)=314.0.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[CH:6]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:16]3[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=3)=[CH:6][C:5]=2[CH:7]=1
Reactant: Clc1ccc2sc(Br)cc2c1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc3cc(Cl)ccc3s2)cc1

Procedure:
The compound was prepared in the same manner as described in Preparation 48, Step B, from 2.06 g (8.32 mmol) 2-bromo-5-chlorobenzothiophene and 2.44 g (17.95 mmol) 4-methylbenzeneboronic acid and isolated by crystallization from ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: Fc1ccccc1-c1ccc(Cl)nn1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccccc3F)nn12

Procedure:
As in Example 36, a mixture of 2.5 g. of 3-chloro-6-(o-fluorophenyl)-pyridazine and 1.76 g. of acetylhydrazine in 50 ml. of n-butanol is refluxed for 48 hrs. to give 2.0 g. of product as off-white crystals, m.p. 147°-149° C.
Reaction SMILES: [P:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]2)([O:6]CC)([O:3]CC)=[O:2].I[Si](C)(C)C.NC1C=CC(C)=CC=1>C(Cl)Cl>[C:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][P:1](=[O:2])([OH:3])[OH:6])[CH:11]=2)[N:16]=1)#[N:21]
Reactant: CCOP(=O)(OCC)Oc1ccc2nc(C#N)ccc2c1
Agent: C[Si](C)(C)I
Solvent: Cc1ccc(N)cc1
Solvent: ClCCl
Product: N#Cc1ccc2cc(OP(=O)(O)O)ccc2n1
Yield: 92 %

Procedure:
To the solution of diethyl (2-cyano-quinolin-6-yl) phosphate (0.58 g, 1.86 mmol) in 10 ml of methylene chloride was added iodotrimethylsilane (0.82 g, 4.1 mmol). The resultant mixture was stirred for 40 minutes and then added to the solution of p-toluidine (1.50 g, 14.0 mmol) in 20 ml. After the solvent was partially removed, the white yellow precipitate was collected by filtration and washed with ethanol and ether to give a yield of 92%.