Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[C:4]=1[CH:5]=[O:6])[CH3:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[CH2:1]([C:3]1[CH:10]=[C:9]([O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:8]=[C:7]([OH:12])[C:4]=1[CH:5]=[O:6])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCc1cc(O)cc(O)c1C=O
Solvent: ClCCl
Product: CCc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
To a mixture of 2-ethyl-4,6-dihydroxy-benzaldehyde (1 g, 6.02 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (1.1 mL, 12.05 mmol) and pyridium p-toluenesulfonic acid (0.010 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-ethyl-6-hydroxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.56 g, 100%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.08 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.50 (m, 1H), 3.84 (m, 1H), 3.60 (m, 1H), 2.90 (m, 2H), 2.00-1.50 (m, 6H), 1.30 (m, 3H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[F:15][C:8]([F:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][N:19]=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OCC(F)(F)c1ccccn1)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(F)(F)c1ccccn1
Reaction time: 1.5 h

Procedure:
A solution of 105 mg (0.31 mmol) of 2,2-difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate and 43 mg (0.66 mmol) of sodium azide in 1.0 ml of DMF was heated at 60° C. After 1.5 h, the mixture was cooled, diluted with water and extracted with two portions of ether. The combined organic layers were washed twice with water, brine and dried over MgSO4. The solvents were removed at reduced pressure to give 1-9 as a brown oil: 1H NMR (CDCl3) δ8.68 (d, 1H, 4.2 Hz), 7.86 (td,1H, 7.8, 1.5 Hz), 7.72 (d, 1H, 7.8 Hz), 7.40-7.45 (m, 1H), 4.03 (t, 2 H, 13.2 Hz).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH2:31]([N:38]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=1)[S:39]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>CN(C)C=O>[CH2:31]([N:38]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=1)[S:39]([C:42]1[CH:43]=[CH:44][C:45]([N:48]2[CH2:49][CH2:50][CH:51]([NH:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]3[C:28]4[NH:27][C:26](=[O:29])[NH:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH2:52][CH2:53]2)=[CH:46][CH:47]=1)(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(NCC(O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
Sodium Triacetoxyborohydride (0.015 g, 0.72 mM) was added to a solution of 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one(0.08 g, 0.36 mM), N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide (0.19 g, 0.39 mM), and acetic acid (0.025 ml, 0.43 mM) in anhydrous dimethylforamide (5 ml). The reaction was stirred overnight. The reaction was quenched with 50% H2O/sat. NaHCO3aq. (20 ml). The solids were captured on a filter and washed with ethyl acetate, diethyl ether, and hexanes to afford 0.075 g of the desired product as a brown solid. 1H NMR (DMSO) δ 1.31 (m, 2H), 1.89 (m, 2H), 2.71 (m, 2H), 2.87 (m, 3H), 3.53(s, 3H), 3.67 (s, 3H), 3.87 (m, 4H), 3.98 (m, 1H), 4.67(s, 2H), 4.95(bs, 1H), 6.44 (s, 1H), 6.59(m, 2H), 6.79 (m, 2H), 7.05 (d, 2H, J=8.7 Hz), 7.25 (m, 6H), 7.41(d, 2H, J=8.4 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 688.1 (MH+); HRMS for C36H41N5O7S: 688.2799 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][C:13]2[O:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)=[N:15][N:14]=2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[O:17][C:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)=[N:14][N:15]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1O
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 68 °C
Reaction time: 2 h

Procedure:
A suspension of cesium carbonate (0.54 g, 1.66 mmol), 5-[5-(4-chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol (0.36 g, 1.20 mmol) (from Example 40 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 68° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.36 g, 1.08 mmol) (from Example 1 supra) was added. Heating was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue washed with ethyl acetate and dried to give 4-chloro-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:24]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:24])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCOCC
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and Mel (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:30][C@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNC[C@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 6 H) 2.33 (s, 3 H) 2.65-2.79 (m, 2 H) 2.88-3.02 (m, 2 H) 3.06 (d, J=10.86 Hz, 1 H) 3.10-3.21 (m, 1 H) 3.39 (br. s., 1 H) 3.57-4.21 (m, 2 H) 7.52 (d, J=7.07 Hz, 1 H) 7.84-7.92 (m, 1 H) 7.95 (s, 1 H) 8.23 (d, J=13.14 Hz, 1 H) 8.37-8.50 (m, 2H); ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl-2-(p-aminobenzyl)-butyrate (3.3 g) and triethylamine (1.5 g) in anhydrous THF (70 ml) is slowly (10 minutes) addioned with a solution of p-chlorobenzoylchloride (2.6 g) in 30 ml of anhydrous THF. It is stirred for an hour at room temperature, then filtered and the solution as obtained is vacuum evaporated. The obtained solid residue is crystallized from methanol providing 4 g amide with m.p. 119°-120° C. Analysis:
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C1OCCOCCOCCOCCOC1.[H-].[Na+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1F>CN(C=O)C>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1[N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=2[C:2]([I:1])=[CH:3]1
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2-c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (200 mg) in DMF (6 ml) were added 15-crown-5 (0.159 ml) and sodium hydride (60% dispersion in mineral oil, 32.1 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,2,3-trifluoro-5-nitrobenzene (0.101 ml), and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (258 mg).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][NH:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][N:34]=4)[N:29]=[CH:28][C:27]=3[NH2:36])[O:21][N:20]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:26]4[C:35]5[N:34]=[CH:33][CH:32]=[CH:31][C:30]=5[N:29]=[CH:28][C:27]=4[N:36]=[C:1]3[CH3:2])[O:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 31.7 %

Procedure:
Triethyl orthoacetate (2.8 mL, 15.2 mmol) was added to a solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (prepared in Part B of Example 12, 3.4 g, 10.1 mmol) and pyridine hydrochloride (0.023 g, 0.20 mmol) in toluene (100 mL), and the reaction was heated at 110° C. under a nitrogen atmosphere for 15.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The work-up and purification procedures described in Part D of Example 12 were followed with the modification that the silica column was eluted with 5% methanol in ethyl acetate. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.15 g) was obtained as a light gray solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][C:8](=[O:10])[CH3:9].[H-].[Na+].[CH2:13](I)[CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([N:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:8](=[O:10])[CH3:9])[CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)Nc1cccn1C
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(C(C)=O)c1cccn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
N-(1-Methylpyrrol-2-yl)acetamide (3.20 g, 0.0231 mol) in dry dimethylformamide was maintained at a temperature less than 0° C, with stirring under nitrogen, during the slow addition of 50% sodium hydride/oil (1.11 g, 0.0231 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then the temperature allowed to rise to 15° C. when n-butyl iodide (8.50 g, 0.0461 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the resulting oil distilled to give a colourless oil 3.72 g (83%) b.p. (airbath) 100° C/0.4 mm.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2
Reactant: O=S(Cl)Cl
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CCl)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-N-(5-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.053 mmol, 450 mg) in CH2Cl2 (8 mL) was added Thionyl chloride (2.316 mmol, 0.169 mL, 276 mg) and the whole was stirred for 2 h at RT before the reaction mixture was concentrated under reduced pressure and re-dissovled in DCM. The process was repeated ×4 to drive off the excess thionyl chloride. The material was used immediately in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]1>>[CH3:35][C:31]1([CH3:36])[CH2:30][CH:29]([CH2:28][CH2:27][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:34][CH2:33][O:32]1
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])cnc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2cc(N)cnc21
Yield: 65.1 %

Procedure:
A suspension of 0.43 g (2.08 mmol) of 1-acetyl-2,3-dihydro-5-nitro-1H-pyrrolo[2,3-b]pyridine (Tetrahedron Lett. 1987, 1589) and 0.044 g of 10% palladium-on-charcoal in 15 mL of ethanol is stirred vigorously for 6 hours at room temperature and under 5 atmospheres of hydrogen. After this time, the suspension is filtered through Celite and the filtrate is concentrated under reduced pressure to give 0.24 g of the expected product in the form of a solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([C:8]([CH2:10][CH3:11])=[O:9])[CH3:7]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:9][C:8]([CH2:10][CH3:11])=[CH:6][CH3:7]
Reactant: CCC(=O)CC
Reactant: C[Si](C)(C)Cl
Product: CC=C(CC)O[Si](C)(C)C

Procedure:
From reaction between diethylketone and trimethylchlorosilane to form 3-trimethylsilyloxy-2-pentene (1.2.4.17). This product was reacted with 1-fluoropyridinium triflate (1.2.4.5) to obtain 2-fluoro-3-pentanone (1.2.4.9). After bromination with pyridinium bromide followed by reduction using diborane 2-fluoro-4-bromopentane-3-ol (1.2.4.18) was obtained. Reaction of this product with sodium methylate yielded the title compound (1.2.4.16). This compound was made also by reacting 2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) with HF/Py (70%) followed by treatment of the resulting 2-bromo-4-fluoropentan-3-ol (1.2.4.18) with K2CO3 /MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCOc1ccncc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCOc1ccncc1

Procedure:
5-Methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide (2.15 g, 6.4 mmol) and 10% palladium-on-charcoal catalyst (100 mg) were suspended in methanol (400 ml) and placed under hydrogen at atmospheric pressure. The reaction mixture was heated at 40° C. for 1 hour, cooled to ambient temperature, filtered through diatomaceous earth and the solvent was removed by evaporation. The precipitate was slurried with ether and collected by filtration to give 2-amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (1.95 g, 99%). 2-Amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide (1.95 g, 6.4 mmol) and formamide (10 ml) were heated at 190-200° C. for 1 hour. The reaction mixture was allowed to cool to 50° C. as the product precipitated out. Water (50 ml) was added and the solid was collected by filtration, washed with more water and ether and dried under vacuum to give 6-methoxy-7-(2-(4-pyridyloxy)ethoxy)-3,4-dihydroquinazolin-4-one (0.99 g, 49%) as a cream solid. The 6-methoxy-7-(2-(4-pyridyioxy)ethoxy)-3,4-dihydroquinazolin-4-one (312 mg, 1 mmol) was heated at reflux in thionyl chloride (10 ml) and DMF (5 drops) for 1 hour, then evaporated to dryness and partitioned between a saturated solution of sodium hydrogen carbonate and methylene chloride. The methylene chloride phase was dried by filtration through a phase separator paper and the solvent was removed by evaporation to give crude 4-chloro-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline which was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23]>CS(C)=O.O>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23])#[N:2]
Reactant: [C-]#N
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
To a solution of sodium cyanide (99 mg) in dimethyl sulfoxide (5 ml), a solution of the compound (605 mg) obtained in Example 249 in dimethyl sulfoxide (10 ml) was added dropwise at 60° C. and stirred at 60° C. for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate-diethyl ether (1:1); thereafter, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 164 mg of the titled compound (yield, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:46]I>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20][I:46])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCO)C(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCI)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A modified procedure described in Tetrahedron 2001, 57, 4759-4766 was followed. To a vigorously stirred solution of alcohol 25 (640 mg, 2.11 mmol), imidazole (359 mg, 5.28 mmol), and PPh3 (1.38 g, 5.28 mmol) in CH2Cl2 (20 mL) was added with I2 (1.07 g, 4.22 mmol) portionwise over 15 minutes. The resulting suspension was stirred for an additional 2 hrs and quenched with saturated Na2S2O3 (10 mL). The phases were separated and the aqueous layer was extracted with additional portions of CH2Cl2. The combined extracts were dried (MgSO4) and evaporated in vacuo. The solid residue was suspended in hexane/EtOAc (10/1 v/v, 15 mL) and the liquid decanted. This operation was performed two more times and the decanted liquid fractions were combined and evaporated in vacuo to give a yellow oil. Purification by flash chromatography (silica gel; hexanes→hexanes/EtOAc, 20/1) gave the title compound 30 (851 mg, 98%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:26][C:27]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)(=O)=O.O>CN(C=O)C>[CH2:32]([O:31][CH2:30][C:27]1([CH2:26][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:29][CH2:28]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OCC1(COCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.62 g, 44.4 mmol) in DMF (12 mL) was treated with cesium carbonate (14.6 g, 44.4 mmol) and stirred at RT for 10 min. A solution of {1-[(benzyloxy)methyl]cyclopropyl}methyl methanesulfonate (Compound 63D, 12 g, 44.4 mmol) in DMF was added and heated to 70° C. for 24 hrs. The reaction mixture was cooled to RT, poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to give 12 g (73%) of required compound as a colorless gum which was used without further purification. 1H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H), 7.68 (s, 1H), 7.25-7.34 (m, 5H), 4.48 (s, 2H), 4.15 (s, 2H), 3.16 (s, 2H), 1.33 (s, 12H), 0.71 (s, 2H), 0.56 (s, 2H).
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH3:14])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH2:14][Br:1])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)Nc1ccccc1C(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1C(=O)CBr

Procedure:
45.0 g (0.282 mol) of dry bromine were added dropwise to a boiling solution of 50.0 g (0.282 mol) of 1-[2-(acetylamino)phenyl]ethanone in 400 ml of chloroform at room temperature. The solvent was distilled off, the residue was distributed between dichloromethane and saturated ice-cold sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, evaporated down in vacuo, the residue was triturated with diethylether and suction filtered. After drying in vacuo 35.4 g (49% of theory) of colourless crystals were obtained, Rf=0.48 (eluant: petroleum ether/ethyl acetate 2/1 v/v).