Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=[C:10]2[CH:9]=1)([O-])=O.Cl.C(O)C>C(=O)([O-])O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=[C:10]2[CH:9]=1
Reactant: O=C(Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(Oc2ccn3nc(NC(=O)C4CC4)nc3c2)c1
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A mixture of N-[7-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (125 mg, 0.368 mmol), reduced iron (500 mg), concentrated hydrochloric acid (500 μL) and ethanol (5 mL) was stirred under refluxing conditions for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate to give the title compound (40.0 mg, 32%) as a white solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[Cl:27][C:28]1[C:33]([CH:34]=[O:35])=[CH:32][C:31]([C:36]#[N:37])=[CH:30][C:29]=1[NH:38][C:39]1[N:44]=[C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)[C:42]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:41]2[N:40]=1>C1COCC1>[Cl:27][C:28]1[C:33]([CH:34]([OH:35])[C:20]([F:22])([F:21])[F:19])=[CH:32][C:31]([C:36]#[N:37])=[CH:30][C:29]=1[NH:38][C:39]1[N:44]=[C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)[C:42]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:41]2[N:40]=1
Reactant: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
TBAF (1 M in THF, 0.026 mL, 0.026 mmol) was added to a suspension of (trifluoromethyl)trimethylsilane (2 M solution in THF, 0.079 mL, 0.16 mmol) and 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (20 mg, 0.053 mmol) in dry THF (1 mL) under nitrogen in an ice bath. The bath was removed and the reaction was left stirring at room temperature overnight. Aqueous 1 N HCl was added and the reaction was left stirring for 20 min. This was neutralized with 1.3 N potassium phosphate buffer and extracted three times with EtOAc. The organic extracts were washed with brine and dried with sodium sulfate. Radial silica gel chromatography eluting with DCM containing 0 to 15% EtOAc afforded the title compound (4.1 mg) as oil.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14][OH:15].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)(O)=O>C(#N)C.O.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>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH2:14][OH:15])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc2nc(CO)c(Br)c(=O)n12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.09450 g, 0.3512 mmol), 3-fluorophenylboronic acid (0.09827 g, 0.7024 mmol), tetrakis(triphenylphosphine)palladium (0.02029 g, 0.01756 mmol), and sodium carbonate anhydrous (0.1861 g, 1.756 mmol) in acetonitrile-water (3:1) (4 mL) was stirred at 85° C. After 2 h, the mixture was cooled to rt and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 20 min as eluent to give 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: Mass Spectrum (ESI) m/e=285.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27]>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][S:26]([NH2:29])(=[O:28])=[O:27])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1cnc(CN(CCCCNS(N)(=O)=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (110 mg, 0.328 mmol) and sulfamide (94 mg, 0.98 mmol) in 1,4-dioxane (6 mL) was refluxed for 25 hours then cooled to room temperature and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 51 mg (35%) of COMPOUND 152 as a white foam. 1H NMR (CDCl3) δ 1.03 (d, 6H, J=6.6 Hz), 1.42-1.50 (m, 2H), 1.59-1.66 (m, 2H), 2.15 (s, 3H), 2.28 (s, 3H), 2.58 (t, 2H, J=6.6 Hz), 2.93-3.03 (m, 3H), 3.70 (s, 2H), 3.73 (s, 2H), 5.15 (br s, 2H), 6.04 (br s, 1H), 7.16 (dd, 1H, J=7.8, 4.8 Hz), 7.25 (s, 1H), 7.54 (dd, 1H, J=7.8, 1.0 Hz), 8.25 (s, 1H), 8.41 (dd, 1H, J=4.8, 1.0 Hz); 13C NMR (CDCl3) δ 18.29, 18.37, 21.98, 23.60 (2 carbons), 27.53, 27.73, 42.81, 53.61, 57.69, 58.48, 123.28, 132.37, 133.15, 133.93, 139.23, 144.17, 146.13, 146.64, 154.10, 155.82; ES-MS m/z 420 (M+H). Anal. Calcd. For C21H33N5O2S.0.3CH2Cl2.0.5H2O: C, 56.34; H, 7.68; N, 15.42; S, 7.06. Found: C, 56.69; H, 7.45; N, 15.05; S, 6.76.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:81]2[CH:85]=[N:84][C:83]([O:86][CH2:87][CH2:88][O:89][C:90]3[CH:91]=[C:92]([CH2:96][NH2:97])[CH:93]=[CH:94][CH:95]=3)=[N:82]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:97][CH2:96][C:92]2[CH:93]=[CH:94][CH:95]=[C:90]([O:89][CH2:88][CH2:87][O:86][C:83]3[N:84]=[CH:85][NH:81][N:82]=3)[CH:91]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[C:19]1=2
Reactant: CCOC(=O)c1nc2scc(-c3ccncc3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccncc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-pyridin-4-yl-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 66 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (142.0 mg, 59%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>O1CCOCC1>[CH3:12][C:11]1[C:3]([N:2]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2ccoc2cc1N
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2ccoc2cc1-n1cccc1

Procedure:
2 ml of 6N hydrochloric acid are added to a mixture of 2.95 g (20 mmole) of 6-amino-5-methylbenzofuran, 3.17 g (24 mmole) of 2,5-dimethoxytetrahydrofuran and 50 ml of dioxane and the whole is boiled under reflux for 40 minutes. The whole is then concentrated in vacuo, the residue is taken up in methylene chloride and the organic phase is washed three times with water. The crude product remaining after drying and removal of the methylene chloride is chromatographed over silica gel with ether/petroleum ether. Subsequent distillation of the pure fractions in a bulb tube (105°, 5.10-2 torr) yields 5-methyl-6-(pyrrol-1-yl)-benzofuran in the form of a pale yellow oil.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15][CH3:16])[C@@H:13]([O:17]CC2C=CC=CC=2)[C@H:12]([CH2:25][OH:26])[O:11][CH2:10]1)C1C=CC=CC=1.N>CCOCC>[CH3:16][O:15][C@@H:14]1[C@@H:13]([OH:17])[C@H:12]([CH2:25][OH:26])[O:11][CH2:10][C@H:9]1[OH:8]
Reactant: CO[C@@H]1[C@@H](OCc2ccccc2)[C@H](CO)OC[C@H]1OCc1ccccc1
Agent: N
Solvent: CCOCC
Product: CO[C@@H]1[C@@H](O)[C@H](CO)OC[C@H]1O
Yield: 78.6 %

Procedure:
A solution of 2,4-di-O-benzyl-3-O-methyl-1,5-anhydro-L-glucitol (41.18 g, 115 mmole) in dry ether (80 ml) was added to a vigorously stirred solution of Na (15.8 g, 3.0 eq) in liquid ammonia under nitrogen atmosphere at -78° C. After 4 hr at the liquid ammonia boiling point (-33° C.), the blue reaction mixture was carefully quenched by the slow addition of MeOH until the blue color disappeared. After evaporation of the liquid ammonia, water-MeOH (1:1) mixture (500 ml) was added and the resulting solution was neutralized by passing through Dowex 50W×8 (ca. 500 ml) column. The column was washed thoroughly with water-MeOH (1:1) mixture (500 ml) and the combined water-MeOH solution was evaporated under reduced pressure to give a crude product (38 g) as a brown oil. The brown oil was purified by silica gel column chromatography [SiO2 : ca. 1 kg] with CHCl3 /MeOH (4:1) as an eluent to give 3-O-methyl-1,5-anhydro-L-glucitol (16.09 g, 90.4 mmole) as a yellow viscous oil in 78.6% yield; FAB-MS: m/z 179 (MH+); 1H-NMR, (CDCl3)d: 1.95 (1H,t,J=6 Hz), 2.10 (1H,d,J=4 Hz), 2.45 (1H,d,J=4 Hz), 3.13 (1H,t,J=9 Hz), 3.28 (1H,t,J=10 Hz), 3.31 (1H,ddd,J=4, 5 & 9 Hz), 3.54 (1H,d,J=4 & 9 Hz), 3.69 (3H,s), 3.66-3.80 (2H,m), 3.90 (1H,m), 4.0 (1H,dd,J=5.5 & 10 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:8])[S:5][C:6]=1[CH3:7].[C:9](OC=O)(=[O:11])C>>[Br:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([NH:1][CH:9]=[O:11])[N:3]=1
Reactant: CC(=O)OC=O
Reactant: Cc1sc(Br)nc1N
Product: Cc1sc(Br)nc1NC=O

Procedure:
4-Amino-2-bromo-5-methylthiazole is treated with formic-acetic anhydride (prepared as described in Example 12b) to give the title compound.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][C:47]4[S:48][CH:49]=[CH:50][CH:51]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[S:48]1[CH:49]=[CH:50][CH:51]=[C:47]1[CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCCCc4cccs4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCc1cccs1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 41.3 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[3-(2-thienyl)propyl]-1-piperidinecarboxamide (0.182 g, 0.230 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.095 mmol)
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[C:9]([C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:9]([C:13]1[CH:14]=[C:15]([N+:7]([O-:8])=[O:6])[C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Temperature: -15 °C

Procedure:
At −30° C. 4.84 g nitroniumtetrafluoroborate are added to a solution of 5.00 g 5-tert-butyl-2-hydroxy-benzaldehyde in 200 ml acetonitrile. The solution is heated to −15° C. within 1 h and then combined with ethyl acetate and saturated aqueous NaHCO3 solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with saturated aqueous saline solution, dried (MgSO4) and evaporated down. The residue is taken up in 2 ml of water and 40 ml concentrated acetic acid, and the resulting mixture is refluxed for 2 h. The cooled solution is poured into ice-cold water, and the precipitate formed is filtered off and dissolved in ethyl acetate. The organic solution is dried (MgSO4) and evaporated down. The oil remaining rapidly solidifies.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:20]=[C:19]([B:30]2[O:34][C:33](C)(C)C(C)(C)[O:31]2)[C:16]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:33]1[O:34][B:30]([OH:31])[C:19]2[CH:20]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:22]=[C:15]([O:14][CH3:13])[C:16]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC)c21
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a mixture of zinc powder (0.98 g, 15.0 mmol) in anhydrous THF (30 mL) was added TMSCl (0.39 mL, 3.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and cooled to 37° C. After addition of ethyl 2-bromoacetate (1.35 mL, 12.0 mmol), the reaction mixture was stirred at this temperature for an additional 30 min. To a solution of 2-methoxy-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.09 g, 3.0 mmol) in anhydrous THF (40 mL) was added dropwise the above prepared solution at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h before quenched by aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL×2) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/4) on silica gel to give the title compound as a yellow solid. (0.86 g, Y: 82.3%). MS (ESI) m/z=267 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]CC)=[C:11]([F:18])[CH:10]=2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:18])[CH:10]=2)[CH:7]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1F
Reaction time: 4 h
Yield: 96.5 %

Procedure:
4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene 4e (31.7 g, 92.3 mmol) was dissolved in 300 mL dichloromethane, followed by addition of boron tribromide (11.4 mL, 120 mmol) in an ice bath, then the reaction mixture was warmed and stirred for 4 hours. Thereafter, the reaction mixture was extracted with ethyl acetate (100 mL×4) after 300 mL saturated sodium carbonate solution was dropwise added slowly. The organic extract was washed with saturated sodium chloride solution (30 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound 4-[(5-bromo-2-chloro-phenyl)methyl]-2-fluorophenol 8a (28.1 g, white solid), yield: 96.7%. 1H NMR (400 MHz, CDCl3): δ 7.36-7.18 (m, 3H), 7.01-6.80 (m, 3H), 5.08 (br, 1H), 3.99 (s, 2H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[CH2:14]CC[CH2:11][CH2:10]1.[OH:15][C:16]1[CH:21]=[C:20]([CH3:22])[O:19][C:18](=[O:23])[C:17]=1[C:24](=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ICCCC.CN(P(N(C)C)(N(C)C)=O)C.Cl>C1COCC1>[OH:15][C:16]1[CH:21]=[C:20]([CH2:22][CH2:14][CH2:9][CH2:10][CH3:11])[O:19][C:18](=[O:23])[C:17]=1[C:24](=[O:33])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(O)c(C(=O)CCc2ccccc2)c(=O)o1
Reactant: C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c(C(=O)CCc2ccccc2)c(=O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
1.5 M LDA in cyclohexane (1.34 ml; 2 mmol; Aldrich) was added to 4-hydroxy-6-methyl-3-(3-phenylpropanoyl)-2-pyrone (258.27 mg; 1 mmol; Example 1.1) in 8.4 ml anhydrous THF, and the reaction mixture was stirred under N2 for 0.5 h at 0° C. 1-iodo-butane (136.8 μl; 1.2 mmol; Aldrich) and HMPA (167 ul; 0.96 mmol: Aldrich) were added sequentially under N2, and the reaction mixture was stirred under N2 for 2 h at 0° C. and 5 h at room temperature. The reaction mixture was acidified by addition of 1 N HCl (16 ml) and extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The product was isolated by chromatography on silica gel. Yield: 20%. MS (MALDI): calculated, m/z 315.2 (MH+); found, 315.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:13]=[CH:12][NH:11][C:6]=2[N:7]=[C:8]([NH2:10])[N:9]=1.Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:11]1[C:6]2[N:7]=[C:8]([NH2:10])[N:9]=[C:4]([Cl:3])[C:5]=2[CH:13]=[CH:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.618 g, 15.45 mmol) in anhydrous DMF (15 mL) at 0° C. is added slowly a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 11.86 mmol) in 5 mL of anhydrous DMF. The mixture is stirred at this temperature under N2 for 15 min, then (2-bromoethoxy)-t-butyldimethylsilane (4.0 mL, 18.64 mmol) is added at 0° C. The mixture is stirred at RT overnight. The reaction mixture is poured into water and extracted with ethyl acetate (EtOAc; 4×). The organic layer is dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash cromatography using EtOAc/cyclohexane (1/1) as eluent to yield 7-[2-(t-butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo [2,3-d]pyrimidin-2-amine as white needles: LC/MS (M+1=327). 1H NMR (CDCl3, 400 MHz) δ-0.08 (s, 6H), 0.84 (s, 9H), 3.88 (t, 2H, J=5.2 Hz), 4.17 (t, 2H, J=5.2 Hz), 4.89 (s, 2H, NH2), 6.35 (d, 1H, J=3.6 Hz), 6.96 (d, 1H, J=16 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (CDCl3) mixture of rotamers δ 10.20 (1H, br), 8.55 and 8.50 (1H, s), 7.34 and 7.10 (1H, s), 7.15-6.97 (4H, m), 5.21 and 4.98 (2H, s), 4.10 (2H, s), 3.64-3.41 (8H, m), 3.40 and 3.39 (3H, s), 3.34 and 3.32 (3H, s), 3.17 and 2.97 (3H, s); HRMS calcd for C25H29FN4O6+H+: 501.2149. Found: 501.2140.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=[CH:25][N:26]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=1)[CH:4]=O.[Si:36]([O:43][CH2:44][CH2:45][NH2:46])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[Si:36]([O:43][CH2:44][CH2:45][NH:46][CH2:4][C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[CH:24]=[CH:25][N:26]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=1)[CH:2]([CH3:35])[CH3:1])([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: CC(C)[C@@H](C=O)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)[C@@H](CNCCO[Si](C)(C)C(C)(C)C)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-3-methyl-2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)butanal (27 mg, 0.055 mmol) in DCE (1 mL) was added a solution of 2-(tert-butyldimethylsilyloxy)ethanamine (29 mg, 0.17 mmol) in THF (0.2 mL). The reaction was allowed to stir at ambient temperature for 15 minutes, at which point Na(OAc)3BH was added and the reaction allowed to stir at ambient temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous NaHCO3 and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined extracts were washed with brine, dried and concentrated to give (S)—N1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-N2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)butane-1,2-diamine. The crude was used in the next step without further purification. LCMS (APCI+) m/z 650.9 [M+H]+.