Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:10][CH2:11][CH:12]([CH2:19][CH3:20])[CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O1CCCC1.[C:35](Cl)(=[O:45])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CCCC>O>[CH2:1]([O:10][CH2:11][CH:12]([CH2:19][CH3:20])[CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][O:16][C:35](=[O:45])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN(C)c1ccccc1
Reactant: CCCCCCCCCOCC(CC)CC(CC)CO
Reactant: CCCCCCCCCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC(CC)CC(CC)COCCCCCCCCC
Temperature: 25 °C
Yield: 43 %

Procedure:
To a 1-L three-neck flask provided with a stirrer, thermometer, condenser and dropping funnel with a gas inlet tube, 260 g (0.91 mol) of 5-nonyloxy-2,4-diethyl-1-pentanol, 112 g (0.92 mol) of N,N-dimethylaniline and 150 mL of tetrahydrofuran were put, to which 197 g (0.9 mol) of decanoyl chloride was dropped and stirred at the room temperature under nitrogen stream. After the dropping, the mixture was heated to 45 degrees C. and stirred for four hours. After the reaction, a small amount of distilled water was added to the reactant to dissolve the generated white solid. The reactant was transferred to a separating funnel. After an aqueous layer was separated while an organic layer was added with 150 mL of tetrahydrofuran, washed with 300 mL of saturated saline and with 20 mL of dilute sulfuric acid and then washed with distilled water until the organic layer became neutral. The obtained organic layer was dried with magnesium sulfate. After the solvent was removed by an evaporator, the organic layer was subjected to vacuum distillation to be fractioned. The obtained fraction was subjected to mass analysis, NMR analysis and IR analysis, whereby the fraction was confirmed to be a monoester compound (target compound) (mass analysis result: m/z=468). The obtained amount was 185 g (a yield of 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][O:18][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (0.4300 g, 1.02 mmol), 4-dimethylaminopyridine (0.0783 g, 0.64 mmol), triethylamine (0.8 mL, 5.74 mmol), and tert-butyldimethylsilyl chloride (0.2870 g, 1.90 mmol) in CH2Cl2 was stirred for 16 h at rt. After the solvents were removed in vacuo, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to give 0.2856 g of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a solid. LC-MS Method 1 tR=2.49 min, m/z 560, 558 (MNa+), 538, 536 (MH+), 494, 492; 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 4H), 7.10-7.05 (m, 2H), 6.78 (d, J=8.5 Hz, 2H), 5.63 (q, J=7.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.44-3.38 (m, 1H), 2.96-2.90 (m, 1H), 2.78-2.27 (m, 3H), 2.18-2.04 (m, 2H), 1.52 (d, J=7.3 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −114.99 (m).
Reaction SMILES: C1([CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])[OH:5])CC1.[H-].[Na+].[N+]([C:19]1[CH:20]=[C:21](S(OC[C@@H]2OC2)(=O)=O)[CH:22]=[CH:23][CH:24]=1)([O-])=O.[OH2:33]>CN(C)C=O>[CH:22]1([CH:21]([O:5][CH2:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])[C@H:20]2[CH2:19][O:33]2)[CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: O
Reactant: COc1ccccc1C(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COC(C1CC1)[C@H]1CO1
Reaction time: 0.05 h

Procedure:
(Cyclopropyl)(2-methoxyphenyl)methanol (3.57 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (50 ml), sodium hydride (960 mg, 60% oil) was added and the mixture was stirred for 3 min. To the resulting mixture was added (R)-glycidyl 3-nitrobenzenesulfonate (6.22 g) and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12) to give the title compound (1.10 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.C(Cl)(Cl)Cl.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 77 °C
Yield: 71.1 %

Procedure:
Ethyl (6-bromo-2-nitropyridin-3-yloxy)acetate (41 g, 0.132 mole) was dissolved in glacial AcOH (400 mL) and the solution was heated to 77° C. with mechanical stirring. Iron powder (50 g, 0.89 mole) was added portionwise over 2 hr, so that the temperature did not rise above 90° C. The mixture was mechanically stirred and heated at 77° C. for 10 hr then was cooled to room temperature and diluted with 1:4 EtOAc/CHCl3 (1 L). The mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1 kg; 0-10% EtOAc/CHCl3) to afford the title compound (21.5 g, 70%): MS (ES) m/e 229 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].CC1C=CC=C(C)N=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a mixture of 5.0 g of 3-[(2,6-difluorobenzyl)oxy]pyridin-2-amine, 4.1 ml of ethyl 2-chloroacetoacetate, 3.5 ml of 2,6-dimethylpyridine, and 50 ml of toluene was stirred at 130° C. for 24 hours. After leaving to be cooled to room temperature, the reaction mixture was washed with water, a 1 M aqueous sodium hydroxide solution, a 10% aqueous citric acid solution, and a saturated aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 5.47 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[S:5][CH:6]=1.CC[N:12](C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:12][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:8])[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cc(Br)cs1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NN1CCOCC1)c1cc(Br)cs1

Procedure:
To a solution of 4-bromo-2-thiophenecarbonyl chloride (1.0 g, 4.4 mmol) in DCM (10 ml) cooled to 0° C. was added DIPEA (0.85 ml, 4.8 mmol) and morpholine (0.4 g, 4.6 mmol) dropwise. Stirring was continued until complete consumption of the starting material was observed by LC-MS. The reaction was quenched by the addition of water, which was washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired compound without need for further purification (1.2 g, 100%). δH (500 MHz, CHLOROFORM-d) 7.38 (1H, s), 7.18 (1H, s), 3.63-3.83 (8H, m); TR=1.52 min.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH2:38]([O:40][C:41](=[O:45])[CH2:42][CH2:43]N)[CH3:39].C([N:48](CC)CC)C>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:48][CH:42]([CH3:43])[C:41]([O:40][CH2:38][CH3:39])=[O:45])=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCN
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Product: CCOC(=O)C(C)NC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 70.3 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF), β-alanine ethyl ester hydrochloride (77 mg, 0.5 mmol, 1.0M in DMF) and triethylamine (51 mg, 0.5 mmol, 1.0M in DMF) were combined to give 42 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28](=[O:37])[NH:29][C:30](=[NH:36])[N:31]2[CH:35]=[CH:34][CH:33]=N2)=[C:10]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:18])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([NH:29][C:30]([NH:31][CH2:35][CH2:34][CH2:33][OH:42])=[NH:36])=[O:37])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[O:18])=[CH:25][CH:26]=2)[S:11][CH:12]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of 4-(4-(2-chloro-phenyl)-3-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-thiophen-2-yl)-N-(1-ethyl-propyl)-benzamide (0.87 g, 0.16 mmol) in CH2Cl2 (2 mL) was added 3-aminopropanol (0.037 g, 0.040 mL, 0.50 mmol) and diisopropyl ethylamine (0.064 g, 0.087 mL, 0.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(1-ethylpropyl)benzamide (0.047 g) as a white solid. mp 109-110° C. MS (ES) m/z 541.12 ([M+H]+); Anal. Calcd for C28H33ClN4O3S.0.60 H2O: C, 60.93; H, 6.25; N, 10.15. Found: C, 60.57; H, 6.07; N, 10.02.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:19]([Br:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br>CN(C)C=O.CCOCC.O>[BrH:26].[C:20]1([CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CN1CCC(c2nn(Cc3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a stirred suspension of 0.86 g of sodium hydride (50% oil dispension) in 50 ml of dimethylformamide under nitrogen, was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 15 ml of hot dimethylformamide. After stirring one hr at ambient temperature, 2.6 g of benzyl bromide in 5 ml of dimethylformamide was added. The reaction mixture was stirred at ambient temperature for 15 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated in vacuo to yield an oil. The oil was dissolved in ether and gaseous hydrogen bromide was passed through the solution to yield an oily material. The oily material was triturated with boiling ethyl acetate. The solid was collected and recrystallized from absolute ethanol to yield 2.4 g (44.3%) of product, mp 218°-220° C.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(=O)(O)[O-].[Na+]>[CH3:9][N:10]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][OH:13]
Reactant: CNCCO
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCO)c1ccncc1

Procedure:
A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling to rt the crude mixture was added slowly to saturated solution of sodium bicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL), the combined EtOAc was washed with brine (50 mL), dried (Na2SO4) and removed in vacuo to give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]1([C:15]2[CH:24]=[C:23]([OH:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:9]1([C:15]2[CH:24]=[C:23]([O:25][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cc(-c2ccccc2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1cc(-c2ccccc2)nc2ccccc12

Procedure:
Ethyl 2-bromopropionate (4.3 cc) is added dropwise to a stirred suspension of 2-phenyl-4-quinolinol (6.63 g) and potassium carbonate (8.3 g) in methyl ethyl ketone (200 cc). The mixture is heated for three hours under reflux. The mixture is brought back to room temperature (approximately 20° C.), the insoluble material drained and the solvents removed under reduced pressure. The residue is taken up with 40°-70° petroleum ether (100 cc) and drained. Ethyl 2-[(2-phenyl-4-quinolyl)oxy]propionate (9.2 g), m.p. 80° C., is thereby isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, 4-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=481.1 [M−H]−.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cncc(Br)c1
Reaction time: 16 h
Yield: 99 %

Procedure:
Add trimethylsilylacetylene (54.6 mL, 389.4 mmol) to a stirred mixture of 3-bromo-5-iodopyridine (100 g, 354 mmol) in triethylamine (800 mL) and acetonitrile (800 mL). Purge the system with nitrogen and add bis(triphenylphosphine)palladium(II) dichloride (3.54 mmol, 2.48 g) and stir for 16 h. Concentrate and suspend the residue in 1800 mL of hexanes. Stir for 2 h, filter and concentrate to give the title compound as a brown solid (92g, 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].CN(CCN(C)C)C.[Li].[I:23]I>O1CCCC1.C(OCC)C>[I:23][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A solution of 2,2-dimethyl-N-pyridin-3-ylpropanamide [(1 g, 5.61 mmol), J. Org. Chem, 48(20), 3401;1998]in tetrahydrofuran (10 mL) and diethyl ether (30 mL) was cooled to −78° C. and TMEDA (2.1 mL, 14 mmol) and nbutyl lithium (1.6M in hexane, 8.8 mL, 14 mmol,) were added dropwise. The mixture was stirred for 15 minutes and was then warmed to −10° C. and stirred for a further 2 hours. The reaction mixture was again cooled to −78° C. and a solution of iodine (3.56 g, 14 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting slurry was stirred at −78° C. for 2 hours. The mixture was warmed to 0° C. and was quenched with saturated aqueous sodium thiosulfate solution (50 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 50:50 afforded the title compound as a yellow solid in 38% yield, 655 mg.
Reaction SMILES: [C:1]([O:4][C:5]([C:7]([F:10])([F:9])[F:8])=[CH2:6])(=[O:3])[CH3:2].[Cl:11][SiH:12]([Cl:14])[Cl:13].CCCCCCC>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH:5]([C:7]([F:10])([F:9])[F:8])[CH2:6][Si:12]([Cl:14])([Cl:13])[Cl:11])(=[O:3])[CH3:2]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=C(OC(C)=O)C(F)(F)F
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: CC(=O)OC(C[Si](Cl)(Cl)Cl)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Trifluoromethyl)ethenyl acetate (Aldrich, 188.0 grams, 1.22 mole), trichlorosilane (80.6 grams, 0.60 mole), and 200 ml heptane were placed in a round bottom flask equipped with a water condenser and nitrogen inlet. Platinum(O)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylene (10 ml) was added to this solution and heated to reflux for 18 hours. Afterwards, the solution was cooled to room temperature and additional portions of trichlorosilane (80.6 grams, 0.60 mole) and platinum complex (5 ml) were added and heated to reflux for 48 hours. Proton NMR of the solution indicated about 75% conversion. A third portion of trichlorosilane (67.7 grams, 0.50 mole) and platinum complex (5 ml) were then added and the solution heated to reflux for 48 hours. Solvents were distilled off at atmospheric pressure and the residue was fractionally distilled under reduced pressure. 2-Acetoxy-3,3,3-trifluoropropyltrichlorosilane (251.7 grams) (1.A) was collected between 100–125° C. at 20 mm pressure as a clear liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]3[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]3=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CC(C)n1ncc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Product: CC(C)n1ncc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)phenol (b) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][S:14](=[O:17])(=[O:16])O[S:12](=[O:19])(=[O:18])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:27]2[S:12](=[O:18])(=[O:19])[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][S:14]2(=[O:16])=[O:17])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(C2CS(=O)(=O)OS(=O)(=O)C2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CN2S(=O)(=O)CC(c3ccc([N+](=O)[O-])cc3)CS2(=O)=O)cc1

Procedure:
A solution of 4-(4-nitro-phenyl)-[1,2,6]oxadithiane 2,2,6,6-tetraoxide (as prepared in the previous step) is treated with 4-methoxy-benzylamine according to the procedure of Example 2, step (c) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]12[CH2:27][CH:23]([CH:24](O)[CH2:25]1)[CH:22]=[CH:21]2>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([O-:17])=[O:16])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:20]12[CH2:27][CH:23]([CH:22]=[CH:21]1)[CH2:24][CH2:25]2
Reactant: O=C(O)C=Cc1ccc(OCc2ccccc2)cc1
Reactant: OC1CC2C=CC1C2
Solvent: Cc1ccccc1C
Product: C1=CC2CCC1C2
Product: O=C([O-])C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 190 °C
Reaction time: 24 h

Procedure:
The 4-benzyloxy-cinnamic acid (5 g, 19.7 mmol), norbornene-5-ol (19 mmol) and Zr(AcAc) (0.2 mol. %) were put in xylene and stirred at 190° C. for 24 hours. Then, the reaction mixture was washed with 1M HCl and 1M NaHCO3 aqueous solutions and removed of the solvent to obtain a yellowish solid, 4-benzyloxy-cinnamate-5-norbornene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C)[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:14](Cl)(=O)[C:15](Cl)=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([Cl:11])=[C:6]([C:7]([C:15]2[CH:14]=[CH:6][CH:10]=[CH:2][CH:3]=2)=[O:9])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Br)cc(O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 208.2 %

Procedure:
To a suspension of compound 56 (6.0 g, 22.6 mmol) in CH2Cl2 (100 mL) were added oxalyl chloride (2.4 mL, 27.1 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with benzene (100 mL) and cooled to 0° C. To the reaction mixture was added AlCl3 (6.9 g, 52.0 mmol) portionwise at 0° C. The mixture was stirred at 90° C. for 15 hours. The mixture was cooled to rt and evaporated in vacuo. The residue was cooled to 0° C. and aq. 1N HCl solution was added. The mixture was extracted with EtOAc (150 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 166 (7.33 g, quantitative yield).