Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH:29]=[CH:28][C:27]=1[N+:38]([O-:40])=[O:39]>CN(C)C=O>[N+:38]([C:27]1[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[CH:31][C:26]=1[NH:15][CH:12]1[CH2:13][CH2:14][N:9]([CH:6]2[CH2:5][CH2:4][O:3][CH2:8][CH2:7]2)[CH2:10][CH2:11]1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
A stirred suspension of 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (diHCl salt of D9, 350 mg, 1.4 mmol) in dimethylformamide (6 ml) at room temperature under argon was treated with N,N-diisopropylethylamine 51 mg, 4.0 mmol), then stirred for 10 minutes before adding 2-fluoro-1-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzene (D55, 280 mg, 1.2 mmol) and heating at 75° C. for 36 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (20 g) eluting with 0-20% methanol/ethyl acetate to afford the title compound as a bright yellow solid (210 mg, 45%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][CH3:7])\[CH3:22])[CH3:17]
Reactant: CSc1ccccc1O
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1SC
Temperature: 23 °C
Yield: 76 %

Procedure:
Potassium t-butoxide (1.23 g, 0.011 mol) was added to a stirred solution of 2-methylsulfanyl-phenol (1.00 g, 0.007 mol) in tetrahydrofuran (15 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 0.94 g, 0.006 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.15 g, 72%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[O:40][C@H:41]1[C@H:50]([OH:51])[C@@H:49]([CH2:52][OH:53])[O:48][C@H:43]([O:44][CH2:45][CH:46]=[CH2:47])[C@@H:42]1[O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:62][O:63][C:64]1[CH:69]=[CH:68][C:67](O)=[CH:66][CH:65]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[O:40][C@H:41]1[C@H:50]([OH:51])[C@@H:49]([CH2:52][O:53][C:67]2[CH:68]=[CH:69][C:64]([O:63][CH3:62])=[CH:65][CH:66]=2)[O:48][C@H:43]([O:44][CH2:45][CH:46]=[CH2:47])[C@@H:42]1[O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCO[C@H]1O[C@H](COc2ccc(OC)cc2)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
Allyl 3-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-2-O-benzyl-α-D-glucopyranoside 14 (10.1 g, 12.1 mmol), 4-methoxyphenol (3.76 g, 30.3 mmol), and triphenylphosphine (4,77 g, 18.2 mmol) were combined in a flask, cooled to 0° C. before adding anhydrous CH2Cl2 (100 mL). This solution was stirred for 40 minutes and then a solution of diethylazodicarboxylate (DEAD) in toluene (40% by weight, 8.84 mL, 19.4 mmol) was added. The reaction mixture was stirred at 0° C. for 45 minutes, and then allowed to warm to room temperature overnight. The reaction mixture was diluted with CH2Cl2, washed with 1N NaOH (200 mL, 100 mL), 1 N HCl (200 mL), saturated NaHCO3 (200 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluted using an ethyl acetate:heptane step gradient (1:10→1:5→1:3) to give allyl 3-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-2-O-benzyl-6-O-(4-methoxyphenyl)-α-D-glucopyranoside 14 (7.81 g, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccncc2)cc1OC
Yield: 63.2 %

Procedure:
4-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 3.36 g, 63%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH:8]([CH3:10])[CH3:9])=[N:3]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[C:4]([CH:8]([CH3:10])[CH3:9])=[N:3]1
Reactant: O=C1CCCCC1
Reactant: CC(C)c1cc(N)n(C)n1
Solvent: CC(=O)O
Product: CC(C)c1nn(C)c(N)c1C1=CCCCC1
Reaction time: 8 h
Yield: 54 %

Procedure:
Under nitrogen atmosphere, to a 100 mL of round bottom flask were added the compound of Example 2B (5.2 g, 38 mmol) and 40 mL of glacial acetic acid. After the compound was dissolved with stirring, cyclohexanone (8.22 g, 76 mmol) was added. The resultant mixture was warmed to 50° C. The reaction was kept overnight. The reaction was stopped. Glacial acetic acid was rotary-evaporated. The resultant product was dissolved with ethyl acetate and washed to alkalescence with aqueous solution of sodium bicarbonate. The ethyl acetate layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and dried over MgSO4. The solvent was rotary-evaporated. The product was purified with column chromatography (eluant: petroleum ether:ethyl acetate=1:1) to give 4.5 g of the title compound. MS (ESI): m/z 220 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:30])[CH3:7]>C(Cl)Cl.O>[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[CH:17]=[CH:16][C:15]=1[NH:30][C:3](=[O:4])[CH2:2][Br:1])[CH3:7]
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NC(=O)CBr
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g (7.15 mmol, 1.1 eq.) bromoacetyl bromide in 10 mL of methylene chloride was added over 10 mins. to a stirred biphasic solution of 2.38 g (6.5 mmol, 1.0 eq.) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-β-alanine ethyl ester in 100 ml of methylene chloride and 30 mL of water cooled to 0° C. The reaction was complete in 1/2 hr. (TLC, 96 CH2Cl2 :4 MeOH, product Rf =0.71) and was partitioned between dilute aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to give 3.11 g (98%) of off white crystals of N-(5-(4-cyanobenzyloxy)-2-(bromoacetyl)aminobenzoyl)-β-alanine ethyl ester which was used unpurified but may be recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3, δTMS) 8.41(1H,d,ArH), 7.60 (4H,abq,ArH), 7.02(2H,d,ArH), 6.98(1H,t,NH), 5.12 (2H,s,ArCH2O),4.16 (2H,q,COOCH2), 3.97 (2H,s,CH2Br), 3.68 (2H,q,NCH2), 2.61 (2H,t,CH2COO), 1.25 (3H,t,CH3). IR (KBr): 3389(NH), 3355(NH), 2226(CN), 1735(ester), 1675,1642(amides), 1609,1523,1423,1244,1184,819. MS (FAB, M+H+) cald for C22H22N3O5Br 488.3, found (M+H+) 489.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:28]#[N:29].[H][H]>CCO.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:3]=1[C:28]#[N:29]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(OCc3ccccc3)cc2)c(C#N)c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Yield: 85 %

Procedure:
A mixture of compound 31E (1.3 g, 3.33 mmol) and Pd/C (0.071 g) in EtOH (15 mL) was hydrogenated with a balloon of hydrogen at rt for 6 hours. The solvent was removed, and residue was purified by flash column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 0.85 g of the desired product 31F: 1H NMR (DMSO-d6): δ 9.88 (s, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.64 (s, 2H), 6.87 (d, J=8.9 Hz, 2H), 1.59 (s, 9H). MS (DCI(+)): m/z 301 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH2:15])=[CH:8][C:7]=1[CH3:16])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.O>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH:15][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:8][C:7]=1[CH3:16])[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Nc1c(C)cc(N)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-Amino-2-methyl-6-nitro-phenyl)-carbamic acid ethyl ester (0.50 g) and 4-trifluoromethyl-benzaldehyde (0.29 mL) were dissolved in ethanol (10 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (0.3 g) and acetic acid (0.5 mL) were added to the precipitate dispersed in methanol (10 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (50 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (100 mL) to furnish 0.47 g (75% yield) of the title compound as a yellow solid. LC-MS (m/z) 398 (MH+); tR=3.18, (UV, ELSD) 86%, 94%. 1H NMR (500 MHz, DMSO-d6): 1.20 (1,3H), 2.10 (s, 3H), 4.05 (m, 2H), 4.45 (m, 2H), 6.75 (m, 1H), 6.90 (m, 1H), 7.55 (m, 2H), 7.73 (m, 2H), 8.75 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH:13]([CH3:15])[CH3:14])[C:9](=O)[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH:13]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][Cl:11])([CH3:15])[CH3:14]
Reactant: CC(C)N(Cc1ccccc1)C(=O)CCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CCCl)Cc1ccccc1
Yield: 50.2 %

Procedure:
A solution of 7.66 g of the N-benzyl-2-chloro-N-isopropylacetamide in 20 ml of dry diethyl ether was added dropwise to a suspension of 1.29 g of lithium aluminum hydride in 300 ml of dry diethyl ether with stirring under ice-cooling, and the mixture was heated under reflux for 4 hours. After the reaction mixture was cooled, and to the cooled reaction mixture was added dropwise water with stirring under ice-cooling. Insoluble materials were filtered off. The filtrate was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluent: chloroform) to obtain 3.61 g of 2-(N-isopropylbenzylamino)ethyl chloride in an oil.
Reaction SMILES: [CH2:1]([C:11]1[C:16](N)=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+:18]([C:21]1C=C(S(O)(=O)=O)C=[CH:25][CH:26]=1)([O-])=O.S(=O)(=O)(O)O.B(O)(O)O>OCC(CO)O.[Fe]=S.O>[CH2:1]([C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[N:18]=[CH:21][CH:26]=[CH:25]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccccc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: S=[Fe]
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: OCC(O)CO
Solvent: O
Product: CCCCCCCCCCc1ccc2ncccc2c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 30.2 %

Procedure:
12.5 g of 6-decylaniline, 5.0 g of 3-nitrobenzenesulfonic acid, 1.5 g of iron (II) sulfide, 10 ml of sulfuric acid, and 2.8 g of boric acid were dissolved in 13 ml of glycerin (glycerol), followed by stirring for 6 hours at 140° C. After the reaction, the reaction mixture was poured into water and alkalinized by adding thereto an appropriately amount of sodium hydroxide aqueous solution, followed by extraction with diethyl ether. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography to obtain 2.0 g of 6-decylquinoline.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in AMY (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine (3.46 g, 6.79 mmol, 96% yield). MS ESI: [M+H]+ m/z 510.0.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]>C1COCC1.O1CCOCC1.O=[Mn]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([C:15](=[O:16])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(Br)cc1C(=O)C#Cc1ccccc1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgC1 in THF (1.25 ml) was added drop wise at 0° C. under N2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [1H-NMR (CDCl3) 7.68 (d, 1H, J=2.49 Hz); 7.46-7.43 (m, 2H); 7.36 (dd, 1H, J=8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1H, J=6.77 Hz); 5.79 (d, 1H, J=5.23 Hz); 4.64-4.58 (m, 1H); 3.13 (d, 1H, J=5.91 Hz); 1.37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. 1H-NMR (CDCl3) 8.00 (d, 1H, J=2.61 Hz); 7.61-7.52 (m, 3H); 7.44-7.35 (m, 3H); 6.88 (d, 1H, J=8.91 Hz); 4.68-4.60 (m, 1H); 1.36 (d, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CC(=O)[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C.CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: BrCCCCOCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)CCCCCOCCc1ccccn1
Yield: 83.3 %

Procedure:
A mixture of 2-[2-[(4-bromobutyl)oxy]ethyl]pyridine (6.2 g), 2,4-pentanedione (3.61 g), potassium carbonate (4.75 g) and potassium iodide (3.95 g) in ethanol (125 ml) was stirred and heated overnight under reflux. The solids were removed by filtration and the filtrate evaporated to leave a dark brown semi-solid. Addition of ether (200 ml) and filtration of the solid produced a brown solution which was evaporated to give a brown oil (4.71 g). Purification by FCC eluting with ether-hexane (1:1→3:1) gave the title compound as a pale yellow oil (1.93 g).
Reaction SMILES: [Br:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:19])=[O:4]
Reactant: CO
Reactant: O=C(O)C(Br)COCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Br)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 2-bromo-3-[(phenylmethyl)oxy]propanoic acid (6 g, 23.2 mmol) in methanol (40 ml) at rt under argon was treated with thionyl chloride (1.7 ml, 23.2 mmol) and the reaction was then stirred at rt for 3 h and then evaporated to give product as a yellow oil (6.3 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:32])(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 4-(benzyloxycarbonylaminomethyl)-1-Boc-piperidine (0.360 g, 1.03 mmol) in DMF (10 mL) was treated with sodium hydride (60%, 0.050 g, 1.25 mmol). After 0.5 h, methyl tosylate (0.18 mL, 1.20 mmol) was added and the mixture heated to 6° C. After 12 h, the mixture was poured into EtOAc and saturated aqueous sodium bicarbonate. The combined extracts were washed with water, brine and concentrated to afford 0.300 g (79%) the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 50.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.35 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([NH:25][CH3:26])=[O:24])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([O:19][CH2:18][C:5]1[N:4]([C:20]2[CH:21]=[C:22]([C:23]([NH:25][CH3:26])=[O:24])[CH:27]=[CH:28][C:29]=2[CH3:30])[C:3](=[O:31])[C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:6]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1ccc(C)c(-n2c(CO)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(C)c(-n2c(COC(C)=O)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide, (225 mg, 0.50 mmol) stirred in CH2Cl2 was added pyridine (55 μL, 0.69 mmol). To the resulting homogeneous solution was then added acetic anhydride (47 μL, 0.51 mmol). The mixture was stirred at rt for 3 h. Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL, 1.05 mmol) were then added and the reaction was allowed to stir overnight at rt. The reaction was then quenched with 1N NHCl4 and diluted with CH2Cl2. The layers were separated and the organic layer was then extracted with CH2Cl2 (3×). The organics were then combined, dried, and concentrated in vacuo. The residue was then triturated with Et2O and filtered to give (150 mg, 61%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.87 (app d, J=7.8 Hz, 1H), 7.74-7.69 (m, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.40 (app t, J=8.1 Hz, 1H), 7.28-7.19 (m, 1H), 6.91 (s, 1H), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C24H22N2F2BrO5 requires 535.0675).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:44]=[N:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cn1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 6-methoxypyridine-3-boronic acid were treated in a manner similar to Example 168 to give the target compound. APCI-Mass m/Z 478/480 (M+H).