Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[ClH:28].O1CCOCC1>C(O)C>[ClH:28].[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
7-Nitro-1,2,3,4-tetrahydroisoquinoline (5.78 g) was dissolved in ethanol (400 ml), triethylamine (7.8 ml) and ethyl bromoacetate (4.5 g) were added, and the mixture was heated and refluxed for 1 hour. Most of the solvent was distilled off under reduced pressure, concentrated residue was extracted with ethyl acetate and the extracted solution was dried with anhydrous magnesium sulfate. The solvent distilled off under reduced pressure and the crude product obtained was purified by silica gel column chromatography using a solvent mixture, ethyl acetate:n-hexane=1:3, as a developer. The compound obtained was treated with a hydrochloric acid/dioxane solution to obtain ethyl 7-nitro-1,2,3,4-tetrahydro-isoquinoline-2-acetate hydrochloride (4.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[N:8]=[C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]2)[CH:6]=1)=O.[CH2:38]([NH2:43])[CH2:39][CH2:40][CH2:41][CH3:42].[C-]#N.[Na+]>>[CH2:13]([O:12][C:10]([N:9]1[C:5]([C:3](=[O:2])[NH:43][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:6][C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:36])[F:35])[CH2:22][CH2:21]2)=[N:8]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1C(=O)OCc1ccccc1
Reactant: CCCCCN
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of above 3-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]-pyrazole-1,5-dicarboxylic acid 1-benzyl ester 5-methyl ester (0.800 g, ca. 1.5 mmol), amylamine (3.0 mL) and sodium cyanide (0.150 g, 3.0 mmol) was stirred at room temperature overnight and then purified by column chromatography to give the title compound (0.238 g, 10% in 2 steps). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.5 Hz, 1H), 7.61-7.49 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.17 (m, 5H), 5.93-5.85 (m, 2H), 5.56 (s, 2H), 3.98-3.84 (m, 2H), 3.33-3.05 (m, 8H), 1.57-1.44 (m, 2H), 1.31-1.18 (m, 4H), 0.86 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 159.7, 157.0, 137.7, 136.3, 134.6, 132.2, 129.2, 128.3, 127.6, 127.4, 127.2, 127.1, 126.6, 126.2, 125.4, 92.2, 53.9, 48.1, 47.8, 46.4, 41.0, 39.5, 29.1, 28.9, 22.3, 13.9. MS (ES+) m/z 572.0 (M+1). m.p. 58-61° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](=O)[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>CO.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26](/[C:28](=[N:33]/[OH:34])/[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: NO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(C)=O)[nH]2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(/C(C)=N/O)[nH]2)c1
Yield: 41.9 %

Procedure:
1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)ethanone (117 mg, 0.26 mmol) synthesized in Example (15c) was dissolved in methanol (6 mL), and hydroxylamine hydrochloride (37 mg, 0.53 mmol) and sodium acetate (26 mg, 0.32 mmol) were added, followed by heating to reflux for 6 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 mL), washed with water and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired product (50 mg, yield 41%) as a white solid.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[CH:14]1([CH2:13][N:9]2[C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]=3[C:11]([I:12])=[CH:10]2)[CH2:16][CH2:15]1
Reactant: N
Reactant: Clc1ncnc2c1c(I)cn2CC1CC1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2CC1CC1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (394.8 mg, 1.184 mmol) in dioxane (3 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈1 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=0.36-0.43 (m, 2H), 0.58-0.66 (m, 2H), 1.19-1.29 (m, 1H), 4.03 (d, J=6.8 Hz, 2H), 5.63 (brs, 2H), 7.19 (s, 1H), 8.27 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.02 (2C, −), 11.28 (+), 48.46 (Cquart), 49.19 (−), 103.96 (Cquart), 128.70 (+), 150.03 (Cquart), 152.05 (+), 156.88 (Cquart). MS (ES+): m/z 315.1 (100) [MH+]. HPLC: tR=2.3 min (OpenLynx, polar—5 min).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:14]([O:19][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)CCO
Agent: [Na]
Product: CC(C)CCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:27])[NH:14][C@@H:15]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:27])[NH:14][C@@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCNC2)C1

Procedure:
To a solution of [(R)-1-((R)-1-benzyl-pyrrolidin-3-ylcarbamoyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in ethanol under an inert atmosphere of argon is added palladium hydroxide on carbon. The reaction mixture is purged with argon and placed under an atmosphere of hydrogen for over night. The mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: BrCCCCBr
Reactant: CCOC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OCCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-(4-hydroxy-2-nitrophenoxy)acetate 9 (0.17 g, 0.0007 mol) in 10 mL acetone was added potassium carbonate (0.39 g, 0.0028 mol). The reaction mixture was stirred at room temperature for 10 min Then 1,4-dibromobutane 10 (0.33 mL, 0.0028 mol) was added. The resulting mixture was heated at reflux for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Acetone was evaporated and the residue was diluted with water, extracted with ethyl acetate and dried over sodium sulfate to give ethyl 2-(4-(4-bromobutoxy)-2-nitrophenoxy)acetate 11 which was purified by silica gel column chromatography using 0-20% gradient of hexane and ethyl acetate. Yellow oil (0.52 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=6.8 Hz, 3H); 1.91-1.98 (m, 2H); 2.02-2.09 (m, 2H); 3.48 (t, J=6.8 Hz, 2H); 3.99 (t, J=6.0 Hz, 2H); 4.26 (q, J=6.8 Hz, 2H); 4.70 (s, 2H); 6.99-7.02 (m, 2H); 7.38 (d, J=3.2 Hz, 1H).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.[H-].[Na+]>>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][N:2]2[CH2:3][CH2:4][CH2:5][S:1]2(=[O:7])=[O:6])[CH:12]=[N:11][CH:10]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=S1(=O)CCCN1
Agent: [H-]
Agent: [Na+]
Product: O=S1(=O)CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-12 [B], isothiazolidine 1,1-dioxide was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a light yellow oil. MS: 292.8 and 290.9 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCCN2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 43.4 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), 4-(2-aminoethyl)morpholine (Aldrich Chemical Company) (0.270 g, 2.06 mmol) and K2CO3 (0.36 g, 2.60 mmol) in H2O (2.5 mL) to give crude pink solids. Recrystallization from EtOAc/MeOH gave 0.060 g (43%) of the title compound as a white solid. Mp: >280° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.39 (s, 3), 3.61 (t, 4, J=4.5), 3.65 (q, 2, J=6.1), 4.04 (s, 2), 6.75 (s, 1), 6.81 (br s, 1), 7.38 (t, 1, J=7.4), 7.51 (t, 2, J=7.6), 7.78 (d, 2, J=7.6), 11.39 (s, 1). 13C NMR (CD3OD, 100 MHz): δ 26.3, 39.2, 55.9, 60.1, 68.8, 99.9, 127.3, 128.3, 130.6, 131.2, 134.0, 143.1, 149.8, 151.1, 161.5. MS m/z: 338 (M+1). Anal. Calcd for C19H23N5O.0.25H2O: C, 66.74; H, 6.93; N, 20.48. Found: C, 66.84; H, 6.83; N, 20.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:37])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:36])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:35])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:31]([C:30]([CH3:34])=[CH:29][CH2:28][CH2:27][C:26]([CH3:35])=[CH:25][CH2:24][CH2:23][C:22]([CH3:36])=[CH:21][CH2:20][CH2:19][C:18]([CH3:37])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:33])=[O:32]
Reactant: COc1c(C)cc(O)c(OC)c1OC
Reactant: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: COc1c(C)c(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
5 g of 2,3,4-trimethoxy-5-methylphenol was dissolved in 10 ml of benzene and 6 g of silica gel (Wako gel C-200) and 3 g of zinc chloride were added thereto. 3 g of 16-hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid dissolved in 5 ml of benzene was added to the above solution. After reacting at room temperature for 30 min, the reaction mixture was filtered and the precipitate was washed with ethyl ether while the filtrate was washed with water, dried over magnesium sulfate anhydride and concentrated. The concentrate was purified by means of silica gel chromatography with the use of ether/n-hexane as the eluent to give 2.1 g of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)=[O:15])=[C:11]([NH:24][C:25]([C@H:27]3[CH2:32]C[C@H](NC)[CH2:29][CH2:28]3)=[O:26])[C:10]=2[CH:35]=1)=[O:5].C(Cl)(=[O:38])C.[CH2:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])C.C(=O)([O-])O.[Na+]>ClCCl>[C:43]([N:42]([C@H:45]1[CH2:46][CH2:32][C@H:27]([C:25]([NH:24][C:11]2[C:10]3[CH:35]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=[CH:8][C:9]=3[O:13][C:12]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:26])[CH2:28][CH2:29]1)[CH3:40])(=[O:38])[CH3:44]
Reactant: CC(=O)Cl
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)OC)cc23)CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(C)=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-5-methoxycarbonyl-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (1.50 g) obtained in Example 218 is suspended in dichloromethane (80 ml), and thereto are added acetyl chloride (307 μl) and triethylamine (1.60 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for 2 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform, washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform) to give the title compound (1.51 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23].O.Cl>[OH-].[Na+].O1CCOCC1>[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)c(C)c1
Yield: 45.3 %

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in aqueous sodium hydroxide (10 ml)-dioxane (10 ml), and dioxane (5 ml) solution of mesitylenesulfonylchloride (2.19 g, 10 mmole) was added dropwise to the solution while cooling and stirring while keeping pH value thereof to 10 to 11 with 1N aqueous sodium hydroxide. After that; the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N hydrochloric acid while cooling and stirring to precipitate white solid material. The material was dissolved in 0.5N aqueous sodium hydroxide and the solution thus obtained was crystallized by addition of 1N aqueous hydrochloric acid to give N-mesitylenesulfonyl-L-alanyl-L-proline yield: 1.67 g, 45.3%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.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>[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cnc(Cl)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2ccccc2)cc1N
Yield: 62.1 %

Procedure:
Phenylboronic acid (188 mg, 1.5 mmol, 1.1 equiv.) and 11 (200 mg, 1.4 mmol, 1.0 equiv.) were dissolved in benzene (5 mL). Aqueous Na2CO3 (1 mL) was then added, followed by Pd(PPh3)4 (324 mg, 0.28 mmol, 0.2 equiv.). The resulting mixture was refluxed for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. The organic extract was dried over Na2SO4 and the solvent evaporated. The crude material was purified by reverse phase HPLC (Acetonitrile/water/TFA), to give 12 as a colorless solid (160 mg, 0.87 mmol, HPLC Rt=3.373 minutes; FIA ES+ 185.1, ES− not observed).
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.CC[O:27]C(C)=O.CCCCCCC.O>>[C:19]([O:18][C:17]([N:16]([CH3:24])[C@@H:6]([C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)[C:2]([OH:1])=[O:27])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(C)=O
Reactant: C[C@H](CO[C@H]1CCOC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCCCCCC
Product: C[C@H](CO[C@H]1CCOC1)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A flask was charged with 2.16b (50 mg, 0.15 mmol), NalO4 (189 mg, 0.88 mmol, 6 equiv.) and EtOAc/heptane/water (1.5 mL/0.5 mL/2 mL). With vigorous stirring, RuCl3 (6 mg, 0.03 mmol, 0.2 equiv) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of saturated aqueous NaHSO3 solution and the mixture was extracted with EtOAc. The combined organic layers was washed with saturated aqueous NaHSO3 solution, brine, dried over Na2SO4 and concentrated to give product 2.16c (34 mg, 73% yield). MS (m/z): 318 [M+1].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][O:10][CH2:11][C:12](Cl)=[O:13]>N1C=CC=CC=1>[CH3:9][O:10][CH2:11][C:12]([NH:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([NH:8][C:12](=[O:13])[CH2:11][O:10][CH3:9])[CH:2]=1)=[O:13]
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(N)c1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cccc(NC(=O)COC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of m-phenylenediamine (5.41 g) in pyridine (100 ml) is added dropwise methoxyacetyl chloride (10 ml). The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (9.89 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8](C(F)(F)F)=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].BrC1C=CC([O:23][C:24]([F:27])([F:26])[F:25])=C(F)C=1.C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:23][C:24]([F:27])([F:26])[F:25])=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Br)ccc(C(F)(F)F)c1F
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Br)ccc(OC(F)(F)F)c1F
Reaction time: 2 h

Procedure:
2-Bromo-6-fluoro-5-trifluoromethylbenzoic acid 50 mmol of 4-bromo-2-fluoro-1-trifluoromethoxybenzene [105529-58-6] are added at −75° C. to a solution of 52.5 mmol of diisopropylamine and 52.5 mmol of n-butyllithium (1.6 M solution in n-hexane) in 100 ml of dry tetrahydrofuran. The reaction mixture is left at this temperature for 2 h and then added to dry ice. Hydrolysis is effected using water, acidification with hydrochloric acid and extraction with tert-butyl methylether. The combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product is purified by recrystallization from n-heptane. 2-Bromo-6-fluoro-5-trifluoromethoxybenzoic acid is obtained in the form of colorless crystals. Melting point: 112° C. 1H NMR (300 MHz, DMSO-d6/TMS): δ=7.67 and 7.71 (overlapping multiplets, 2H)—19F NMR (282.4 MHz, 1H broadband decoupled, DMSO-d6/CFCl3): δ=−57.6 (d, 5J(FF)=5 Hz, OCF3), 129.0 (q, 5J(FF)=5 Hz, CF).
Reaction SMILES: [F:1][C:2]1(F)[C:7](F)(F)[C:6](F)(F)[C:5](F)(F)[C:4](F)(F)[N:3]1F>F>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: FN1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Agent: F
Product: Fc1ccccn1
Product: c1ccncc1
Yield: 13 %
Yield: 8 %

Procedure:
Recently attention has been directed to the use of compounds of the N-F class, i.e. having an N-F bond, as electrophilic fluorinating agents. The prototypical member of this class is perfluoro-N-fluoropiperidine (R. E. Banks and G. E. Williamson, Chem. Ind. (London), 1964, 1864 and R. E. Banks et al, J. Chem. Soc., Perkin Trans. I, 1972, 1098). However, this compound is obtainable only in low yields by electrochemical fluorination of pyridine (about 8% yield) or 2-fluoropyridine (about 13% yield) in anhydrous hydrogen fluoride. Further, it has been found to be inadequately reactive in several applications and, on transfer of fluorine to a carbanionic substrate, liberates the imidoyl fluoride perfluoro-1-azacyclohex-1-ene which then competes for the substrate. Similar problems militate against use of the analogous compounds perfluoro-(N-fluoro-2,6-dimethylpiperidine) and perfluoro-N-fluoromorpholine (R. E. Banks et al, J. Chem. Soc., Perkin Trans. I, 1988, 2805) and of poly[perfluoro-(N-fluoropiperidin-4-ylethylene)] (R. E. Banks & E. Tsiliopoulos, J. Fluorine Chem., 1986, 34, 281) as electrophilic fluorinating agents.
Reaction SMILES: CC1[S:13][CH2:12][C:4]2([CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[O:3]1.C=C1C2CCN(CC2)C1.S>>[OH:3][C:4]1([CH2:12][SH:13])[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1
Reactant: CC1OC2(CS1)CN1CCC2CC1
Agent: C=C1CN2CCC1CC2
Agent: S
Product: OC1(CS)CN2CCC1CC2

Procedure:
U.S. Pat. No. 4,855,290 describes a process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) (1), which comprises the preparation of the epoxide of 3-methylenequinuclidine, which is subsequently reacted with hydrogen sulfide to produce 3-hydroxy-3-mercaptomethylquinuclidine and is condensed with acetaldehyde in the presence of a Lewis acid (e.g. boron trifluoride etherate) to provide 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine).