Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1cccnc1
Product: N=C(Nc1ccc(F)cc1)c1cccnc1
Yield: 76.9 %

Procedure:
The title compound was prepared from 3-cyanopyridine (0.94 g, 9 mmol) and 4-fluoroaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.5 g, yield 76.9%, purity 97.95% by HPLC). 1H-NMR (CDCl3):δ 4.93 (bs, 2H, D2O exchangeable), 6.92-6.96 (m, 2H), 7.05-7.07 (m, 2H), 7.38-7.41 (m, 1H), 8.22 (s, 1H), 8.71-8.72 (d, 1H), 9.06 (s, 1H). MS m/z:216.3 (M+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[C:18]([CH3:31])[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:31][C:18]1[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=[C:16]([O:12][C@H:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@@H:2]([NH2:1])[CH2:3][CH2:4]2)[CH:17]=1
Reactant: Cc1cc(F)cn2c([C@@H]3CCCN3C)nnc12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O[C@@H]2CC[C@H](N)c3ccccc32)cn2c([C@@H]3CCCN3C)nnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
A mixture of Intermediate A (44 mg, 0.267 mmol) and sodium hydride (60% in mineral oil, 29 mg, 0.729 mmol) in anhydrous DMF (1 mL) was stirred at RT for 20 min under argon atmosphere. To the reaction mixture was added a solution of Intermediate 105d (57 mg, 0.243 mmol) in anhydrous DMF (2 mL) and stirring at 60° C. was continued for 2.5 h. After cooling to RT, the reaction mixture was diluted with EtOAc and poured into ice-water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by SCX cartridge by washing the cartridge with 10% MeOH in DCM and eluting the product with 10% (2M NH3 in MeOH) in DCM and then by FCC on silica, using 10% MeOH in DCM followed by 10% [2M NH3 in MeOH] in DCM, to give the title compound (53 mg, 58%). LCMS (Method 1): Rt 0.38, 1.54 min, m/z 378 [MH+].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][C:14]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][N:18]([C:26](=[O:28])[CH3:27])[CH2:17]4)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[K+]>CC(O)=O.O>[C:26]([N:18]1[CH2:17][C:14]2([CH2:13][CH2:12][N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[CH2:16][CH2:15]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC4(CC3)OCCO4)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC(=O)CC3)CC2)C1
Yield: 70.8 %

Procedure:
1-(1′-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)ethanone 6d (350 mg; 0.83 mmol.) was dissolved in 80% aq. AcOH (20 mL) and the solution was refluxed overnight. The reaction mixture was diluted with water (20 mL), cooled on an ice bath and neutralized by addition of solid KOH. The resulting suspension was extracted with DCM (3×30 mL) and the combined organic extracts were dried on Na2SO4 and concentrated to provide the crude 4-(2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)cyclohexanone 6e (200 mg, 70% yield) as a white foam. LC/MS m/z [M+H]+ 341.0 retention time 1.47 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N+:35]([O-])=O)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:7][CH2:6]1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2N)CC1
Temperature: 60 °C
Yield: 89.9 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(2-nitro-phenyl)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 190 prepared at example 1.4.1 above; 2 g, 3.64 mmoles), SnCl2 (3.45 g, 18.2 mmoles) and MeOH (40 ml) and the reaction mixture was heated at 60° C. for 3 hours. MeOH was evaporated in vacuo and the crude was taken up in water. The pH was adjusted to 8-9 by addition of aqueous NaOH and the solution was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated. The resulting oil was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 99/1/0.1 v/v/v) to yield {4-[1-(2-Amino-phenyl)-2-(3,5-bis-trifluoromethyl-benzyloxy)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 323; 1.7 g, 90%) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH3:8])C.[H][H]>O1CCCC1.[Rh]>[C:12]([O:11][C:9]([N:6]([CH2:7][CH3:8])[C@H:5]([C:4]([OH:23])=[O:3])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)N(CC)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Rh]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](CC1CCCCC1)C(=O)O
Yield: 82.6 %

Procedure:
To a mixture of 2.65 g (10 mmole) of Boc-Phe in 50 ml of cold (ca. -78°), dry tetrahydrofuran was added 12 ml (ca. 22 mmole) of 1.9M t-butyllithium. After thirty minutes, the mixture was allowed to warm to -20° and then to react with 4.2 g (22 mmole) of triethyloxonium tetrafluoroborate. After thirty minutes, the mixture was allowed to warm to 0° and was then poured into water and extracted with dichloromethane. The organic extract was washed sequentially with portions of 5% aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered, and concentrated to dryness. Distillation (ca. 130°-200°) afforded an oil that was further purified by column chromatography on silica gel to give t-butoxycarbonyl-N-ethylphenylalanine ethyl ester. To a stirred mixture of this ester intermediate in tetrahydrofuran was added a two-fold (molar) quantity of potassium hydroxide in water. After the mixture was stirred overnight, an equal volume of dichloromethane was added and acidified to pH 3 with 0.5M sodium bisulfate. The aqueous layer was separated and washed with dichloromethane, and all organic layers were recombined. This organic solution was further washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to dryness. Column chromatography on silica gel afforded de-esterified t-butoxycarbonyl-N-ethylphenylalanine. A solution of 2.6 g of this protected amino acid intermediate in about 100 ml of tetrahydrofuran was catalytically hydrogenated at 80° using 60 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate was concentrated to an oil which crystallized on standing to afford 2.0 g of the title compound. The title compound was used in subsequent reactions without further purification.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.N#N.CCO.[Li]C(CC)C.[Cl:19][C:20]1[CH:28]=C[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:3]([CH3:4])[CH:28]=1
Reactant: CN(C)CCN(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: N#N
Agent: [Li]C(C)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g, 78% yield).
Reaction SMILES: O.[C:2]([NH2:8])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[S:15](F)(F)(=[O:17])=[O:16]>CC(C)=O>[CH3:6][C:4]1[O:5][S:15](=[O:17])(=[O:16])[NH:8][C:2](=[O:7])[CH:3]=1
Reactant: O=S(=O)(F)F
Reactant: CC(=O)CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=CC(=O)NS(=O)(=O)O1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Different quantities of water were added to 150 ml of acetone. 10.1 g (0.1 mol) of acetoacetamide and 69 g (0.5 mol) of finely powdered, dry K2CO3 were added to each of these mixtures. 15.3 g (0.15 mol) of sulfuryl fluoride gas were then passed in--initially at room temperature. The temperature of the reaction mixture increased to about 40° C. during this process. The mixture was stirred for a further 2 hours and the product was filtered off with suction. The filter residue contained Acesulfam K, which was found to be identical to a reference sample by thin layer chromatography (silica gel, solvent system: ethyl acetate/glacial acetic acid 5:1). The filter residue was introduced into a mixture of excess hydrochloric acid with ice and extracted with ethyl acetate. The ethyl acetate extract was dried over Na2SO4 and evaporated in vacuo. Crystalline 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide was obtained and this was converted to Acesulfam K with methanolic KOH. The results are collated in the table which follows. In the last experiment listed in the table, the K2CO3 was used as a 50% aqueous solution.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([OH:15])=O)#[N:2].[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:24]([CH2:23][C:21]1[CH:20]=[N:19][N:18]([CH2:16][CH3:17])[CH:22]=1)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=1)=[O:15])#[N:2]
Reactant: N#Cc1cccc2c1OCCC2C(=O)O
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCOc3c(C#N)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 81.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-cyanochroman-4-carboxylic acid (0.7 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.84 g) as starting materials, 8-cyano-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1.2 g) was obtained.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8]O.[NH2:10][CH2:11][CH2:12][SH:13]>Cl>[ClH:1].[ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:13][CH2:12][CH2:11][NH2:10]
Reactant: Cc1nc[nH]c1CO
Reactant: NCCS
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Yield: 166.3 %

Procedure:
30 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 23 g of cysteamine in 450 ml of concentrated hydrochloric acid are refluxed for 17 hours. The solution is evaporated to dryness under reduced pressure. The residue (61 g) is recrystallized from 500 ml of alcohol. 41 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride (corresponding to a yield of 84.0% of theory), of melting point 184°-191° C., are obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][C:28]([NH:31]C(C)(C)C)=[CH:29][CH:30]=[C:25]3[CH2:24][C@H:23]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[F:43])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O>>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=[C:25]3[CH2:24][C@H:23]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[F:43])[CH2:22][CH2:21]2)=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 70 °C

Procedure:
The mixture of (6R,9R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (0.1537 g, 0.117 mmol) and TFA (4 mL, 1.18E+04 mmol) was heat to 70° C. for 1 hour. LCMS showed that most of the starting material was converted to the desired product. There was no sign of hydrolysis of the carbamate to alcohol. TFA was removed via vacuum and the crude was partitioned between ethyl acetate and NaOH (1N). The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 3.5% to 5%. At this point the desired product was not eluted out. The flash column was continued to eluted with 5% methanol in CH2Cl2 to gave the desired product as a white solid (64.8 mg, 90%). MS (ESI)[M+H+]=535; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.44 (br. s., 1H) 8.13 (d, J=4.53 Hz, 1H) 7.36 (br. s., 1H) 7.14-7.24 (m, 1H) 6.99-7.10 (m, 4H) 6.37 (d, J=7.55 Hz, 1H) 5.87 (d, J=10.32 Hz, 1H) 5.57 (d, J=1.51 Hz, 1H) 4.48-4.83 (m, 2H) 4.17 (br. s., 1H) 3.23 (dd, J=13.72, 11.96 Hz, 1H) 2.95 (d, J=10.32 Hz, 3H) 2.69 (d, J=14.10 Hz, 2H) 2.08-2.31 (m, 3H) 1.83-2.08 (m, 3H) 1.19-1.35 (m, 1H) 0.81-0.95 (m, 1H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][N:27](C(OCC)=O)[CH2:26][CH2:25]1>>[F:9][C:8]([F:11])([F:10])[CH2:7][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: FC(F)(F)Cn1c(NC2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 14 using 2,2,2-trifluoroethyl trifluoromethanesulfonate and (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine to give the title compound.
Reaction SMILES: [O:1]1[CH2:12][C@@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:13]>CCO.CO.[OH-].[NH4+]>[NH2:13][CH2:12][C@@H:2]([OH:1])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: NC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of (2R)-benzyl 2-epoxypropyl ether, 6 (21.0 g, 0.128 mol) in EtOH (100 mL) was added slowly to a solution of 7.0 M ammonia in MeOH (100 mL) and 28% aq. ammonium hydroxide (210 mL) at rt. The reaction vessel was tightly capped and stirred at rt for 23 h. The completed reaction was concentrated in vacuo, and the crude product was azeotroped to dry twice with toluene (100 mL) to provide (R)-1-amino-3-(benzyloxy)propan-2-ol, 23 (23 g) as waxy solid containing approximately 15% of dimer. The crude was used for next reaction without further purification.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)[F:32].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([F:32])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1F
Reaction time: 72 h
Yield: 19 %

Procedure:
A suspension of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (9.91 mg, 0.0245 mmol and selectfluor (10.0 mg, 0.0282 mmol) in acetonitrile (0.1 mL) was sonicated for 3 hrs at 40° C. then allowed to stand for 3 days. It was quenched with water (3 ml) and extracted with ethyl acetate (3×1 mL). The combined organic solution was transferred to a preparative TLC plate (SiO2, 0.25 mm×20 cm×20 cm) and eluted with ethyl acetate to give the crude title product (4 mg, 19% yield). LC-MS (m/z) 423.2 (MH+); tR=1.44.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](OC)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:36]C(CC)=O.C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)=O
Reactant: CCCCc1nc2ccc(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1C
Product: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4 '-[(2-n-butyl-6-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylethylketone/xylene=1:2)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)C.C(OO)(=[O:13])C.[ClH:16]>O>[ClH:16].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:13]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1ccccn1
Agent: Cl
Solvent: O
Product: Nc1cccc[n+]1[O-]
Temperature: 70 °C

Procedure:
The solution of 2-acetamidopyridine was chilled in an ice bath to 10°-15° C and treated with 118 g. of commercial 40% peracetic acid which was slowly added over a 40-minute period with ice-cooling and stirring. During the course of the addition the temperature was between 15°-25° C. After 1 hour stirring, with little cooling (temperature 20°-30° C), the turbid solution was heated for 3.5 hours at 70° C with stirring. To the clear hot solution were added 85 g. 37.5% hydrochloric acid and 37 g. water, and to the resulting cloudy solution was added 3.5 g. 37% formaldehyde solution to destroy any unreacted excess of peroxide compounds. The mixture was stirred and heated 2.5 hours at 80°-82° C. After cooling to room temperature, 40 g. xylene was added and the cloudy solution was evaporated, under vacuum, in a rotary evaporator, until the residue was solid. The resulting moist crystals were dried at 50°-60° C under vacuum, to give 116 g. of 2-aminopyridine-1-oxide hydrochloride, which on recrystallization from 1:1 ethanoltoluene mixture, weighed 98.8 g. The resulting colorless crystals gave a m.p. of 155°-156° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH2:24]>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)c1cc(Cl)ccc1N
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Yield: 75 %

Procedure:
The title compound (1.56 g, 75%) was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-5-chloro-benzoic acid methyl ester as in Example 1, Part A. HPLC: RT=10.77 min. MS (ESI+): mass calcd. for C14H10ClN3O4S2, 382.98; m/z found, 406 [M+Na]+. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.82 (d, J=2.5, 1H), 7.72-7.68 (m, 2H), 7.34 (dd, J=9.0, 2.5, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]([C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)=[CH2:19]
Reactant: O=C1Nc2ccccc2Nc2nnc(Cl)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(nn1)Nc1ccccc1NC2=O
Temperature: 100 °C
Yield: 32.3 %

Procedure:
To a solution of 2-chloro-5,10-dihydro-3,4,5,10-tetraaza-dibenzo[a,d]cyclohepten-11-one from Example 2 (150 mg, 0.61 mmol) in toluene (3 ml) was added tri-n-butyl(vinyl)tin (231 mg, 0.73 mmol) followed by triphenylphosphine (4.8 mg, 0.02 mmol) and tetrakistriphenylphosphine palladium (7 mg, 0.01 mmol) and the resulting mixture was heated at 100° C. for 15 hours. The mixture was cooled to room temperature, concentrated in vacuo and purified directly by flash column chromatography (silica gel, 10% MeOH 90% dichloromethane) to afford the title compound as a yellow solid (47 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:22](=[O:24])[CH3:23])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: 85 °C

Procedure:
6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (2.53 g, 9.44 mmol) was dissolved in pyridine (8.39 mL, 104 mmol) and acetic anhydride (1.34 mL, 14.2 mmol) was added followed by DMAP (0.0576 g, 0.472 mmol). The reaction was heated to 85° C. for 90 min. After this time the reaction was concentrated in vacuo and the resulting oil was partitioned between EtOAc and 0.5N HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to give 1-(6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)ethanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:14](O)[CH2:15][CH:16]=[CH2:17]>>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:12][CH2:17][CH2:16][CH:15]=[CH2:14])=[O:11]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCC1
Reactant: C=CCCO
Product: C=CCCOC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid and 3-buten-1-ol were reacted to obtain 3-buten-1-yl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate.