Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.II.[I:16]([O-])(=O)(=O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:7]=1[I:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1cc(C)c(N)cn1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)c(N)c(I)n1
Temperature: 60 °C
Reaction time: 144 h
Yield: 132.3 %

Procedure:
A mixture of ethyl 5-amino-4-methylpyridine-2-carboxylate (2.58 g), iodine (2.91 g) and sodium periodate (1.22 g) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 6 days. The reaction mixture was cooled to room temperature. To the reaction mixture was added 1 mol/L aqueous sodium thiosulfate solution, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give ethyl 5-amino-6-iodo-4-methylpyridine-2-carboxylate (2.31 g). To sodium hexamethyldisilazide (1.03 mol/L tetrahydrofuran solution, 10.5 mL) was added a solution of ethyl 5-amino-6-iodo-4-methylpyridine-2-carboxylate (1.51 g) in tetrahydrofuran (9 mL) in a dropwise manner at −10° C., and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of di(tert-butyl)dicarbonate (1.18 g) in tetrahydrofuran (4 mL) in a dropwise manner, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give the title compound (1.11 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(=O)C.[Na+].CO[CH:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH:18](OC)O1>O.C(O)(=O)C>[C:21]1([C:20]2[CH:19]=[CH:18][N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN
Reactant: COC1CC(c2ccccc2)C(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Glycine ethyl ester hydrochloride (0.44 g, 3.17 mmol), sodium acetate (0.47 g, 5.76 mmol) were dissolved in minimum amount of water (5 mL) and added to glacial acetic acid (5 mL). The mixture was heated to 80° C. and then added to a solution of 2,5-dimethoxy-3-phenyl-tetrahydrofuran (0.6 g, 2.88 mmol) in glacial acetic acid (5 mL). The reaction was stirred at 80° C. for 2 h and then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with copious amount of water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl 2-(3-phenylpyrrol-1-yl)acetate (0.55 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]([CH:13]=[N:14][OH:15])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23]>>[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]1[O:15][N:14]=[C:13]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:23]=1
Reactant: CC(C)CC(C=NO)NC(=O)OC(C)(C)C
Reactant: C#CCC(C)(C)C(=O)OC
Product: COC(=O)C(C)(C)Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
Prepared from [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (7I) and 2,2-dimethyl-pent-4-ynoic acid methyl ester according to the procedure outlined in example 6A. MS (CI) m/z: 313.2 (M-tBu), 269.3 (M−99)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: CCOC(=O)c1c(-c2ccccc2)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxo-3-phenylpropanoate as a yellow solid (45%). 1H NR (400 MHz, DMSO-d6) δ 0.72 (t, J=8.0 Hz, 3H), 3.92 (q, J=8.0 Hz, 2H), 7.44 (m, 5H), 7.50 (m, 1H), 7.61 (bs, 2H), 7.73 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H). MS 293 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanol and concentrated onto 364 mg of alumina on a rotary evaporator. The residue is irradiated in a microwave at 150° C. for a total of 60 min. After cooling, the residue is stirred with ethyl acetate and water, filtered, and the aqueous phase of the filtrate is separated. The organic phase is washed with a sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product is reacted further without additional purification.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)#[N:17]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]1([N:22]2[CH:23]=[C:19]([CH2:18][C:16]#[N:17])[N:20]=[CH:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1c[nH]cn1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CCc1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Molecular sieve 4A (4.88 g), copper (II) sulfate (7.71 g), phenylboronic acid (6.76 g), and pyridine (4.49 mL) were added to a solution of 4-cyanomethylimidazole (3.00 g) in methylene chloride (120 mL), and the mixture was stirred overnight at room temperature under an air atmosphere at normal pressure. The reaction solution was filtered through celite and washed with methylene chloride. Then, a saturated aqueous solution of sodium bicarbonate (200 mL) and disodium dihydrogen ethylenediaminetetraacetate dihydrate (15.5 g) were added to the filtrate, and the mixture was stirred at room temperature for 20 minutes. After separation into aqueous and organic layers, the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (2.34 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36][N:8]4[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]4)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Sodium hydride (60%, oily, 160 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (849 mg) and 5-chloro-2-(4-chloromethyl-2-pyridyloxymethyl)imidazo[1,2-a]pyridine (1230 mg) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (1570 mg, yield: 81%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([NH:11][CH2:12][CH2:13][NH2:14])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([NH:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH3:9])(=[O:5])=[O:4]
Reactant: CC(=O)NCCN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNS(=O)(=O)N(C)C
Reaction time: 0.5 h

Procedure:
A solution of 14.3 g (0.1 mole) of dimethylsulfamoyl chloride in 50 ml of methylene chloride was added dropwise to a rapidly stirred solution of 10.2 g (0.1 mole) of acetylethylene diamine and 10.1 g (0.1 mole) of triethylamine in 150 ml of methylene chloride at 25° C. After the addition was completed, the solution was stirred for 30 min and then washed in a separatory funnel with two 100 ml portions of water. The organic phase was separated, and dried over MgSO4, and then concentrated under reduced pressure to afford N-[2[(dimethylamino)sulfonylamino]ethyl]acetamide as an oil. The N-acetyl group was then removed by treatment of the oil with 100 ml of 15% HCl at 80° C. for 6 h. This solution was concentrated under reduced pressure to provide 12.6 g (73%) of product as an oil. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.14 ml (10.5 mmol) of phenyl isocyanate are slowly added dropwise to a solution of 1.90 g (10.0 mmol) of 4-amino-1-benzylpiperidine and 1.46 ml (10.5 mmol) of triethylamine in 40 ml of dichloromethane. The reaction mixture may subsequently be stirred at room temperature for 1 h, and is then evaporated to dryness in vacuo. The residue is mixed with 50 ml of diethyl ether, stirred well, separated off by filtration, washed with 5 ml of diethyl ether and dried in a high vacuum. 2.62 g (85%) of the title compound are obtained as colourless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (˜4.7 mmol) in ClCH2CH2Cl (100 mL) was added formaldehyde (1.92 mL of a 37% solution in H2O, 23.65 mmol, 5 eq.) and HOAc (1 mL, 1% v/v). The mixture was stirred for 0.5 h at room temperature and then NaBH(OAc)3 (1.48 g, 7 mmol, 1.5 eq.) was added. The reaction mixture was stirred for 16 h and then quenched by the addition of saturated aqueous NaHCO3 solution (50 mL). The resulting mixture was extracted with EtOAc (200 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (50 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carbonitrile (1.5 g, 97%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, 2H), 7.36 (dd, 2H), 3.08 (dt, 2H), 2.60 (m, 2H), 2.50 (s, 3H), 2.20 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([OH:23])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:29][CH3:30])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12

Procedure:
1-(4-Nitrophenyl)isoquinoline-5-acetic acid (5.0 g) was dissolved in 300 ml of ethanol, and 4.0 ml of conc. sulfuric acid was added. The mixture was heated for 6 hours. After the reaction, the solvent was distilled off. Benzene was added to the residue. It was washed in water and dried. The solvent was distilled off, and the residue was recrystallized from ethanehexane to afford 4.8 g of ethyl 1-(4-nitrophenyl)isoquinoline-5-acetate as colorless needles having a melting point of 89.5° to 90.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([F:27])[CH:19]=2)[CH2:13][S:12](=[O:29])(=[O:28])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:42](C1NC=CN=1)(C1NC=CN=1)=[O:43].Cl>C(#N)C.CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][N:9]1[C@@H:10]2[C@H:15]([C@H:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([F:27])[CH:19]=3)[CH2:13][S:12](=[O:28])(=[O:29])[CH2:11]2)[O:16][C:42]1=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3ccc([N+](=O)[O-])c(F)c3)[C@@H]2O)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc([N+](=O)[O-])c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Reaction time: 16 h

Procedure:
To a suspension of (3R*,4S*,5S*)-3-(3-tert-butyl-benzylamino)-5-(3-fluoro-4-nitro-benzyl)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (4.4 g, 8.7 mmol) in ACN was added at 25° C. the DIPEA and the carbonyl-diimidazole. After addition of a catalytic amount of DMAP, the clear reaction mixture was kept at 25° C. for 16 h. The reaction mixture was poured onto ice-water and acidified with 4N aq. HCl. The precipitate was filtered off and washed with H2O and Et2O, dried under reduced pressure for 6 h at 50° C. to yield the title product as light yellow crystals: TLC (toluene-THF 1:1) Rf=0.66; HPLC RtA=2.25 min; ESIMS [M+NH4]+=508; 1H NMR (400 MHz, DMSO-d6): δ 8.11 (dd, 1H), 7.48 (dd, 1H), 7.38 (s, 1H), 7.28 (m, 3H), 7.12 (d, 1H), 4.41 (d, 1H), 4.20 (m, 2H), 3.72 (m, 2H), 3.42 (dd, 1H), 3.14 (d, 2H), 3.04 (dd, 1H), 2.76 (dd, 1H), 2.64 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (5 mL, 43.6 mmol), ethyl 2-aminobenzoate (7.6 g, 46.0 mmol), di-isopropyl-ethylamine (8.3 mL, 48.0 mmol) and ethanol (60 mL). The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to room temperature, and the solid was filtered off and washed with ethanol (100 mL), ethanol/hexane (1:1, 200 mL) and hexane (200 mL) to afford the product (10.2 g, 32.7 mmol, 75% yield) as a white solid. MS: M(C13H11Cl2N3O2)=312.15, (M+H)+=312.0 and 314.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of (3S)-1-(2-amino-6-chloro-4-pyrimidinyl)-3-piperidinecarboxylic acid (1.9 g, 7.40 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.465 g, 8.88 mmol) and NaHCO3 (0.622 g, 7.40 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred for 10 minutes under nitrogen. Pd(Ph3P)4 (0.171 g, 0.148 mmol) was added, and the microwave tube was heated at 140° C. for 50 minutes in microwave. LCMS showed 50% desired product. The reaction was then heated at 100° C. overnight. The yellow mixture was filtered and dried. The solid was washed with Et2O (3×), and dried. The filtrate was poured into water. The formed solid was filtered and dried. The solids were combined to afford the title compound (1.8 g) as a yellow solid. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1B(O)O.N1(CCOC2C=CC(C=O)=CC=2)CCCCC1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=3[F:39])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=Cc1ccc(OCCN2CCCCC2)cc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Yield: 85.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2 g, 7.6 mmol) by the procedure described for the preparation of 2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 1.1 g (85%) of the title compound: mass spectrum (ion spray) m/z=516.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:6].[C:22]([Mg]Cl)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]([CH:7]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8]2)([OH:6])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(O)(c2cc(F)cc(F)c2)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3.07 g (10.34 mmol) of tert-butyl 3-(3,5-difluorobenzoyl)azetidine-1-carboxylate in 20 mL of THF, 36.19 mL (36.19 mmol) of tert-butyl magnesium chloride was added and stirred for 3.5 h at −78° C. To the solution was added 8 mL of aq. NH4Cl and the solution was filtered to remove the solid. The filtrate was washed with ether. The combined organic layer was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound; 1H-NMR (CDCl3) δ 0.897 (s, 9H), 1.425 (s, 9H), 2.234 (br, 1H), 3.25 (m, 1H), 3.55 (m, 1H), 3.71 (t, J=8.9 Hz, 1H), 3.97 (t, J=8.4 Hz, 1H), 4.17 (m, 1H), 6.53-6.74 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([NH:24][CH3:25])[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>C(Cl)Cl>[CH3:25][NH:24][C:22]1[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: CNc1nc(N)nc(OCC(F)(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CNc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Carbomethoxybenzenesulfonyl isocyanate (0.5 g) was dissolved in 5 ml of methylene chloride. The aminoheterocycle (0.46 g) prepared in Example 2 was added and the mixture was stirred overnight under nitrogen at room temperature. The resulting solids were filtered off, washed with methylene chloride and dried to give 0.54 g of ~80% pure subject compound; m.p. 195°-197° C. decomp. No attempt was made at further purification. The resulting product named above had the following characteristics: IR (nujol) showed carbonyl bands at 1723 cm-1 and 1740 cm-1. NMR (CDCl3, DMSO-d6): δ 2.9, m, (NHCH3); 3.8, s, (CO2CH3); 4.9, m, (OCH2CF3); 7.7-8.4, m, (aromatic H's) plus ~20% heterocycle.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[CH:11][C:10]([CH3:27])=[N:9]1)=O)(C)(C)C.C(OC(N1C(C)=CC(C2C(=O)N(C3C=CC=CC=3)N(C)C=2C)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:27][C:10]1[CH:11]=[C:12]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])[NH:8][N:9]=1
Reactant: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)n(C(=O)OC(C)(C)C)n1
Agent: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)nn1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of the N-methyl isomers (E) and (F) of Example 26 (0.012 g, 0.035 mmol) in dichloromethane (1 ml) add trifluoroacetic acid (1 ml). Stir this mixture at room temperature for 1 hour, and then evaporate the mixture to dryness. Dilute the residue with dichloromethane, wash sequentially with water, aqueous sodium bicarbonate solution, and water. Dry the organic layer (sodium sulfate) and concentrate to give 0.009 g (0.035 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH2:13]1[S:18](=[O:20])(=[O:19])[O:17][CH2:16][CH2:15][CH2:14]1>CC(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N+:3]=1[CH2:16][CH2:15][CH2:14][CH2:13][S:18]([O-:20])(=[O:19])=[O:17]
Reactant: Cc1ccc2nc(C)ccc2c1
Reactant: O=S1(=O)CCCCO1
Solvent: CC(C)=O
Product: Cc1ccc2c(ccc(C)[n+]2CCCCS(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
After 72.3 g (0.46 mol) of 2,6-dimethylquinoline and 188 g (1.4 mol) of butane sultone were heated at 145° C. with stirring for 4 hours, the mixture was allowed to cool to room temperature, and 500 ml of acetone was added thereto. While cooling, crystallization was conducted for 30 minutes. The resulting crystal was recovered by filtration, washed with acetone and dried to obtain 127.3 g (yield: 94%) of 4-[2,6-dimethyl-1-quinolinio]butane sulfonate.