Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]([C:21]([F:20])([F:34])[F:33])[CH:23]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[(S)-1-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester (5 g, 18.8 mmol) and 3,5-bis(trifluoromethyl)bromobenzene (4.04 mL, 23.5 mmol) were dissolved in THF (20 mL). The solution was degassed with N2 for 5 minutes, and then cooled to 0° C. Isopropylmagnesium chloride (2M in THF; 23.5 mL, 46.9 mmol) was added slowly, and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. 1N Aqueous HCl (55 mL) was added, and the organic layer was separated and washed with brine. After concentrating, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncccn3)CC2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 4-methylbenzyl 4-(aminomethyl)-1-piperidinecarboxylate (INTERMEDIATE 2A) (20.00 g, 76.23 mmol), 2-chloro-pyrimidine (8.73 g, 76.23 mmol) and triethylamine (21.25 mL, 152.46 mmol) in DMF (40 mL) was heated at 100° C. for 6 h. The reaction solution was cooled to rt, then diluted with ethyl acetate (800 mL), washed with sat. aq. NaHCO3 (100 mL), water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-methylbenzyl 4-[(2-pyrimidinylamino)methyl]-1-piperidinecarboxylate. M.S. (M+1): 341.30
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32](I)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4C[C@@H](O)CN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (240 mg, 1.13 mmol) (Example 99C above) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (43 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.4 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the solution was poured in ammonium hydroxide and extracted with a 5:1 (V/V) mixture of EtOAc and DMF. The organic layer was dried over Na2SO4 and concentrated. (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2CO2 gradient and trituration with CH2Cl2. (Yield 50 mg, 35%).
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[OH:27])[CH2:18]1)[CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[O:8]1)[CH2:2][CH3:3].CCOC(C)=O>C1COCC1>[CH:7]1([CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:17]2[CH2:26][CH2:25][C:24]3[C:23]([OH:27])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][O:8]1
Reactant: CCCN(CC[C@@H]1OC(=O)c2ccccc21)[C@@H]1CCc2c(O)cccc2C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC1OCc2ccccc21)C1CCc2c(O)cccc2C1

Procedure:
A racemic mixture of the product of Example 36 (66 mg, 0.180 mmol) was dissolved in THF and added dropwise to a solution of BH3 in THF (2 mL) and the mixture was refluxed overnight. After workup the crude mixture was subjected to flash chromatography (Silica: EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.3-6.5(m, 7H), 5.4-5.0(m, 3H), 0.9(t, 3H). Anal. calc. for C22H29NO2 ° HCl: Theor. C; 71.21; H; 7.79; N, 3.61. Observed: C, 71.16, H, 7.61; N, 3.55.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40].CCOC(C)=O>C(Cl)Cl>[F:48][C:42]1[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1

Procedure:
Benzoyl isothiocyanate (6 g) was added dropwise to a solution containing ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol, obtained in Preparation Example 1-(3), (15.42 g) in CH2Cl2 (80 mL), and the mixture was stirred at RT for 18 h. EtOAc was added and the mixture was extracted with NaHCO3 (3×100 mL), dried over MgSO4, evaporated, and the residue was purified by silica gel column chromatography (0% to 30% EtOAc in hexanes) to obtain the title compound (19.06 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.00 (t, J=6.2 Hz, 1H), 3.08-3.17 (m, 1H), 3.26 (dd, J=10.2, 4.2 Hz, 1H), 3.38 (dd, J=10.2, 3.9 Hz, 1H), 3.73-3.95 (m, 2H), 4.04-4.12 (m, 1H), 4.54 (d, J=9.6 Hz, 1H), 4.69 (d, J=9.9 Hz, 1H), 7.05-7.68 (m, 21H) 7.88 (d, J=7.1 Hz, 2H), 8.88 (s, 1H), 11.83 (s, 1H)
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].C[Si](C)(C)C.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[C:15]=1[F:27].CO>O1CCCC1>[CH3:2][O:19][C:18](=[O:20])[C:17]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:14]([NH2:13])=[C:15]([F:27])[C:16]=1[F:26]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Solvent: C[Si](C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2 M solution of tetramethylsilane (TMS) diazomethane in hexanes (6.88 ml, 13.75 mmol) was added to a suspension of 4-amino-2,3-difluoro-5-nitrobenzoic acid (2.00 g, 9.17 mmol) in 25 ml of 4:1 Tetrahydrofuran (THF):MeOH at 0° C. under nitrogen atmosphere. Upon completion of addition, reaction mixture was warmed to room temperature. After 0.5 hours, excess TMS diazomethane was destroyed by the careful addition of acetic acid. The reaction was then concentrated under reduced pressure and dried in vacuo 1.95 g (92%) of pure desired product: MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=N)=[CH:6][CH:5]=1.C[N:14](C=O)C.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[NH2:14][N:10]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: N=C(N)c1ccc(N)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Aminobenzamidine di-HCl (25 g, 120 mmol), which is commercially available particularly from Aldrich, was added to dry DMF (100 ml). To this solution dry pyridine (100 ml) and succinic anhydride (12 g, 120 mmol) followed by dimethylaminopyridine (DMAP 1.5 g 0.012 mmol) were added. The product precipitated after heating for 1/2 h at 100° C. The product was filtered, washed with water, acetonitrile and ether. The light solid was suspended in dioxane, 4N HCl in dioxane (100 ml) was added and the suspension was stirred for 1 h, filtered and dried in a desiccator to give 28 g, 88% of 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxo-butanoic acid as a white yellow solid which decomposes between 270° and 290° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=N)=[CH:6][CH:5]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.C[N:21](C)C=O>N1C=CC=CC=1>[NH2:21][N:10]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: c1ccncc1
Product: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1

Procedure:
Treatment of 4-aminobenzamidine dihydrochloride, which is commercially available, with succinic anhydride in the presence of N,N-dimethylformamide and pyridine gives 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, as a mixture of the zwitterion and the hydrochloride. The product is isolated from the crude reaction mixture by the addition of conc HCl in acetone followed by additional acetone. Filtration and treatment with aqueous HCl gives 4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic, monohydrochloride.
Reaction SMILES: [Cl-].[CH2:2]([O:4][P:5](=O)([OH:9])[O:6][CH2:7][CH3:8])[CH3:3].[CH2:11]([OH:14])[C:12]#[CH:13]>C(Cl)Cl>[CH2:11]([O:14][P:5](=[O:9])([O:6][CH2:7][CH3:8])[O:4][CH2:2][CH3:3])[C:12]#[CH:13]
Reactant: C#CCO
Reactant: CCOP(=O)(O)OCC
Agent: [Cl-]
Solvent: ClCCl
Product: C#CCOP(=O)(OCC)OCC

Procedure:
1 mol of phosphoric acid diethyl ester chloride was added dropwise to 1.2 mols of propargyl alcohol at 20°-30° C., while stirring and passing nitrogen through. The mixture was allowed to react at 20°-30° C. for 2 hours and at 50° C. for 1 hour and was then taken up in 500 ml of methylene chloride and the methylene chloride mixture was washed twice with dilute sodium carbonate solution and once with water. On distillation, 0.76 mol of phosphoric acid diethyl ester chloride (boiling point: 76°-53° C./0.6-0.7 mbar) was recovered and no phosphoric acid diethyl propargyl ester was isolated. If the reaction was carried out at 80° to 100° C. for 6 hours, about 15% of impure diethyl propargyl phosphate was obtained, boiling point: 70°-82° C./0.2 mbar.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.CC(C)(O)C#N.[CH3:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([N+:37]([O-:39])=[O:38])[CH:29]=1)(=[O:27])=[O:26]>C(#N)C.C(OCC)(=O)C>[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:1]=1[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][C:30]=1[N+:37]([O-:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: C=C1OC(=O)C2CCC1C2
Agent: CC(C)(O)C#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 41.7 %

Procedure:
2.76 g (0.02 mol) of 93% 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 4.45 g (0.044 mmol) of triethylamine are stirred for 6 hours at a temperature of 20° C. in 50 ml of acetonitrile in the presence of 170 mg (2 mmol) of acetone cyanohydrin. 4.22 g (0.16 mol) of 4-methanesulfonyl-2-nitrobenzoyl chloride are then introduced and stirring is continued for a further 12 hours at a temperature of 20° C. A further 170 mg (2 mmol) of acetone cyano-hydrin are then added and stirring is continued for a further 30 minutes until conversion is complete. The reaction mixture is then taken up in ethyl acetate and extracted at a pH value of 13 against water. The aqueous phase is acidifed and extracted with fresh ethyl acetate, once at pH 5 and once at pH 4, dried and concentrated by evaporation. 3.05 g of 4-hydroxy-3-(4-methanesulfonyl-2-nitrobenzoyl)-bicyclo[3.2.1]oct-3-en-2-one with a good level of purity are obtained. The yield is 44.9% based on the starting material 4-methylene-3-oxa-bicyclo[3.2.1]octan-2-one or 52.2% based on the starting material 4-methanesulfonyl-2-nitrobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].C1C2C(=CC=CC=2)C=CN=1>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Brc1cccc2cnccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: c1ccc2cnccc2c1
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The procedure described by Osborn AR, et al, J Chem Soc 1956:41191 was used. 5-Bromoisoquinoline (101 g, 0.485 mol) was dissolved in 300 mL concentrated H2SO4. KNO3 (58.85 g, 0.582 mol) was dissolved in 200 mL of concentrated H2SO4 and added dropwise to the isoquinoline/acid solution. After addition, the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice and the acid quenched carefully with the addition of NH4OH until the solution was strongly basic. The solids were dissolved in chloroform and filtered through a silica gel plug and eluted with chloroform. Evaporation, followed by trituration of the yellow solid with 5% ethyl acetate in hexane, gave the product (114.2 g, 93%).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[CH:3](OC)OC.[Cl:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.O>[Cl:16][C:17]1[C:18]2[N:19]([C:2]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=3)=[CH:3][N:23]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(OC)C(Br)c1ccnc(SC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CSc1nccc(-c2cnc3c(Cl)nccn23)n1

Procedure:
The mixture of 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (from Example 43 supra) (7.5 g, 25.6 mmol), 3-chloropyrazin-2-amine (3.96 g, 30.7 mmol) and p-toluenesulfonic acid (1.594 g, 9.22 mmol) in the mix solvent of acetonitrile/water (120 mL:6 mL) was heated at reflux for 6 hours. The reaction mixture was concentrated and purified by chromatography (dichloromethane:methanol, 20:1) to give 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine as a white solid. (Yield 2.3 g, 32.4%). LC-MS: [M+H]+ 278.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:19]([OH:21])[N:20]=1.P(Cl)(Cl)Cl>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) of Preparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.103 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is triturated with HOAc to yield 0.236 g of the title product as a gold solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (96) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in pyridine (0.13 mL, 1.53 mmol) CH2Cl2 (3.7 mL) was stirred at room temperature for 12 h. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 45 (237 mg, 41%, in 3 steps).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:3][CH2:2][CH2:9][CH3:8])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
3,4-Dihydroxybenzaldehyde (5 g., 36.2 mmol, 1 equiv.) is dissolved in 80 mL of acetone. n-Pentytbromide (4.49 mL, 36.2 mmol, 1 equiv.) is added, followed by anhydrous potassium carbonate (5 g., 36.2 mmol, 1 equiv.). The mixture is stirred at room temperature for 3 days, and then poured into half-saturated ammonium chloride solution. The mixture is extracted thrice with ether, and the extracts are washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel using EtOAc/hexane affords 3-hydroxy-4-pentyloxy-benzaldehyde (0.820 g., 3.94 mmol, 11%): mp=55°-56° C.; UVmax (EtOH) 208 nm (ε=24443), 232 nm (ε=23049), 272 nm (ε=16105), 312 nm (ε=13140); 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H, CHO), 7.42-7.24 (m, 2H, ArH), 6.94 (d, J=8 Hz, 1H, ArH), 5.82 (s, 1H, OH), 4.10 (t, J=7 Hz, 2H, OCH2R), 1.88-1.79 (m, 2H, OCH2CH2R), 1.49-1.31 (m, 4H, pentyl), 0.92 (t, J=7 Hz, 3H, RCH3); 13C NMR (75 MHz, CDCl3) δ 191.06 (C=O), 151.30, 146.16, 130.40, 124.55, 113.99, 110.84, 69.27, 28.67, 28.04, 22.39, 13.97; IR (KBr) 3400, 2950, 1680, 1600, 1580, 1280, 1250 cm-1 ; MS (DCI) m/e 209 (MH+). Anal. Calcd for C12H16O3 : C, 69.23; H, 7.69. Found: C, 69.09; H, 7.65.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.ClCCC1C2C(=CC=CC=2)C(C)CO1.C[C@H]1CNC[C@@H](C)N1>>[C@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: OCCC1OCCc2ccccc21
Reactant: NS(=O)(=O)c1ccc(N2CCCNCC2)cc1
Agent: CC1COC(CCCl)c2ccccc21
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure for EXAMPLE 48 and making non-critical variations (-)-2-(isochroman-1-yl)ethanol (LXXIX) and 4-(homopiperazin-1-yl)benzenesulfonamide (IV; prepared from 4-fluorobenzenesulfonamide (III) and homopiperazine (II, Aldrich) by the method of EXAMPLE 47 Step 1) give the title compound, MS (m/z) 415; [α]D -50° (c 0.9996, methylene chloride); IR (mineral oil) 1153, 1595, 1102, 1511 and 1316 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (2.68 g) of Preparation 2 and 4-chloroaniline (1.28 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl8 (0.69 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.97 g of the title product as an orange solid.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[ClH:15].CN(C)CCCN=C=NCC.C(O[C:34]1[CH:48]=[CH:47][C:37]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[CH:36][CH:35]=1)CCCCC>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOCC>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:37]1[CH:47]=[CH:48][C:34]([Cl:15])=[CH:35][CH:36]=1
Reactant: O=C1COC(=O)C1
Reactant: Cl
Reactant: CCCCCCOc1ccc(OCCCCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCCCCOc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
To a stirring solution of 554 mg (5.54 mmol) of tetronic acid in 20 mL of dimethylformamide is added 850 μL (6.09 mmol) of triethylamine and 220 mg (1.765 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.26 g (6.63 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.475 g (6.63 mmol) of 6-[4-(hexyloxy)phenoxy]hexanoic acid are added and the reaction mixture is stirred 2 days at room temperature. The reaction is acidified with 1.0N HCI and extracted three times with ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo giving a yellow solid. Pure material is obtained by trituration in ether, filtering to give 774 mg (43%) of 4-hydroxy-3-[6-(4-chlorophenoxy)-1-oxohexyl]-2(5H)-furanone.