Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[H][H].S(OC)(O[CH3:32])(=O)=O>CN(C)C=O.O>[CH3:32][N:17]1[C:18]([CH3:22])=[CH:19][C:20](=[O:21])[N:15]([C:14]2[C:2]([F:1])=[CH:3][C:4]3[S:8][C:7](=[O:9])[N:6]([CH:10]=[C:11]=[CH2:12])[C:5]=3[CH:13]=2)[C:16]1=[O:23]
Reactant: COS(=O)(=O)OC
Reactant: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)cc(C)[nH]c3=O)cc21
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C=Cn1c(=O)sc2cc(F)c(-n3c(=O)cc(C)n(C)c3=O)cc21
Reaction time: 1 h

Procedure:
A solution of 6.1 g of 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-6-methyl-2,4(1H,3H)-pyrimidinedione (see Example 4) in 50 ml of dimethylformamide is added while stirring to a suspension of 0.8 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide. After the hydrogen evolution has finished the mixture is treated with 2.8 g of dimethyl sulphate and stirred for one hour. Thereafter, the reaction mixture is poured into 500 ml of water, the aqueous mixture is extracted three times with 100 ml of ethyl acetate each time and the organic phase is dried over anhydrous sodium sulphate. The solvent is subsequently distilled off under reduced pressure and the thus-obtained residue (7.2 g) is purified by chromatography on a column of 350 g of aluminium oxide (Brockmann I) using methylene chloride/n-hexane (3:1) as the eluent. The first fraction (1.5 g) is recrystallized from ethyl acetate, whereby there is obtained 1,6-dimethyl-3-[6 -fluoro-2-oxo-3-(1,2-propanedienyl)-5-benzothiazolinyl]-2,4(1H,3H)-pyrimidinedione, m.p.>250° C. By further elution of the column with methylene chloride/ethyl acetate (3:1) there is obtained the second fraction (4.7 g) which is recrystallized from ethyl acetate. In this manner there is obtained 1,6-dimethyl-3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-2,4(1H,3H)-pyrimidinedione, m.p. 180°-181° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:21][S+](C)(C)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH:16]2[CH2:18][CH:17]2[CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S+](C)(C)=O
Reactant: C/C=C/C(=O)c1cccc(OCc2ccccc2)c1
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CC1C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of 93.C (5.33 g, 21.1 mmol) in ACN (200 mL) were added trimethylsulfoxonium iodide (available from Aldrich) (5.58 g, 25.3 mmol) and DBU (4.11 mL, 27.5 mmol). The mixture was stirred overnight at 60° C. under N2, cooled to room temperature, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 93.D (2.04 g, 36% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C1COCC1>[C:13]1([CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][NH:11][C:26](=[O:29])[CH2:27][CH3:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of 5.0 g (21 mmol) N,N-dibenzylethylenediamine and 30mL (21 mmol) triethylamine in 20 mL THF is added 1.8 mL (21 mmol) propionylchloride, dropwise. The temperature of the reaction mixture is maintained below 0° C. during addition. The reaction mixture is stirred for 30minutes at 0° C. After this time, the reaction mixture is filtered and the solvents are evaporated to give the product which can be purified via column chromatography.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][O:12][C:8]=2[CH:7]=1)[CH2:2][C:3]#[CH:4].C([O:24][C:25](=[O:44])[C@@H:26]([O:42][CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)C.[O-]S(C(F)(F)F)(=O)=O>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[C:9]3[CH:20]=[CH:21][C:6]([O:5][CH2:1][CH2:2][C:3]#[C:4][C:31]4[CH:30]=[CH:29][C:28]([CH2:27][C@H:26]([O:42][CH3:43])[C:25]([OH:44])=[O:24])=[CH:33][CH:32]=4)=[CH:7][C:8]=3[O:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Reactant: C#CCCOc1ccc2c(-c3ccc(F)cc3)coc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc3c(-c4ccc(F)cc4)coc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 6-But-3-ynyloxy-3-(4-fluoro-phenyl)-benzofuran and (2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester Example 1, Step A) following the procedure described in Example 40, Step C. The ethyl ester derivative was contaminated with starting triflate. The mixture was hydrolyzed using the Standard Procedure C. The residue was purified by chromatography. MS(ES) for C28H23FO5 [M−H]−: 457.2.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:34])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:35]1[CH:40]=[C:39]([O:41]C)[C:38]([O:43]C)=[C:37]([O:45]C)[CH:36]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[OH:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:34])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:35]1[CH:40]=[C:39]([OH:41])[C:38]([OH:43])=[C:37]([OH:45])[CH:36]=1
Reactant: COc1cc(-c2oc3cc(CCC(C)CCCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirring solution of 48 (0.048 g, 0.08 mmol) in dichloromethane (2.5 ml) under argon at 0° C. was added boron tribromide (1.0M in DCM, 2.5 ml, 26 eq). The reaction was then warmed to room temperature and stirred for 19 hours. The mixture was then cooled to 0° C., methanol (2 ml) added heated to reflux for 2 hours. The reaction was then cooled and concentrated in vacuo to give a solid that was chromatographed (silica gel, chloroform:methanol, 9:1) to give 9i* (0.033g, 87%) as a waxy solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.S(Cl)([Cl:14])=O>>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 25 °C

Procedure:
1-Methylpiperidine-4-carboxylic acid hydrochloride salt 10 g (55.7 mmol) was added to thionyl chloride (25 ml) and resulting mixture stirred at room temperature until the solid dissolved completely. The reaction mixture was stirred for another 20 minutes and concentrated. The product was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[NH2:6].[OH-].[Na+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:6][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)aniline (9.1 g) was dissolved in 200 ml of toluene, and 30 ml of 40% aqueous sodium hydroxide solution and 6.5 g of N,N-dimethylcarbamyl chloride were added thereto. The reaction mixture was heated under reflux for 10 hours and then cooled to room temperature. The toluene layer was washed with water, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from ethanol to obtain 5.1 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N,N-dimethylurea as white needles. M.P. 210°-211° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]([NH:14][C:15]([N:18]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C1CCCCN1
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCCN1C(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C
Yield: 83.2 %

Procedure:
5.15 g (0.02 mol) of 4-chloro-2-fluoro-5-isopropoxycarbonylphenyl isocyanate were added to a solution of 3.31 g (0.02 mol) of ethyl pipecolate (95% purity) dissolved in 30 ml of benzene. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The resulting crystal was recrystallized from a mixed solvent of hexane, toluene and ethyl acetate to give 6.9 g (yield 83.2%) of the desired product as white crystals with a melting point of 83°-85° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][C:15]1[S:19][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)=[N:17][C:16]=1[CH3:29].C([O-])(O)=O.[Na+].C(=O)=O>>[CH3:29][C:16]1[N:17]=[C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)[S:19][C:15]=1[CH2:14][CH2:13][O:2][N+:1]([O-:4])=[O:3]
Reactant: Cc1nc(NC(=O)c2cccnc2)sc1CCO
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(NC(=O)c2cccnc2)sc1CCO[N+](=O)[O-]
Temperature: 25 °C

Procedure:
70% nitric acid (1.2 ml) was added to acetic anhydride (5 ml) while stirring and maintaining the temperature between 20-30° C. by external cooling. The mixture was cooled to −5° C. while stirring, followed by the addition of 1 gram of N-[5-(2-hydroxy-ethyl)-4-methyl-thiazol-2-yl]-nicotinamide. After 30 minutes at −5° C. the mixture was heated to 10° C. and stirred for one additional hour. The resulting mixture was poured into ice-water and stirred for 1 hour. Aliquots of NaHCO3 were added until CO2 evolution ceased. The orange-yellow water solution was extracted with three portions of 15 ml ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated by evaporation.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][O:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C1C=CC=CC=1>[C:8]1([C@H:5]2[O:4][CH2:3][C@@H:2]([O:1][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:7][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CO[C@@H](c2ccccc2)OC1
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: c1ccc([C@H]2OC[C@@H](OCc3ccccn3)CO2)cc1
Temperature: 25 °C

Procedure:
A solution of cis-5-hydroxy-2-phenyl-1,3-dioxane in 300 ml of benzene was treated with 4.45 g of 54% sodium hydride and the mixture stirred at ambient temperature until gas evolution ceased. To this mixture was added a solution of 2-chloromethylpyridine (obtained by extracting with benzene a carefully neutralized solution of 18.04 g of 2-chloromethylpyridine hydrochloride in 50 ml of water, then drying the benzene extracts) and the mixture was heated under reflux for 19 hours. The mixture was filtered and the filtrate washed with water and dried over sodium sulfate. Removal of the benzene under reduced pressure gave yellow solid which on recrystallization from benzene-petroleum ether (65°-110°) gave 14.2 g of cis-2-phenyl-5-(2-pyridyl)methoxy-1,3 -dioxane, m.p. 95°-98°. The nmr spectrum was consistent with the assigned structure and indicated pure cis isomer.
Reaction SMILES: C1N=C[N:3]([C:6]([N:8]2[CH:12]=N[CH:10]=[CH:9]2)=[O:7])C=1.[C:13]([C:17]1[CH:18]=C[C:20]([C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][C:25]=2[CH3:30])=[C:21]([CH:23]=1)N)([CH3:16])([CH3:15])[CH3:14].[CH3:31][NH:32][C:33]([C:35]1[CH:40]=[C:39]([O:41][C:42]2[CH:48]=CC(N)=[CH:44][CH:43]=2)[CH:38]=[CH:37][N:36]=1)=[O:34]>C(Cl)Cl.CCOC(C)=O>[C:13]([C:17]1[CH:23]=[CH:21][C:20]([C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][C:25]=2[CH3:30])=[C:12]([N:8]([C:9]2[CH:10]=[CH:48][C:42]([O:41][C:39]3[CH:38]=[CH:37][N:36]=[C:35]([C:33](=[O:34])[NH:32][CH3:31])[CH:40]=3)=[CH:43][CH:44]=2)[C:6]([NH2:3])=[O:7])[CH:18]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2N)c(C)[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(N(C(N)=O)c3cc(C(C)(C)C)ccc3-c3cc(C)[nH]c3C)cc2)ccn1
Temperature: 36 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a stirring solution of CDI (0.21 g, 1.30 mmol) in CH2Cl2 (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267 mmol) was then added in one portion. The resulting mixture was heated at 36° C. overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N HCl solution (15 mL), dried (MgSO4), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) Rf 0.24; 1H NMR (acetone-d6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([N:12]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:32]=1>CN(C=O)C.C(N(CC)CC)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>[CH3:1][O:2][C:3](=[O:26])[CH:4]([N:12]([CH2:13][C:14]#[C:15][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:32]=1)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Ic1cc2ccccc2o1
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)N(CC#Cc1cc2ccccc2o1)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (prepared according to example 9) (50 mg, 0.128 mmol) and 2-iodobenzofuran (41 mg, 0.166 mmol) in DMF (2 mL), triethylamine (2 mL) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) were added and the reaction mixture was stirred under reflux conditions for 4 h under a N2 atmosphere. DMF and triethylamine were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4), concentrated and the residue was purified by column chromatography using ethyl acetate and hexane (1:4) as eluent to obtain 2-[(3-Benzofuran-2-yl-prop-2-ynyl)-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid methyl ester as a thick syrup, 50 mg (76%). The compound contains two other rotamers. 1H-NMR (CDCl3, 300 MHz): δ7.58-7.09 (m, 12H), 6.98 (s, minor rotamer), 6.97 (d, minor rotamer), 6.85 (dd, minor rotamer), 6.83 (s, 1H), 5.82 (d, minor rotamer), 5.25 (bs, minor rotamer), 5.10 (bs, minor rotamer), 4.88-4.52 (m, minor rotamer), 4.35-3.21 (m, 5H), 3.78 (s, 3H), 3.76, 3.65 (2s, minor rotamer).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
rac-1,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate is concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1.0 g (37%) of 1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1149): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.66); mp 153°-154° C.
Reaction SMILES: [Cl-:1].[C:2]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[NH+:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3]>CO.[Pd]>[Cl-:1].[C:2]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[NH+:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(Nc2cc[nH+]c3ccc([N+](=O)[O-])cc23)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: CC(=O)Nc1ccc(Nc2cc[nH+]c3ccc(N)cc23)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a suspension of (A3 (1.75 g, 4.88 mmol) in MeOH (10 mL) was added 10% Pd/C (0.1 g) and hydrogenated (under 40 psi). for 2 h. The reaction mixture was filtered and washed with more MeOH. The filtrated was concentrated to half the volume, diluted with EtOAc and the rest of the MeOH was evaporated. The Resulting precipitate was filtered washed with more EtOAc and dried to give essentially pure (A4) (1.255 g 78%); mp (MeOH/EtOAc)>280° C.; 1H NMR [(CD3)2SO] δ 13.95 (br, 1H, N+H), 10.14 (s, 1H, NH), 10.01 (s, 1H, NH), 8.10 (d, J=6.7 Hz, 1H, ArH), 7.74 (d, J=8.9 Hz, 3H, ArH), 7.43 (d, J=2.2 Hz, 1H, ArH), 7.38-7.32 (m, 3H, ArH), 6.61 (d, J=6.7 Hz, 1H, ArH), 5.94 (s, 2H, NH2), 2.08 (s, 3H, COCH3); APCl+ve 293.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:33])[C:9]([CH2:22][NH:23]S(C2C=CC=CC=2)(=O)=O)=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].[C:34]1([S:40](C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:33])[C:9]([CH:22]([S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[NH2:23])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:2])[CH3:3]
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Product: CC(C)NC(=O)c1c(O)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Yield: 48.56 %

Procedure:
6-(Benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropyl amide (18-01) (110.0 mg, 48.56%, purified by Prep-HPLC) was synthesized as an off white solid from 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropyl amide (17-01) (280.0 mg, 0.597 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]=[S:12]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:11]([NH:10][C:13](=[O:14])[O:15][CH2:16][CH3:17])=[S:12])=[N:7][CH:8]=1
Reactant: COc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 5-methoxypyridin-2-amine (1.05 g, 8.43 mmol) in dimethyl sulfoxide (5 mL) was added ethyl isothiocyanatoformate (1.44 g, 11.0 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.34 g, 62%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Cl)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CCl)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL of dimethylformamide and treated with dibenzylamine (22.0 g, 110 mmol). The mixture was stirred at room temperature overnight and then the solvent was removed. The residue was purified by silica gel chromatography using 20-50% ethyl acetate/hexanes as eluent to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) δ2.94 (s, 3 H), 3.77 (s, 2 H), 3.82 (s, 2 H), 5.16 (s, 2 H), 6.75 (brs, 1 H), 6.96 (d, J=8.7 Hz, 1 H), 7.20-7.50 (m, 15 H), 7.67 (dd, J=8.7, 2.1 Hz, 1 H), 8.10 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 515.2 (MH+); HRMS Calcd. for C30H30N2O4S(M+): 514.1926. Found: 514.1927.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.O.[Sn](Cl)Cl>C(OC(=O)C)C>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Cc2c(Cl)cc(N)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In 11 ml of ethylacetate were dissolved 1.1 g 4-(4-Acetylbenzyl)-3,5-dichloronitrobenzene and 3.8 g Tin (11) chloride dihydrate. The solution was allowed to proceed for one hour at temperatures ranging from 40-50° C. After completion of the reaction. The reaction mixture was poured into 100 ml ice-water, followed by extraction with 150 ml ethylacetate. The extract was washed with water and 25% ammonia solution, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 100%, m.p. 97-98° C.