Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C.[OH:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:24]1[CH:25]=[CH:26][C:21]([C:20]#[C:19][CH2:18][OH:17])=[CH:22][CH:23]=1
Reactant: OCC#Cc1ccc(B(O)O)cc1
Reactant: Clc1cnccn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCC#Cc1ccc(-c2cnccn2)cc1
Yield: 66.5 %

Procedure:
Chloropyrazine (0.78 mL, 8.73 mmol), 1 M aq. Na2CO3 (10 mL), and ethanol (5 mL) were successively added to a mixture of [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.30 g, 0.50 mmol) and [4-(3-hydroxy-1-propynyl)phenyl]boronic acid (1.85 g, 10.51 mmol, prepared as described in Reference Example 235) in toluene (20 mL) and the resulting mixture was heated to reflux for 3 h. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 97:3 dichloromethane/methanol) followed by a second chromatography (SiO2, 1:1 hexane/ethyl acetate) provided 1.22 g (66%) of the title compound as a colorless solid. MS 211 (M+H)+.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.N([O-])=O.[Na+].CO.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>[H+].[B-](F)(F)(F)F.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:18](=[O:21])[CH:19]=[CH:20][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc(N)cc(C)c1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Product: COC(=O)C=Cc1cc(C)c(C=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-amino-2,6-dimethylbenzaldehyde (1.0 g., 6.71 mmol) in enough 42% HBF4 to be stirred at 0° C. was added a solution of NaNO2 (463 mg, 6.71 mmol) in water (5 mL) slowly. After 30 min at 0° C., MeOH (20 mL) was added followed by Pd(OAc)2 (229 mg) and methyl acrylate (1155 mg, 13.42 mmol). The reaction mixture was heated at 80° C. for 30 min then the suspension was filtered through Celite and washed with CH2Cl2. The filtrate was extracted with CH2Cl2 and the organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc=10:1 to 5:1) to give the title compound. MS: m/z 219 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[C:11]([F:21])[C:10]=1[F:22].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[C:12]([F:20])=[C:13]([F:19])[C:14]=1[S:15]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:17])=[O:16]
Reactant: COC(C)CCO
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
To a solution of 3-methoxybutane-1-ol (0.78 g, 7.5 mmol) and TEA (0.388 g, 3.8 mmol), in CH2Cl2 (15 mL) was added pentafluorobenzenesulfonyl chloride (0.79 g, 3.0 mmol). The solution was stirred at rt for 4 h. Saturated aqueous NaHCO3 (10 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (30 mL) and washed with 0.5 M HCl (2×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (15% ethyl acetate in hexanes) yielded the desired product (0.39 g, 36%). 1H NMR (400 MHz CDCl3) δ 4.40 (m, 2H), 3.45 (m, 1H), 3.26 (s, 3H), 1.87 (m, 2H), 1.15 (d, 3H, J=6.1 Hz). Anal. Calcd. For C11H11F5O4S: C, 39.53; H, 3.32. Found: C, 39.83; H, 3.45.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C([O:16][B:17](OC(C)C)[O:18]C(C)C)(C)C.Cl>CCOCC.C1COCC1.CCOCC>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7]([B:17]([OH:18])[OH:16])=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
An oven dried Schlenk tube was charged with magnesium turnings (766 mg, 31.5 mmol), evacuated, and backfilled with argon. To the reaction vessel was added 10 mL of ether followed by 4-(trifluoromethyl)phenyl bromide (4.20 mL, 30.0 mmol). The reaction mixture was stirred without external heating for 1 hour, during which time an exotherm occurred and then subsided. The solution was diluted with ether (10 mL) and transferred via cannula to a flask containing triisopropylborate (13.8 mL, 60.0 mmol) in 1:1 THF/ether (20 mL) at −78° C. The resulting reaction mixture was kept at −78° C. for 15 minutes and then was allowed to warm to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was poured onto 2.0 M HCl (60 mL). The mixture was transferred to a separatory funnel, extracted with ethyl acetate (60 mL), washed with water (60 mL), and brine (60 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was dissolved in 2:1 hexane/ethyl acetate (90 mL) and activated charcoal was added. The mixture was filtered and the product crystallized upon cooling. The crystals were collected by filtration to afford 1.98 g (35%) of pale yellow needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[CH:20]=[CH:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:26][C:21]=2[CH:20]=[CH:19]1
Reactant: OB(O)c1ccc2occc2c1
Reactant: Brc1cnc2ccn(Oc3ccccc3)c2c1
Product: c1ccc(On2ccc3ncc(-c4ccc5occc5c4)cc32)cc1
Yield: 25 %

Procedure:
The entitled compound was prepared from 6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine and 1-benzofuran-5-ylboronic acid in a 25% yield according to the procedure described in example 23.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=[C:21]([Br:24])[Br:20])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Temperature: 20 °C
Yield: 75.1 %

Procedure:
A solution of 160.86 g (613.3 mmol) of triphenylphosphine in 600 ml CH2Cl2 was treated with 101.7 g (306.6 mmol) of tetrabromomethane (the reaction heated up to 32° C.) and after 50 min at 20° C., 97.8 ml (705.3 mmol) of triethylamine was added (the reaction heated up to 35° C. and the color became dark violet). After cooling (0° C.), 32.7 g (153.4 mmol) of 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester in 380 ml CH2Cl2 were added slowly (20 min). The solution was stirred over night at RT, evaporated and filtered through silica gel (deactivated with hexane/Et3N; with hexane and then hexane/ether 4:1 to 1:1) to give 42.54 g (75%) of 4-(2,2-dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester, mp: 82.3-83.9° C., MS: 368 (MH+, 2Br).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18]Cl)=[N:16][CH:17]=1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:16][CH:17]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccc(Br)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Brc1ccc(COc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of phenol (1.92 g, 20.4 mmol) was added sodium hydride (815 mg, 20.4 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. To the reaction solution was then added a mixture of 5-bromo-2-chloromethyl-pyridine hydrochloride (4.2 g, 20.4 mmol) described in Manufacturing Example 54-1-2 and triethylamine (28.0 mL, 20.4 mmol), which was stirred first for 30 minutes at room temperature and then for 45 minutes at 70° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:10) to obtain the title compound (4.40 g, 81.7%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][CH:20]([OH:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].I[CH3:40]>>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][CH:20]([O:36][CH3:40])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCC(O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(CCC(OC)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl

Procedure:
Ethyl 2-(2,3-dichloro-4-(3-methoxy-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from ethyl 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate using 1.1 equivalents of sodium hydride and 1.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7](O)[C:8]1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH:12]=1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[C:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:25])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCOC(=O)C(O)C1=CC(C)CC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C=C1CC(=O)C(C)C1
Temperature: 15 °C
Reaction time: 2 h
Yield: 1072.9 %

Procedure:
Step 3 Dehydration (n-Butyl Ester): Into a 5-L, 3-necked, round-bottomed flask equipped with a condenser, thermometer and nitrogen inlet were added 154.8 g (0.68M) alpha-hydroxy-4-methyl-3-oxo-cyclopentene acetic acid butyl ester (as prepared by Example 4), 2.3 L of toluene, and 12.9 g (0.068M) of p-toluenesulfonic acid monohydrate. The resulting reaction mixture was stirred at 75°-78° C. for 61/2 hours under nitrogen. When the reaction was complete, the mixture was cooled to 15° C., poured into a separatory funnel, washed with three 1-L portions of a total of 3 L of water, dried (MgSO4) and evaporated to give 153 g of the homogeneous 4-methyl-3-oxo-cyclopentylidene acetic acid butyl ester bp 82°-84° C./0.05 mm Hg, as a red oil for use in Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7](=[O:19])[NH:8][CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=2[CH2:6][C:7]1=[O:19])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1C1CNC(=O)Cc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
254 mg of the compound from Example 21A (0.84 mol) are dissolved in 5 ml of DMF, and 549 mg of caesium carbonate (1.68 mol) and 190 μl of ethyl bromoacetate (281 mg, 1.68 mol) are added. The reaction mixture is stirred at room temperature overnight. 6 ml of water are added, and the mixture is extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 254 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=3)[CH:20]([C:31]3[CH:36]=[CH:35][C:34]4[O:37][CH2:38][O:39][C:33]=4[CH:32]=3)[CH:19]2[C:40]([O:42]C)=[O:41])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=3)[CH:20]([C:31]3[CH:36]=[CH:35][C:34]4[O:37][CH2:38][O:39][C:33]=4[CH:32]=3)[CH:19]2[C:40]([OH:42])=[O:41])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 25.6 %

Procedure:
Methyl (1RS,2SR,3RS)-3-[2-(3Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (I ml) and aqueous sodium hydroxide (1M, 1 ml ,l mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5% AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][CH2:32][CH2:33][CH3:34].ClCCl>N1C=CC=CC=1>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][CH2:32][CH2:33][CH3:34])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:9])[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
α-Toluenesulfonyl chloride (0.5 g in 10 ml dichloromethane, 2.7 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.75 g, 2.4 mmol), dichloromethane (115 ml), and pyridine (1 ml). The reaction was maintained at room temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol, Rf 0.16). The fractions containing product were combined and washed with saturated aqueous bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated. A final recrystallization from dichloromethanediethyl ether provided 0.65 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]phenylmethanesulfonamide as a white crystalline solid, m.p. 197.0-199.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42 (dt, J=7.5, 1.1 Hz, 1H), 7.35-7.23 (m, 7H), 7.12 (t, J=5.4 Hz, 1H), 6.46 (broad s, 2H), 4.49 (t, J=7.5 Hz, 2H), 4.29 (s, 2H), 2.91 (m, 4H), 1.83-1.42 (m, 8H), 0.96 (t, J=7.4 Hz 3H); IR (KBr) 3460, 3293, 3226, 3158, 2955, 2931, 2867, 1632, 1586, 1534, 1482, 1437, 1389, 1331, 1152, 1094, 752, 700 cm−1; MS (EI) m/e 465.2204 (465.2198 calcd for C25H31N5O2S); Anal calcd for C25H31N5O2S: C, 64.49; H, 6.71; N, 15.04. Found: C, 64.15; H, 6.71; N, 15.00.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.[CH:15]1([CH:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH2:17][CH2:16]1.O>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]([CH:15]2[CH2:17][CH2:16]2)[C:19]([N:5]2[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a separate reaction vessel a stirred solution of 2.0 grams (0.016 mole) of (S)-4-(1-methylethyl)-2-oxazolidinone in 50 mL of tetrahydrofuran was cooled to -78° C., and 6.25 mL (0.016 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 30 minutes, and then the 2-cyclopropyl-2-(4-chlorophenyl)acetyl chloride, prepared above, was added dropwise during several minutes. Upon completion of addition, the reaction mixture was stirred for an additional 30 minutes and then was poured into water. The organic layer was separated and washed with one portion of aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to chromatography on silica gel using hexane:diethyl ether (3:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.85 gram of diastereomer (A) and 0.8 gram of diastereomer (B) of (S)-N-[2-(4-chlorophenyl)-2-cyclopropylacetyl]-4-(1-methylethyl)-2-oxazolidinone. Upon standing, diastereomer (A) crystallized to a solid, m.p. 61°-64° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[CH:4]=1)[CH3:21]
Reactant: CCO
Reactant: Cc1cc(CBr)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCc1cc(C)c([N+](=O)[O-])c(C)c1

Procedure:
The product from Step A (19.0 g) is dissolved in ethanol (600 ml) and anhydrous potassium carbonate (32 g) is added. The reaction mixture is stirred at reflux until the reaction is complete by tlc (two hours). The mixture is cooled, and the solids are filtered, washed, and discarded. The filtrate and washings are evaporated to a residue and purified by column chromatography on silica gel, using as eluant cyclohexane/ethyl acetate (97:3 v/v). The desired product, 4-ethoxymethyl-2,6-dimethylnitrobenzene (10.4 g) is isolated as a colorless oil.
Reaction SMILES: C(N(CC)CCCS(C1C=CC(N)=CC=1)(=NC(OCC1C=CC=CC=1)=O)=[O:8])C.[CH2:29]([N:31]([CH2:56][CH3:57])[CH2:32][CH2:33][CH2:34][S:35]([C:48]1[CH:53]=[CH:52][C:51]([NH:54][OH:55])=[CH:50][CH:49]=1)(=[N:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:36])[CH3:30]>>[CH2:56]([N:31]([CH2:29][CH3:30])[CH2:32][CH2:33][CH2:34][S:35]([C:48]1[CH:49]=[CH:50][C:51]([N+:54]([O-:8])=[O:55])=[CH:52][CH:53]=1)(=[N:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:36])[CH3:57]
Reactant: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc(NO)cc1
Reactant: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc(N)cc1
Product: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of a 3:1 mixture of 4-[S-[3-(diethylamino)propyl]-N-[(phenylmethoxy)carbonyl]sulfonimidoyl]benzeneamine and S-[3-(diethylamino)propyl]-S-[4-(hydroxyamino)phenyl]-N-[(phenylmethoxy)carbonyl]sulfoximine obtained through an incomplete reduction of S-[3-(diethylamino)propyl)-S-(4-nitrophenyl)-N-[(phenylmethoxy)carbonyl]sulfoximine (4.2 g, ~10 mmol) was dissolved in a pyridine (42 mL)-methylene chloride (12 mL) mixture. The resulting solution was cooled in an ice/water bath, and methanesulfonyl chloride (1.2 g, 10 mmol) was added. The reaction mixture was allowed to come to ambient temperature and was stirred for 4 h. The reaction mixture was then added to 200 mL of diethyl ether. The ethereal solution was decanted from the insoluble residue. The residue was triturated with an additional 100 mL of diethyl ether, and the ethereal solution was decanted and discarded. The residue was dried in vacuo to give 3.0 g of a gum that was chromatographed (flash, silica gel, 95:5-90:10 methylene chloride-methanol) to give 0.7 g of product (15%). A 200 mg sample was dissolved in ethanol and treated with ethereal HCl. The solid that formed was recrystallized from ethanol. This solid was triturated with ethyl acetate and then recrystallized from ethanol. The resulting solid was recrystallized from an ethanol/diethyl ether mixture to give 0.02 g of off-white solid, mp 76°-78° C.
Reaction SMILES: O1C2C=CC=CC=2N=C1.[Cl:10]Cl.[Cl:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>[Fe](Cl)(Cl)Cl.O=P(Cl)(Cl)Cl>[Cl:12][C:13]1[O:14][C:15]2[CH:21]=[C:20]([Cl:10])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Clc1nc2ccccc2o1
Reactant: ClCl
Agent: Cl[Fe](Cl)Cl
Agent: c1ccc2ocnc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)oc2c1

Procedure:
With efficient stirring, 10 g (0.083 mol) of 1,3-benzoxazole (>99% pure), together with 100 ml of POCl3 and 0.2 g of iron (III) chloride (dry), were heated to 100° C. At this temperature, chlorine gas was introduced under the surface of the liquid. GC control of the reaction showed that initially 2-chlorobenzoxazole was formed which, with further substitution, then reacted to give 2,6-dichlorobenzoxazole. Once all of the starting material had been consumed, the reaction was terminated. According to GC analysis, 21.5% of 2-chlorobenzoxazole and 71% of 2,6-dichlorobenzoxazol had been formed. The crude mixture was worked up by distillation. POCl3 and 2-chlorobenzoxazole were collected in a first fraction and could be employed directly for a further batch. The second fraction yielded 11.0 g of 2,6-dichlorobenzoxazole (GC>99% pure) (>70% of theory). Taking into account the recycling of the 2-chlorobenzoxazole, a total yield of >92% of theory was obtained.
Reaction SMILES: C([C:3](CC)([P:18]([OH:21])([OH:20])=[O:19])[O:4][C@H:5]([CH3:17])[CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])C.Br>C(O)(=O)C.Cl.CC(O)C>[P:18]([CH2:3][O:4][C@H:5]([CH3:17])[CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])([OH:20])([OH:21])=[O:19]
Reactant: CCC(CC)(O[C@H](C)Cn1cnc2c(N)ncnc21)P(=O)(O)O
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O
Temperature: 92.5 °C

Procedure:
Dealkylation of (R)-9-[2-(Diethyl phosphonomethoxy)propyl]adenine is carried out in presence of a suitable dealkylating reagents selected from mineral acids like aq. HBr, aq. HCl, HBr in acetic acid or HCl gas in IPA with mole ratio ranging from 3 to 15 preferably 7.5 moles and typically at a temperature of about 25 to 110° C., usually at 90 to 95° C. (R)-9-[2-(Diethyl phosphonomethoxy)propyl]adenine and one of the acid described above are maintained at 90 to 95° C. for about 3 to 15 hrs, after completion of reaction, the reaction mass is washed with Methylenedichloride and pH is adjusted to about 1.5 to 3.5 preferably at 2.5 to 3.0 with caustic lye solution. Reaction mass is cooled to about 25 to 35° C. and finally to about 0 to 5° C. over 4 to 10 hrs. The precipitated product is filtered and the wet material is recrystallized in water to get pure (R)-9-[2-(phosphonomethoxy)propyl]adenine with improved yield.