Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:24]([CH3:25])[CH2:23][CH:22]=[CH:21]1>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH2:21][CH2:22][CH2:23][CH:24]1[CH3:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C=CCC2C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCCC2C)c1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A 100 mL round bottom flask was charged with 66.56F (mixture of diastereomers) (0.31 g, 0.91 mmol), EtOAc (10 mL), and Pd/C (10 wt. %) (0.097 g, 0.091 mmol). The mixture was purged three times with H2, stirred overnight under a H2 balloon, filtered through silica gel (EtOAc), and concentrated to afford 66.56G (mixture of diastereomers) (0.31 g, 99% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH:15]=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1ccc(-c2ccccc2CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4′-(Trifluoromethyl)[1,1′-biphenyl]-2-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)/[CH:4]=[CH:5]/[Cl:6].[CH3:8][O:9][C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11].O>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10](=[O:11])[CH:12]=[C:3]([CH2:2][Cl:1])/[CH:4]=[CH:5]/[Cl:6]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(/C=C/Cl)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C(/C=C/Cl)CCl
Yield: 14.1 %

Procedure:
Trans 1,4-Dichlorobut-3-en-2-one (0.56 g, 4.0 mmol) in toluene (10 ml) was stirred with methoxycarbonylmethylenetriphenyl phosphorane (1.32 g, 4.0 mmol) at 90° C. for sixteen hours. Water (50 ml) was added and the mixture extracted with ether (50 ml, 2×25 ml). The extracts were dried (Na2SO4) and evaporated to give the title compound (0.11 g, 14%), spectral details as in Example 11.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[C:14]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O)c1ccccc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a mixture of (±)-(1R,2S,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (547 mg) in water (10 ml) and benzoylchloride (367 mg) in toluene (6 ml) was added dropwise a solution of sodium bicarbonate (420 mg) in water (10 ml) over a period of 30 minutes. Stirring was maintained at room temperature for an additional period of 30 minutes. The mixture was extracted with chloroform, washed with saturated aqueous sodium chloride and evaporated in vacuo. Recrystallization of the residue from a cyclohexane/ethyl acetate mixture yielded the title compound (357 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:13](=[O:14])[CH2:12][CH2:11][C@H:7]2[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:45][C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=1[CH2:53][NH2:54].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:45][C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=1[CH2:53][NH:54][C:8](=[O:10])[C@@H:7]1[CH2:11][CH2:12][C:13](=[O:14])[N:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C1CCCC1
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1C1CCCC1
Reaction time: 0.17 h

Procedure:
1-Cyclopentyl-5-oxoproline (0.100 g, 0.51 mmol, prepared as described below) was dissolved in a mixture of dichloromethane (2.5 ml) and dimethylformamide (0.5 ml) and to this were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.117 g, 0.61 mmol), 1-hydroxybenzotriazole (0.082 g, 0.61 mmol), and N-ethyl morpholine (0.2 ml, 1.52 mmol). The mixture was stirred for 10 minutes and then [(2-chloro-4-fluorophenyl)methyl]amine (0.097 g, 0.61 mmol) was added and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate (10 ml) was added and the mixture stirred vigorously for 15 minutes. The organic phase was separated with a phase separator and the aqueous phase was washed with further aliquots of dichloromethane (3×10 ml). The organic fractions were combined and dried over magnesium sulphate. The solvent was then evaporated and the residue was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-cyclopentyl-5-oxoprolinamide.
Reaction SMILES: [NH2:1][C:2]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=O.B.C1COCC1>Cl>[NH2:1][CH2:2][CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)N(CC(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCN)c1ccc([N+](=O)[O-])cc1

Procedure:
2.3 g (8.4 mmol) of 4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene are refluxed in 35 ml (35 mmol) of borane-THF (1 M solution in THF) 7 hours. Then 30 ml of 6 N hydrochloric acid are added, and the mixture is refluxed for another 8 hours. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The aqueous phase is made alkaline with potassium carbonate and extracted with dichloromethane. The organic phase is separated off, dried and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14]1([CH2:20][CH2:21]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:20][CH2:21][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: OCCc1ccccc1
Product: O=C(C=Cc1ccc(F)c(F)c1)OCCc1ccccc1
Yield: 38 %

Procedure:
Reaction of 3,4-difluorocinnamic acid and β-phenylethyl alcohol as outlined in method A provided 67J-17-A as snow-white crystals (38% yield): mp 53°-57° C., 1H NMR (CDCl3) δ:7,49 (d, 1H, J=16 Hz), 7.30-7.05 (m, 8H) 6.27 (d, 1H, J=16 Hz), 4.36 (t, 2H, J=7.0 Hz), 3.82 (s, 3H), 2.95 (t, 2H, J=7.0 Hz); FABMS (NBA, +VE m/z 289 (M+H). Anal. (C17H14O2F2) C,H.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19](Cl)[Cl:20])([CH3:17])[CH3:16]>C1COCC1>[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19]([Cl:20])[O:1][CH2:2][CH2:3][C:4]#[N:5])([CH3:17])[CH3:16]
Reactant: N#CCCO
Reactant: CC(C)N(C(C)C)P(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Reaction time: 0.42 h

Procedure:
FIG. 15 illustrates the synthesis of bifunctional diphosphitylating, triphosphitylating, and tetraphosphitylating reagents (66, 69, 72). For the preparation of 66, phosphorus trichloride (21, 875 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added to anhydrous THF. Diisopropylamine (1,400 μL, 10 mmol) was added dropwise in 10 min to the solution mixture and the mixture was stirred for 45 min at 0° C. to yield diisopropylphosphoramidodichloridite (29). Then 3-hydroxypropionitrile (22, 683 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise to the solution of 29 in anhydrous THF during 10 min period. The stirring was continued for 25 min at 0° C. to afford 2-cyanoethyl diisopropylphosphoramidochloridite (24). Water (180 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise in 10 min period to the solution. The mixture was stirred for 10 min at 0° C. to yield 2-cyanoethyl diisopropylamine hydroxyphosphite (25). Then 29 (1 eq, 10 mmol) that was prepared at the same time in a separate reaction vessel, was added dropwise in 10 min period to the solution containing 25. The mixture was stirred for 25 min at 0° C. to yield diisopropylphosphoramidochloridite-O-2-cyanoethyl diisopropylphosphoramidite 66 (bifunctional diphosphitylating reagent). The reaction mixture containing diphosphitylating reagent 66 was immediately used in coupling reactions with polymer-bound p-acetoxybenzyl alcohol 78. Further stability studies on 66 using mass spectrometry methods showed that the compound remained stable after 2 months storage at −20° C.
Reaction SMILES: COCCOC.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH2:40][CH2:39][C:34]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:33][CH:32]=2)O1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:31]1[CH2:40][CH2:39][C:34]2([O:38][CH2:37][CH2:36][O:35]2)[CH2:33][CH:32]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1C1=CCC2(CC1)OCCO2
Temperature: 110 °C
Yield: 83 %

Procedure:
A solution of DME (0.2 M) and 2M aq. sodium carbonate (1.7 equiv.) was purged with nitrogen for 20 min. Then 4-chloro-3-nitropyridine (1.6 equiv.), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.0 equiv.), Pd(dppf)Cl2-DCM (0.05 equiv.) were added and stirred in a sealed bomb at 110° C. The reaction was stirred at that temperature for 3.5 hours. The reaction was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl acetate:hexanes=1:1 with 10% methanol) to give 3-nitro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (83%). LC/MS (m/z): MH+=263.2, Rt=0.71.
Reaction SMILES: C(C1C=CC=CC=1C=C)=C.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:18]([C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21])[CH2:19][CH3:20]
Reactant: c1ccccc1
Reactant: CCCC(=O)Cl
Agent: C=Cc1ccccc1C=C
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1ccccc1

Procedure:
About 50 grams of resin beads of polystyrene that has been copolymerized with about 1% divinylbenzene are stirred at room temperature for about 2 hours in butyryl chloride with aluminum chloride as a catalyst, namely Friedel-Crafts conditions. Reaction occurs with the benzene moieties on the resin to form butyrophenone or propylphenylketone. These resulting ketone moieties are then subjected to the Leukardt-Wallach reduction amination reaction using N-propyl formamide to produce N-propyl α-aminobenzyl moieties. The step-by-step synthesis of the nonapeptide as set forth in Example I is repeated. Cleavage, deprotection and purification are carried out under the same conditions and are found to produce the nonapeptide amide having the following formula:
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])[CH3:3].[C:22]([OH:27])(=[O:26])[CH:23]([CH3:25])[CH3:24].CN1CCOCC1.CCCCCC>C(OCC)C>[C:22]([O:27][CH:2]([O:4][C:5]([NH:7][CH2:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])[CH3:3])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)Cl)CCCCC1
Reactant: CC(C)C(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound (14) (38 g, 0.12 mol) in isobutyric acid (55 mL, 52.5 g, 0.6 mol) was added to a mixture of isobutyric acid (55 mL, 52.5 g, 0.6 mol) in N-methylmorpholine (65 mL, 60 g, 0.59 mol) at 0° C. over a period of 30 min. The resulting turbid solution was stirred for 16 h at room temperature. The reaction mixture was diluted with diethyl ether (500 mL) and washed with water (3×200 mL) followed by 10% potassium bicarbonate (4×200 mL) and brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield a viscous liquid. This crude product was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate:hexane to give the desired compound (15) as a clear, viscous liquid (37 g, 84% yield). 1H NMR (CDCl3, 400 MHz): δ 1.15 (d, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, 2H), 4.56 (d, 2H), 5.24 (dd, 1H), 5.32 (dd, 1H), 5.35 (br. s, 1H), 5.84-5.94 (m, 1H), 6.78 (q, 1H). MS (ESI) m/z 392.24 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[F:18][C:15]1[CH:16]=[N:17][C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: OC1CNC1
Reactant: COC(=O)c1cc(F)cnc1Cl
Agent: Cl
Product: COC(=O)c1cc(F)cnc1N1CC(O)C1

Procedure:
The title compound (D70) (75 mg) was prepared according to the experimental procedure described in Description 62 starting from azetidin-3-ol hydrochloride (208 mg, 1.89 mmol) and methyl 2-chloro-5-fluoronicotinate (300 mg, 1.58 mmol, commercially available from Adesis#2-482).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:44][CH:45]1[C:66](=[O:67])[N:47]2[C:48]([C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=3)=[O:54])=[C:49]([OH:52])[CH2:50][S:51][C@H:46]12>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([NH:44][CH:45]2[C:66](=[O:67])[N:47]3[C:48]([C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=4)=[O:54])=[C:49]([OH:52])[CH2:50][S:51][C@H:46]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 0.54 g.), N,N-dimethylformamide (0.16 g.), phosphoryl chloride (0.34 g.) and ethyl acetate (10 ml.) were treated in a similar manner to that of Example 15-(1) to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.62 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.7 g.) in ethyl acetate (10 ml.) and stirred at 40° C. for 30 minutes. The activated acid solution obtained above was added to the solution at -20° C. all at once, and stirred at the same temperature for an hour. Water (10 ml.) was added to the resultant solution, and the organic layer was separated, washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1.09 g.).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH:6]([F:7])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[NH:3]1.[Sn](Cl)Cl.[CH2:20](O)C>>[O:1]=[S:2]1(=[O:16])[C:6]([F:7])([CH3:20])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([NH2:12])[C:4]=2[NH:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)c2c1NS(=O)(=O)C2F
Reactant: CCO
Agent: Cl[Sn]Cl
Product: CC1(F)c2c(Cl)ccc(N)c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To the solution of 1,3-dihydro-2,2-dioxo-4-chloro-3-fluoro-7-nitro-2,1-benzisothiazole (100 mg, 0.4 mmol) in ethanol (10 ml), Tin (II) chloride (443 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for about 16 hours. Then all solvent was evaporated. Chromatography of the residue on silica gel (50% Ethyl acetate/Hexane) gave desired product (43 mg, 47%). EI-MS m/z 237.2 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]([CH2:16][CH3:17])[N:7]=1)=O)C.[NH2:18][NH2:19]>O1CCOCC1>[CH2:16]([C:8]1[N:7]=[C:6]([C:4]([NH:18][NH2:19])=[O:3])[C:11]([O:12][CH3:13])=[CH:10][C:9]=1[O:14][CH3:15])[CH3:17]
Reactant: NN
Reactant: CCOC(=O)c1nc(CC)c(OC)cc1OC
Solvent: C1COCCO1
Product: CCc1nc(C(=O)NN)c(OC)cc1OC
Yield: 71.4 %

Procedure:
A flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid ethyl ester (50 mg.; 0.21 mmol), dioxane (4 mL) and hydrazine (64 mg; 2 mmol). The reaction was heated at reflux for one hour, and all solvents were removed by evaporation. To the dried cake was added ethyl acetate (10 mL) and a 10% aqueous sodium carbonate solution (1 mL). The organic layer was isolated, dried with magnesium sulfate, and evaporated to give 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid hydrazide (34 mg.; 0.15 mmol).
Reaction SMILES: CO.[CH2:3](Cl)CCl.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=[O:18].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:3][O:18][C:17](=[O:19])[CH2:16][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[Cl:7]
Reactant: ClCCCl
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Methanol (12.13 mL), DMAP (609 mg), EDC (19.11 g), and triethylamine (13.88 mL) were added under cooling (ice) to a solution of (2-chloro-4-methoxy-phenyl)-acetic acid (20.00 g, [CAS Reg. No. 91367-09-8]) in CH2Cl2 (400 mL). The reaction mixture was stirred overnight at r.t. The reaction mixture was poured into ice/water and acidified with 1M aqueous HCl to pH 2. The aqueous layer was extracted two times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless oil (18.77 g, 88%). MS (m/e)=215.1 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[C:8]2[C:9]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]=3[CH:17]=[CH:18][CH:19]=2)(=[O:6])=[O:5].[CH3:20]I>CN(C)C=O>[CH3:20][N:12]1[C:13]2[C:9]3[C:8](=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]1=[O:16])[C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=2
Reactant: CI
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
To 25 ml of N,N-dimethylformamide is added 0.6 g of 60% sodium hydride under argon, followed by the rapid dropwise addition of a solution of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) dissolved in 50 ml of N,N-dimethylformamide. The mixture is stirred for 20 minutes then heated at 50° C. for minutes followed by cooling to room temperature. While stirring, a solution of 2.14 g of methyl iodide in 25 ml of N,N-dimethylformamide is added dropwise. The stirring is continued at room temperature for 2 hours. The reaction mixture is poured over 200 ml of crushed ice and the resulting solid collected, washed with water and dried to afford 2.54 g of the desired product, m.p. 216°-218° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[OH-].[Na+].[CH3:13]I.Cl>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O.C(Cl)Cl.O>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:13])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4]
Reactant: Cc1cc(O)cc(C)c1O
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.3 %

Procedure:
A mixture of 10 mL of CH2Cl2, 10 mL of H2O, 460 mg of 2,6-dimethylhydroquinone, 200 mg of NaOH, 940 mg (2 eq) of methyl iodide, and 760 mg of benzyl triethyl ammonium bromide in CH2Cl2 /H2O (C) were stirred at room temperature under argon for 12 hr. Dilute HCl was added to adjust the pH to 7.0, followed by 200 mL of CH2Cl2, and the organic layer was extracted with brine (5×100 mL), dried over Na2SO4, the solvent evaporated under reduced pressure, and the crude product was applied to silica gel (230-400 mesh, CH2Cl2) to yield 356 mg of product 25, about 70% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](S(C)(=O)=O)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][OH:26].[Cl-].[NH4+]>CN(C)C=O>[F:22][C:23]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:26][C:10]1[CH:11]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:7]=[CH:8][N:9]=1
Reactant: CC#CCOc1cc(S(C)(=O)=O)ncn1
Reactant: OCc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(OCc2cccc(F)c2F)ncn1
Temperature: 50 °C
Reaction time: 7 h
Yield: 67.6 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.15 g of 4-(2-butynyloxy)-6-methanesulfonylpyrimidine, 0.14 g of potassium carbonate, and 0.16 g of 2,3-difluorobenzylalcohol, followed by stirring at 50° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.13 g of 4-(2,3-difluorobenzyloxy)-6-(2-butynyloxy)pyrimidine (the present compound (76)), m.p.: 84.9° C.
Reaction SMILES: [Cl-].[C:2]([IH+:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].[P:17]([O:25]CC)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][P:17]([O-:25])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21].[C:13]([IH+:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOP(=O)(OCC)OCC
Agent: CC(C)(C)[IH+](c1ccccc1)C(C)(C)C
Agent: [Cl-]
Product: CCOP(=O)([O-])OCC
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A solution containing di-tert-butylphenyliodonium chloride (443 mg; 1 mmol) and triethyl phosphate (3 g) was stirred at 110-120° C. for 1 hour. The thus-obtained solid matter was washed with ether, to thereby yield 432 mg of the target compound as white crystals (yield: 69.2%).