Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(O)=[O:2].S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O

Procedure:
A solution of ethyl 8-carboxy-12-acetoxyheptadecanoate (12.0 g., 0.03 mole) and thionyl chloride (7.2 g., 0.06 mole) in benzene (50 ml.) is refluxed for 2.5 hours. Volatile materials are removed by using a rotary evaporator in vacuo. The residual product, ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate, is a viscous liquid weighing 12.5 g. (100%), ir (neat) 1790 cm-1 (acid chloride C=O), 1730 cm-1 (ester C=O). This material is used directly in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[CH:13]=[C:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])([O-:9])=[O:8].[C:23]([O:26][CH2:27][CH3:28])(=O)C>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[CH:13]=[C:14]([CH2:18][CH3:19])[C:15]([O:17][C:10]1[CH:11]=[CH:28][C:27]([O:26][CH3:23])=[CH:21][CH:22]=1)=[O:16])([O-:9])=[O:8]
Reactant: CCOC(C)=O
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 22.1 g of m-nitro-α-ethylcinnamic acid suspended in 300 ml of ethyl acetate, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, upon which m-nitro-α-ethylcinnamoyl chloride precipitated. This compound was dissolved in 300 ml of ethyl acetate, and 12.4 g of p-methoxyphenol was added thereto. After the reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain p-methoxyphenyl m-nitro-α-ethylcinnamate. Yield: 30.7 g (93.9%); melting point: 65°-66° C.; IR (cm-1): 1710, 1503, 1351.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Cl:30]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([Cl:30])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c(Cl)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of ((S)-1-{(2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (175 mg, 0.38 mmol) and N-chlorosuccinimide (202 mg, 1.51 mmol) in acetonitrile (4 mL) was stirred at RT overnight. The reaction mixture was concentrated by rotary evaporation and purified by silica gel chromatography (24 g silica, 0-100% hexanes/EtOAc) to provide the title intermediate (208 mg) as a brown solid. (m/z): [M+H]+ calcd for C21H2BrClN4O3 497.09, found 497.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:20])[C:10](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:21][CH3:22]>O>[CH2:11]([CH:10]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([O:21][CH3:22])[CH:4]=2)[C:9]1=[O:20])[CH3:12]
Reactant: CCC(=Cc1ccccc1)C(=O)c1ccc(OC)c(Cl)c1Cl
Solvent: O
Product: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Reaction time: 16 h

Procedure:
A stirred mixture of 2,3-dichloro-4-(2-benzylidenebutyryl)anisole (55.6 g., 0.166 mole) and polyphosphoric acid (550 g.) is heated at 95°-100°C. for six hours then at 80°-85° for 16 hours, then poured into water (2 l.) affording 2-ethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 114°-6°C. after recrystallization from acetic acid-water.
Reaction SMILES: [CH2:1]([O:4]C(F)=C(F)F)[CH:2]=C.C(N(CC)CC)C.[F:17][C:18]([F:25])([CH2:22][CH:23]=[CH2:24])[C:19](F)=[O:20]>C(O)C>[F:17][C:18]([F:25])([CH2:22][CH:23]=[CH2:24])[C:19]([O:4][CH2:1][CH3:2])=[O:20]
Reactant: C=CCC(F)(F)C(=O)F
Reactant: C=CCOC(F)=C(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCC(F)(F)C(=O)OCC
Temperature: 0 °C

Procedure:
The start of the reaction in the reactor is indicated by a rise in temperature within the reaction chamber 5 from originally -74° C. to about -45° C. During the rest of the reaction period the temperature in the reaction chamber varies from about -45° C. to about -55° C. The reaction mixture from outlet conduit 18 containing the 1,2,2-trifluorovinyl allyl ether is conducted to a stirred solution of 434 g (600 mL, 4.3 mol) of triethylamine in 358 g (450 mL, 7.8 mol) of absolute ethanol cooled in an ice bath. Upon warming to the ice bath temperature, the 1,2,2-trifluorovinyl allyl ether spontaneously rearranges to 2,2-difluoro-4-pentenoyl fluoride, which in the presence of ethanol reacts to yield the desired ethyl 2,2-difluoro-4-pentenoate. The reaction mixture is divided into two equal batches which are treated separately. The following describes the workup of one batch.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O>>[CH:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:12][C@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])=[CH:7][CH:8]=1
Reactant: OCc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(=O)Cl
Product: OC[C@H]1O[C@H](OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Acetyl chloride, 80 mL, was added carefully to 1.75 L benzyl alcohol. This was followed by the addition of 180 g glucose. The mixture was heated, with stirring, at 80° C. overnight; then cooled, and poured into a plastic bucket. The product was precipitated as an oil by the addition of ether (3 L) and hexane (15 L). The supernatant liquid was decanted, and the residual oil washed with ether-hexane 1:1 (10 L), then ether. This afforded benzyl-alpha-D-glucopyranoside as a semisolid which was filtered, crushed, and washed with ether, then hexane to afford 237.3 g (0.88 mole; 88%) white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]2[NH:30][C:31](=[O:33])[NH:32][C:28]=2[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:35]=[CH:34][C:29]4[NH:30][C:31](=[O:33])[NH:32][C:28]=4[CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
71 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 33 mg (0.22 mmol, 1.1 eq.) of 5-amino-1,3-dihydro-2H-benzimidazol-2-one were reacted according to General Method 1. Yield: 74 mg (76% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (500 mg) in methanol (20 mL) at 0° C. was added sodium borohydride (66 mg). The reaction was stirred for 2 h then quenched with 1:1 saturated aqueous sodium hydrogencarbonate solution—water (20 mL). The mixture was stirred for 10 min and then filtered, washed with water and air dried to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol as a white solid (489 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=[S:40])[CH2:10][N:9]=1
Reactant: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-thione (IIv) was prepared by reacting 0.00052 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-one (Iv) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:24]([NH:26]O)=[NH:25])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][C:13]=2[CH:23]=1>[Zn].C(O)(=O)C>[F:8][C:9]1[C:10]([C:24]([NH2:26])=[NH:25])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][C:13]=2[CH:23]=1
Reactant: N=C(NO)c1cc2nc(-c3ccccn3)[nH]c2cc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1cc2nc(-c3ccccn3)[nH]c2cc1F

Procedure:
A mixture comprising 6-fluoro-N-hydroxy-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine trifluoroacetate (108 mg, 0.4 mmol), Zn (55 mg, 1.2 mmol) and acetic acid (5 mL) was heated at reflux under nitrogen for 2 hours. The mixture was filtered and concentrated to dryness. The residue was taken up and purified by preparative reverse phase HPLC. The combined pure fractions were lyophilized to provide 6-fluoro-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine; MS (ESI), Calculated for C13H10FN5 : 255.09, Found (MH+): 255.9; 1H-NMR (300 Mhz, DMSO-d6): 7.64-7.69 (m, 2H), 7.97 (d, 1H), 8.08 (m, 1H), 8.42 (d, 1H), 8.78 (d, 1H), 8.48 (d, 4H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:19][CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ccc(OCCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 12.6 ml (90.3 mmol) of triethylamine and a solution of 13.77 g (72.2 mmol) of toluene-4-sulphonyl chloride in 200 ml of dichloromethane are successively added dropwise with stirring to a solution of 10.0 g (60.2 mmol) of 4-(2-hydroxyethoxy)benzaldehyde in 300 ml of dichloromethane. The reaction mixture is stirred at RT for 12 h. After addition of 0.15 g (1.2 mmol) of 4-N,N-dimethylaminopyridine, the mixture is stirred at RT for another 4 h. 250 ml of saturated aqueous sodium bicarbonate solution are then added, and the mixture is extracted three times with in each case 100 ml of dichloromethane. The combined organic phases are dried over sodium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→ethyl acetate).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.O[CH2:28][C:29]1[N:30]=[N:31][N:32]([CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH:33]=1>C(Cl)Cl>[I:20][CH2:28][C:29]1[N:30]=[N:31][N:32]([CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH:33]=1
Reactant: II
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(CO)nn1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1cc(CI)nn1
Yield: 78.9 %

Procedure:
Stir a mixture of triphenylphosphine (0.29 g, 1.10 mmol) and iodine (0.28 g, 1.10 mmol) in DCM (4 mL) for 10 min. Add 1H-imidazole (0.12 g, 1.84 mmol) and stir for 10 min. Add 2-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) ethyl) isoindoline-1,3-dione (0.2 g, 0.73 mmol) and stir overnight at RT. Dilute with DCM and wash with water and saturated aqueous sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (DCM to 20% ethyl acetate in DCM) to afford the title compound as a yellow solid (0.22 g, 78%). MS (EI) m/z 383 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC#N.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3cccs3)cc12
Temperature: 90 °C
Yield: 39.1 %

Procedure:
A mixture of 8 (50.0 mg, 0.128 mmol), 2-(tributylstannyl)thiophene (88 μL, 0.276 mmol), dichlorobis(acetonitrile)palladium (II) (4.0 mg, 0.0138 mmol), tri-o-tolylphosphine (8.0 mg, 0.0276 mmol) and toluene (1.0 mL) were heated at 90° C. overnight. The mixture was separated by PTLC using ethyl acetate:hexane (3:7) as eluent to give 11 as a white solid (18.3 mg, 36%); 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.1 Hz, 1H), 8.28 (m, 3H), 8.16 (d, J=2.1 Hz, 1H), 7.68 (tt, J=7.5, 1.2 Hz, 1H), 7.57 (t, J=4.1 Hz, 2H), 7.37 (m, 2H), 7.13 (dd, J=5.1, 3.6 Hz, 1H).
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]([C:25]1[CH2:26][C@@H:27]2[C@H:30]([CH:31]=1)[C:29](=O)[CH2:28]2)([CH3:24])[CH3:23]>O>[CH:22]([C:25]1[CH2:31][C@@H:30]2[C@H:27]([CH:26]=1)[C:28](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:29]2)([CH3:24])[CH3:23]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.70 g, 16.5 mmol) was added dropwise at 0° C. over 20 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.68 g, 63%, 18.0 mmol), and the mixture was stirred at 0° C. for 20 minutes. To this solution, a tetrahydrofuran (15 mL) solution of (±)-(1S,5R)-3-isopropylbicyclo[3.2.0]hept-3-en-6-one (2.25 g, 15.0 mmol) was added dropwise at 0° C. over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.00 g, 81%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].OS(O)(=O)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:15]#[N:16]>>[F:11][C:12]1[C:13]([N+:1]([O-:4])=[O:2])=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:15]#[N:16]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Potassium nitrate (6.56 g, 64.8 mmol) was added to concentrated H2SO4 (33.7 ml, 633 mmol) at 0° C., followed by slow addition of 3,5-difluorobenzonitrile (4.4 g, 31.6 mmol). The suspension was stirred at this temperature for an additional 3 hours and quenched with ice water (500 ml). The resulting solid was collected by filtration and dried to give the title compound (5.55 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.43 (m, 1H), 7.35 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Cl)cc(Cl)c2o1
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a 2 L round bottom flask fitted with a mechanical stirrer and condenser was added 3,5-dichlorosalicylaldehyde (200 g, 1.05 mol, 1 equiv.), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0 g, 0.94 mol, 0.90 equiv.). The reaction solution was heated at reflux overnight. The dark brown reaction mixture was cooled to 50° C. and water (1 L) added with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). This mixture was heated to 45° C. for one hour, cooled to room temperature, filtered and the solid (fraction A) washed with EtOH (0.5 L). The combined EtOH solutions were concentrated by rotary evaporation to an oil (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution passed through a pad of silica gel (1300 mL volume). The resulting dark brown solution was concentrated to an oil that was triturated with hexanes (1.3 L) to give a solid that was isolated by filtration and washed (hexanes) to give substantially pure 6,8-dichlorocoumarin (163 g). A further 31 g of product was obtained by treating the oil, fraction B, in a similar fashion; the oil was dissolved in methylene chloride (0.5 L) passed through a silica pad (0.5 L volume) and triturated with hexanes. The total isolated yield was 194 g or 86% yield of the brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10]>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccccc3O)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3O)[C@H]2SC1

Procedure:
A solution of diphenylmethyl (6R,7R, 2'R and S)-7-(2'-hydroxyphenylacetamido)-3-methylceph-3-em-4-carboxylate (529mg, 1.03mmole) in trifluoroacetic acid (1.3ml) was stirred at +20° to +25° for 10mins. and then evaporated. The residual oil was dissolved in ethyl acetate (50ml) and washed with 3%-sodium bicarbonate solution (3×15ml). The combined aqueous layers were washed with ethyl acetate (3×15 ml), then covered with ethyl acetate (50ml) and adjusted to pH2.5. The ethyl acetate layer was combined with the ethyl acetate wash (15ml) of the aqueous layer, dried, and evaporated, leaving the title compound (as a 5:3=S:R-mixture of diastereomers, [nmr]) as a foam containing 1/2 mole-equivalent of ethyl acetate (nmr and microanalysis) and 2mole- equivalents of water (i.r. and microanalysis) (258mg, 0.60mmole, 58%); λmax 257.5nm, inflexions at 254 and 262.5nm (ε5,870; 5,780 and 5,830 respectively); νmax 3640 (OH, H2O), 3450 (NH), 1784 (azetidin-2-one), 1730 (CO2H) and 1690, and 1510 cm-1 (CONH); τ assignments of minor component (2'R) follow those of the major component (2'S) 1.52 and 1.36 (total 1H, 2d, J 9Hz, NH), 2.40 to 2.73 (5H,m,C6H5), 4.36 and 4.33 (total 1H,2d, J9 and 4.5Hz, C7 -H), 4.90 and 4.83 (total 1H,2S,C6H5CH), 4.93 and 4.98 (total 1H, 2d, J4.5Hz, C6 -H), 6.51(S) and 6.38 and 6.64 (ABq J18Hz) (total 2H,C 2 -H2), 7.95 (3H,C3 -CH3), and signals at 5.91, 7.98 nd 9.78 revealed the presence of 1/2moleequivalent of ethyl acetate. (Found: C,50.7; H,4.9; N,6.0 and 6.1; S,7.3. C16H16N2O5S. 1/2 CH3CO2C2H5. 2H2O (428.4) requires C,50.4; H,5.6; N,6.5;S,7.5%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([OH:23])=[O:21])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: Cc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[NH:44][C:45](=[O:56])[C:46]2[N:47]=[CH:48][N:49]([CH2:52][C:53](O)=[O:54])[C:50]=2[N:51]=1)=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:49]1[CH:48]=[N:47][C:46]2[C:45](=[O:56])[NH:44][C:43]([NH:42][C:40]([O:39][CH2:29][C:30]3[CH:38]=[CH:37][C:36]4[O:35][CH2:34][O:33][C:32]=4[CH:31]=3)=[O:41])=[N:51][C:50]1=2)[CH3:2]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with N-{[2-N-(piperonyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.37 (brs, 0.4H), 11.35 (brs, 0.6H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.03–7.99 (m, 1H), 7.95 (d, 0.6H), 7.92 (d, 0.4H), 7.82 (s, 0.6H), 7.79 (s, 0.4H), 7.01 (s, 1H), 6.94 (d, 1H), 6.91 (d, 1H), 6.02 (s, 2H), 5.14 (s, 3.2H), 4.93 (s, 0.8H), 4.45 (s, 0.8H), 4.21 (q, 0.8H), 4.08 (s, 1.2H), 4.07 (q, 1.2H), 3.65 (t, 1.2H), 3.48 (t, 1.2H), 3.43 (t, 0.8H), 3.27 (t, 0.8H), 1.25 (t, 1.2H), 1.16 (t, 1.8H).