Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH2:11]1[O:14][CH:12]1[CH3:13]>Cl.[Cl-].[Li+].CN(C)C=O>[OH:14][CH:12]([CH3:11])[CH2:13][N:7]1[C:3]([CH2:1][CH3:2])([CH3:10])[C:4](=[O:9])[N:5]([CH2:11][CH:12]([OH:14])[CH3:13])[C:6]1=[O:8]
Reactant: CC1CO1
Reactant: CCC1(C)NC(=O)NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(C)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Temperature: 50 °C
Yield: 99.7 %

Procedure:
A mixture of 256.3 g of 5-ethyl-5-methylhydantoin (1.805 mols), 675 ml of dimethylformamide and 4.51 g of lithium chloride is stirred at 50° C. 288.0 g of propene oxide (4.96 mols) are slowly added dropwise over the course of 2 hours. Thereafter the temperature is gradually raised to 90° C. over the course of 10 hours. The reaction mixture is brought to pH=7 with 4 drops of 2 N hydrochloric acid, filtered and concentrated on a rotational evaporator at 90° C. bath temperature, under a waterpump vacuum. It is then treated at 90° C. under 0.1 mm Hg until the weight remains constant. 465 g of a clear pale yellow product (99.5% of theory) are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C@@H:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][C@@H:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)N[C@H]2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 25.6 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8.0 mmol) in anhydrous tetrahydrofuran (4 mL) and anhydrous N,N-dimethylformamide (4 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.9 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of (R)-3-aminoquinuclidine (1.54 g, 12.2 mmol) in anhydrous tetrahydrofuran (4 mL) was added, and the mixture was stirred at room temperature for 18 hours, warmed to 55°±5° C. for three hours, and concentrated in vacuo. The residue was partitioned between 3.0N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol, and the organic layer was separated. The aqueous solution was extracted with toluene (50 mL) containing some 2-propanol, and the combined organic solution was concentrated in vacuo. The residue was washed with water to remove most of the imidazole, then dried azeotropically with toluene, taken up in tetrahydrofuran, and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, taken up in warm acetone, and filtered. After a few hours, a solid had crystallized, and this was collected and dried in vacuo to afford (following second crop) 1.05 g (26%) of colorless solid; mp 101.5°-104° C., [α]D22 +6.50° (C=1 in methanol).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:3]\[C:4]([NH2:6])=[O:5].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21].C(N(CC)CC)C>CO>[C:4](/[CH:3]=[C:2](\[CH3:1])/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH2:15][S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])(=[O:5])[NH2:6]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.0 g (0.008 mol) of (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide in 60 ml of methanol is treated with 2.3 ml of methyl thioglycolate and 3.4 ml of triethylamine. The solution is stirred at room temperature for 8 hours under argon. After removing the solvent the residue is taken up in water and methylene chloride. After extraction the organic phase is dried and freed from solvent. The residue is chromatographed on silica gel with ether-methanol 20:1. There is obtained methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]thio]acetate which exhibits the following absorption bands in the IR spectrum: 3447 cm-1, 3352 cm-1, 3195 cm-1, 1735 cm-1, 1712 cm-1, 1669 cm-1, 1638 cm-1 1609 cm-1, 1436 cm-1, 1300 cm-1, 1137 cm-1, 1008 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[C:13]1(=O)[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH:18]=[CH:17][CH:16]=[C:15]3[C:14]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[N:7]=[C:13]1[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]=3[C:15]([C:14]1=[N:10]2)=[CH:16][CH:17]=[CH:18]4
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 91 %

Procedure:
When 0.05 mole each of 4-methoxy-2-nitroaniline and acenaphthenequinone were reacted by the method of Example 1, 12.9 g (91 percent yield) of 9-methoxyacenaphtho[1,2-b]quinoxaline, mp = 194°-195° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.CCOCC.O>[Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cccc(Cl)c1I
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: CSc1cccc(Cl)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 6.0 g (21 mmol) of 3-chloro-2-iodo(methylthio)benzene, 5.1 g (42 mmol) of phenylboronic acid, 14 g (100 mmol) of potassium carbonate, 80 mL of 1,2-dimethoxyethane, and 75 mL of water was prepared and deaerated with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (730 mg, 0.63 mmol) was added and the mixture was heated at about 100° C. under nitrogen with stirring for about 20 hours. Water and ether were added and the aqueous phase was extracted with more ether. The ether phase and extract were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure and then in a Kugelrohr apparatus at 80° C. under 0.5 mm Hg (67 Pascals) pressure. The liquid residue was chromatographed on silica eluting with an 85:15 mixture of hexane and dichloromethane to obtain 4.3 g (87 percent of theory) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1C=CC=[CH:16][CH:15]=1.C(N(CC)CC)C.C(OC(=O)C)C>C(#N)C.CCCCCC>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][CH2:14][CH2:15][CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC#N
Product: CCCNc1nc(Cl)nc2ccccc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
2,4-Dichloroquinazoline (500 mg, 2.5 mmol) was dissolved in acetonitrile (3 mL). Aniline (260 mg, 2.76 mmol) and triethylamine (380 mg, 3.75 mmol) were added. The mixture was shaken in a sealed vial on a sand bath at 60° C. for 12 hours. Filtration and evaporation of the filtrate gave a yellow solid. Column chromatography (ethylacetate:hexane) gave (2-chloro-quinazolin-4-yl)-propylamine (350 mg, 55%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(CN2CCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(CN2CCCC2)cc1

Procedure:
A solution of the product of Step C in DCM (200 mL) was treated with thionyl chloride (20 mL) at 40° C. for 16 hours. Solvent was removed in vacuo to give the titled compound (15 g), which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH2:16]CCC.C(Cl)Cl>O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][CH2:11][CH3:16]
Reactant: CCCCBr
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Solvent: O
Solvent: ClCCl
Product: CCCCOc1ccc([N+](=O)[O-])c(C)c1
Yield: 99 %

Procedure:
This compound was prepared in a similar manner to that for 404b except 1-bromobutane was deployed for the alkyl ether adduct and the partition step during workup utilized DCM (150 mL) and water (150 mL) to provide a yellow oil (2.0 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.88 Hz), 6.79-6.76 (m, 2H), 4.03-4.01 (t, 2H, J=6.48 Hz), 2.63 (s, 3H), 1.80-1.78 (quin, 2H, J=7.44 Hz), 1.53-1.47 (sex, 2H, J=7.44 Hz), 1.0-0.97 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.7, 141.9, 137.1, 127.6, 117.9, 112.2, 68.3, 31.0, 21.8, 19.1, 13.8. Elemental analysis calculated for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.25; H, 7.09; N, 6.69.
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([O:12][C:13]([C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17])=[O:14])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].Cl>C(#N)C.O>[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([O:12][C:13]([C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:17])=[O:18])=[O:14])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OC12CC3CC(C1)C(O)C(C3)C2)C(F)(F)S(=O)(=O)[O-]
Reaction time: 5 h

Procedure:
4.69 Parts of triphenylsulfonium 4-oxo-1-adamantyloxycarbonyldifluoromethanesulfonate was dissolved in 15 parts of acetonitrile. Into the solution was added dropwise a solution obtained by dissolving 0.15 part of sodium borohydride in 1.51 parts of ion-exchanged water. After the added mixture was stirred for 5 hours, 1N hydrochloric acid was added thereto, and extracted with 1.13 parts of chloroform. After repeatedly washed with ion exchanged water, the organic layer obtained was concentrated. To the concentrate, acetonitrile was added, then the added mixture was concentrated. The concentrate was added dropwise into ethyl acetate. The mixture was filtrated to obtain solid. The solid was dried to obtain 2.20 parts of triphenylsulfonium 4-hydroxy-1-adamantyloxycarbonyldifluoromethanesulfonate in the form of white solid, which is called as acid generator B2. As a result of analyses by 1H-NMR and LCMS, the acid generator B2 determined to be a mixture of two isomers.
Reaction SMILES: [Br:1][C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[CH2:4]C(O)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].Cl.[N-:26]=[N+]=[N-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.[N-]=[N+]=[N-].[Na+].OS(O)(=O)=O.OS(O)(=O)=O.ClCCl>[Br:1][C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[CH2:4][NH2:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CC(F)(F)C(F)(F)Br
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: NCC(F)(F)C(F)(F)Br
Reaction time: 20 h

Procedure:
3-bromo-2,2,3,3-tetrafluoropropylamine was prepared through the intermediate of 4-bromo-4,4,3,3-tetrafluorobutanoic acid (from literature: Wei Yuan, R, Long, L., and Yuan-Fa, Z, Chinese J. Chemistry 1990, 3, 281). The reactions can be described by the following scheme: Na2S2O4/NaHCO3 in CH3CN/H2O BrCF2CF2Br+CH2═CHOEt→BrCF2CF2CH2CHBrOEt CrO3/H2SO4 in CH3COCH3, NaN3/H2SO4; HCl→BrCF2CF2CH2COOH→BrCF2CF2NH3Cl BrCF2CF2COOH (1.2 g, 5 mmol) was dissolved in 3 ml of H2SO4. Sodium azide (0.8 g, 12 mmol) was added in portion to the mixture at 80°. After addition was completed the reaction was continued for 20 hr. The mixture was then cooled to 0°. The solution was diluted with dichloromethane and then sodium carbonate (4 g in 20 ml of water). The organic layer was separated and the water layer was extracted with CH2Cl2 (20 ml×2). The combined dichioromethane was dried over magnesium sulfate overnight and gaseous HCl bubbled into the solution. 0.79 g of white solid was collected by filtration and vacuum dried. 1H NMR δ 3.82 (t, J=16 Hz, 2H). 19F NMR δ −66.8 (t, J=16 Hz, 2H), −113.74 (m, 2F). Chemical analysis: Calculated for C3H5BrClF4BN C: 14.6, H: 2.03, N:5.68. Found C: 14.57, H: 1.96, N: 5.56.
Reaction SMILES: Cl.[CH3:2][CH:3]([C:8]#[N:9])[C:4](=[NH:7])[O:5][CH3:6].[N:10]#[C:11]N>C1C=CC=CC=1>[C:11]([N:7]=[C:4]([O:5][CH3:6])[CH:3]([C:8]#[N:9])[CH3:2])#[N:10]
Reactant: COC(=N)C(C)C#N
Reactant: N#CN
Agent: Cl
Solvent: c1ccccc1
Product: COC(=NC#N)C(C)C#N
Yield: 86.8 %

Procedure:
2.97 g of methyl α-methylcyanoacetimidate hydrochloride and 1.26 g of cyanamide were suspended in 30 ml of benzene and made to react for 5 hours at 25°C. Then, ammonium chlordie precipitate was filtered off and then the filtrate was concentrated to dryness in vacuo and 2.38 g of methyl N-cyano-α-methycyanoacetimidate was obtained (yield 86.8%) mp 68.5°C. Analysis calculated for C6H7N3O (%) C 52.54, H 5.15, N 30.64, found C 52.57, H 5.14, N 30.62.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4](=[O:25])[C:3]1=[N:26]NC1C=CC=CC=1>C(O)(=O)C.O.[Zn]>[NH2:26][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4]1=[O:25]
Reactant: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2F)c2ccccc21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCN1C(=O)C(N)C(=O)N(c2ccccc2F)c2ccccc21
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of the intermediate 2 (5.8 g) in glacial acetic acid (50 ml) was added, dropwise, to a suspension of zinc dust (6.37 g) in glacial acetic acid (20 ml) cooled to 0°. The mixture was stirred at 23° for 3 h, then diluted with water (200 ml) and decanted from zinc. Solid sodium carbonate was added until pH=9 and the mixture extracted with ethyl acetate (2×300 ml). The combined organic extracts were washed with brine (300 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in gradient from CH-EA 2:1 to EA) to give the title compound as a white foam (2.8 g). M.p. 125°-6°. T.l.c. DCM-methanol (30:1), Rf 0.38.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:7][C:4]1[S:3][C:2]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1ccc(Br)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1ccc(-c2cccs2)s1
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-chlorothiophene (4.11 g), thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C[O:38][C:39]([C@@H:41]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][C@@H:42]1[NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)=O.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][N:48]2[C:13](=[O:14])[C:12]([C:7]3[NH:6][C:5]4[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)=[C:39]([OH:38])[CH:41]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH:42]23)=[CH:51][CH:52]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)C2CCCCCC2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 0.959 g, 2.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.527 g, 2.75 mmol) and N-methylmorpholine (0.605 mL, 5.50 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.732 g, 2.62 mmol) in N,N-dimethylformamide (20 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (60 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (3.40 mL, 10.4 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Column; 10-70% ethyl acetate in hexanes) to afford the desired product, 1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,8,9,9a-octahydro-cyclohepta[b]pyridin-2-one (0.534 g, 0.891 mmol, 34%) as a beige foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.25-1.42 (2H, m), 1.50-1.57 (3H, m), 1.76-1.98 (1H, m), 1.93 (3H, s), 3.30 (1H, bs), 3.55-3.59 (1H, m), 4.27 (1H, d, J=15.1 Hz), 5.02 (1H, d, J=14.9 Hz), 7.11-7.18 (2H, m), 7.25-7.29 (1H, m), 7.30-7.32 (1H, m), 7.39-7.42 (2H, m), 7.91-7.96 (1H, m), 8.02 (1H, s). LC-MS (ESI) calcd for C24H23FIN3O4S 595.04, found 596.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([NH2:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1.[CH:16]([CH:18]=O)=O.Cl.CCOC(C)=O>CCO.O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([N:12]=[CH:16][CH:18]=[N:9]2)=[C:5]([NH2:13])[CH:4]=1
Reactant: O=CC=O
Reactant: COc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(N)c2nccnc2c1

Procedure:
A solution of 4-methoxy-2,6-dinitro-phenylamine (5 g, 23.5 mmol) in EtOH (200 mL) was hydrogenated over 10% Pd/C (2 g) at 40 psi for 1 hour. After H2 uptake had ceased, the reaction was filtered through a pad of celite and washed with EtOAc (50 mL) and concentrated. Glyoxal (8 ml, 704 mmol) and EtOH (50 mL) were immediately added and the reaction was heated at reflux for 2 hours. The cooled reaction was diluted with H2O (50 mL) and extracted into CH2Cl2 (3×100 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated. The resulting oil was purified by column chromatography (10% MeOH/CH2Cl2) affording 430 mg (10%) as a red oil. An analytical sample was prepared as the HCl salt from EtOAc affording a red solid.
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Mg+2].[Cl-].[Cl-].[CH:24]1[N:25]=[C:26]([NH2:45])[C:27]2[N:32]=[CH:31][N:30]([C@@H:33]3[O:37][C@@H:36]4[CH2:38][O:39]P(O)([O:42][C@H:35]4[C@H:34]3[OH:44])=O)[C:28]=2[N:29]=1>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[C@@H:33]1([N:30]2[C:28]3[NH:29][CH:24]=[N:25][C:26](=[NH:45])[C:27]=3[N:32]=[CH:31]2)[O:37][C@H:36]([CH2:38][OH:39])[C@@H:35]([OH:42])[C@H:34]1[OH:44]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Cl-]
Product: N=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 0.25 h

Procedure:
PDE activity was determined in 50 mM HEPES, pH 7.5, 0.5 mM EDTA, 10 mM MgCl2, and 50 mg/ml BSA in a final assay volume of 100 μl. Each assay contained 50,000 cpm of 3H-labeled cAMP, with unlabeled cAMP added to adjust the desired total substrate concentration. Reactions were performed at 30° C. and were linear for at least 60 minutes. The standard reaction time was set to 15 minutes, and the amount of enzyme was always chosen so that no more than 15% of the substrate was hydrolyzed. Inhibitor studies were done at a cAMP concentration of 1 μM. Inhibitors were dissolved in DMSO, but the final DMSO concentration in the assays never exceeded 1%. Control reactions with DMSO alone were always included. Reactions were stopped by the addition of 25 μl of 0.5 N HCl. For the subsequent dephosphorylation of the AMP, the stopped reactions were neutralized with 20 μl of 1 M Tris base, followed by the addition of 10 μl of alkaline phosphatase (Roche Diagnostics; 1 unit/10 μl). The dephosphorylation reactions were incubated for 15 minutes at 37° C. and were then applied to 1 ml columns of QAE-Sephadex A25 in 30 mM ammonium formiate, pH 6.0. The 3H-adenosine formed as a reaction product was eluted with 1.6 ml of 30 mM ammonium formiate, pH 6.0 and was collected into 3.5 ml of water-soluble scintillation fluid (Packard Ultima Flo). Assays were performed in triplicate, and data were analyzed using the Graph Pad Prism software package.