Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]([Cl:40])([Cl:39])[CH2:14][O:15][C:16]([CH:18]1[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20][C:19]1([CH2:37][Cl:38])[CH3:36])=[O:17]>C(Cl)(Cl)Cl>[Cl:38][CH2:37][C:19]1([CH3:36])[CH:18]([C:16]([O:15][CH2:14][C:13]([Cl:39])([Cl:12])[Cl:40])=[O:17])[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(CCl)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Yield: 79.5 %

Procedure:
A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) was added dropwise to a solution of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (5.0 g) in chloroform (40 ml) at -10°--5° C under stirring and then the mixture was stirred at -10°--5° C for 1 hour. After the solid was filtered off, the filtrate was washed with a saturated sodium becarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After removal of solvent, the residue was crystallized by adding ethanol. The crystal was filtered and recrystallized from ethanol to give 2,2,2-trichloroethyl 2chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide (4.10 g), mp 130°--131° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH3:13])[CH3:7].CN([CH:34]=[O:35])C>>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:34]=[O:35])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH3:13])[CH3:30]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2cc(C=O)ccc21
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
POCl3 (2.37 g, 15.3 mmol) was added dropwise to DMF (1.8 mL) which was cooled in an ice bath. The combined mixture was stirred for 30 minutes and to this a solution of Compound 5 (2.64 g, 7.6 mmol) in DMF (25 mL) was added dropwise over a period of 20 min. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 17 hour. An aqueous solution of sodium acetate (25% w/w, 25 mL) was then added to the reaction mixture and it was heated in an oil bath (T=110° C.) for 15 min. The reaction mixture was cooled and pH was adjusted with 10 N NaOH to ˜11. It was diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed twice with water (75 mL) followed by brine (3×50 mL), dried over magnesium sulfate and then evaporated to dryness to yield 1.44 g of an orange viscous liquid which was used without any further purification. The structure of Compound 6 is given below:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]1[CH:31]=[CH:30][O:29][CH:28]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.14 g (3.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 30 ml of anhydrous DMF and, at room temperature, carefully added to a suspension containing 0.24 g (6.05 mmol) of 60% sodium hydride. This mixture was stirred for 30 minutes and 8.2 ml (4.92 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylfuran in ethyl ether were dropwise added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between ethyl acetate and water. The organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel affording 1.4 g (97% of yield) of the expected product.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.CCOCC.Cl>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([B:1]([OH:6])[OH:2])=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of triisopropyl borate (4.6 mL, 20 mmol) in THF (1 mL) at -78° C. under nitrogen was added 4-fluorophenylmagnesium bromide (2M solution in diethylether, 10 mL) dropwise. The mixture was allowed to warm to room temperature. Ether (50 mL) was added, followed by 10% HCl (50 mL). The ether layer was then washed with H2O (25 mL) and brine (25 mL). The dried (MgSO4) ether layer was concentrated to dryness. The residue was triturated with hexanes to provide an off-white solid which was filtered and dried under vacuum to afford 1.38 g of 4-fluorophenyl boronic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:5][C:4]([C:12]([O:14]C(C)C)=[O:13])([C:6]([O:8]C(C)C)=[O:7])[CH2:3]1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1([CH3:18])[CH2:5][C:4]([C:6]([OH:8])=[O:7])([C:12]([OH:14])=[O:13])[CH2:3]1
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(C(=O)O)(C(=O)O)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a stirred solution of Intermediate 285B (1.5 g, 5.85 mmol) in ethanol (20 ml) was added a solution of KOH (1.313 g, 23.41 mmol) in water (10 mL). The resulting solution was stirred at 80° C. for 16 h. The reaction mixture was cooled to RT, quenched with crushed ice and extracted with diethyl ether (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford Intermediate 285C as a viscous liquid (0.9 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64 (br. s., 2H), 2.17-2.29 (m, 4H), 1.01-1.12 (m, 6H).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@H:10]1[C@H:9]([N:5]2[CH2:6][CH2:7][NH:8][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:21])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.62 g) and acetic anhydride (0.47 ml) in dry pyridine (3.1 ml) was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (30 ml) and washed with 5% hydrochloric acid (20 ml×2), brine (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and n-hexane to give trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.44 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][CH2:24][C:25]([O:27]CC)=O)=[C:17]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:16]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][CH2:24][C:25]([N:46]2[CH2:45][CH2:44][N:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[CH2:48][CH2:47]2)=[O:27])=[C:17]([N:30]2[CH:31]=[CH:32][CH:33]=[CH:34]2)[CH:16]=1
Reactant: CCOC(=O)CCc1cc(OC)c(OC)cc1-n1cccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)N2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Reaction time: 1 h

Procedure:
In 20 ml of tetrahydrofuran was dissolved 1.20 g of N,N-carbonyldiimidazole, and a solution of 2.0 g of ethyl 3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)propionate in 40 ml of tetrahydrofuran was added to the solution at room temperature while stirring. The stirring was continued at that temperature for additional 1 hour, 2.98 g of 1-(2-methoxyphenyl)piperazine was added thereto, followed by stirring at 40° to 60° C. for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel colunun chromatography (chloroform-methanol) to yield 1.9 g of a colorless oily substance. Recrystallization from ethanol gave the title compound as a colorless crystal.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[NH:11][NH2:12].C(O[CH:16]=[C:17]([C:23]([CH3:25])=O)[C:18]([O:20]CC)=[O:19])C.[OH-].[Na+]>C(O)C>[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[N:11]1[C:23]([CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=[N:12]1
Reactant: NNc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)c(F)c1F
Yield: 68 %

Procedure:
To a mixed solvent of 1N hydrochloric acid aqueous solution (120 ml) and ethanol (120 ml), were added 2,3,4-trifluorophenylhydrazine (9.3 g) and ethyl 2-(ethoxymethylene)acetoacetate (10.7 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), and the mixture was stirred at reflux temperature for three hours. Next, sodium hydroxide (2.8 g) was added and the mixture was further stirred for an hour. Ethanol was evaporated in vacuo, the organic layer was separated with toluene, hydrochloric acid was added to the aqueous layer and the precipitated solid was collected by filtration to give the titled compound (10 g).
Reaction SMILES: [N+]([O-])([O-])=O.[Ca+2:5].[N+]([O-])([O-])=O.[P:10]([O-:14])([O-:13])([OH:12])=[O:11].[NH4+].[NH4+]>>[P:10]([O-:14])([O-:13])([O-:12])=[O:11].[Ca+2:5].[P:10]([O-:14])([O-:13])([O-:12])=[O:11].[Ca+2:5].[Ca+2:5]
Reactant: O=P([O-])([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Agent: [NH4+]
Product: O=P([O-])([O-])[O-]

Procedure:
First, calcium nitrate and diammonium hydrogen phosphate in a molar ratio of about 1.2-1.5:1 are interacted in aqueous solution at a pH of about 10-12 to produce a gelatinous precipitate of calcium phosphate. Temperature is not critical and the precipitation can be carried out from about 0° C. to 100° C., but is preferably carried out at about room temperature. The gelatinous precipitate thus obtained is separated from the solution by suitable means, for example by centrifugation and decantation of the supernatant. The residual mineral sludge can be washed free of any remaining soluble salts by suspending in distilled water, centrifuging and decanting the supernatant. The residual product is then homogeneously suspended in 1-3 percent (w/w) aqueous ammonium sulfate. Ordinarily, 10-20 ml. of 1-3 percent (w/w) aqueous ammonium sulfate per gram of theoretically expected whitlockite ceramic is employed. The solid is then separated from the solution by centrifugation or vacuum filtration and the resulting wet precipitate is diluted with water to give a pourable slurry which is then cast in accordance with the process of the present invention as described hereinabove.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:30])C(=O)C1>CC#N>[Br:30][C:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1Br
Yield: 92.8 %

Procedure:
A mixture of 202 (2.05 g, 6.38 mmol) and NBS (1.31 g, 7.36 mmol) in MeCN (40 mL) was stirred at reflux for 2 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was washed with 10% aqueous Na2SO3 and water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2/EtOAc (19:1), followed by recrystallization from MeOH to give tert-butyl 1-bromo-7-(methylsulfonyl)-2-naphthylcarbamate (203) (2.37 g, 93%) as a white solid: mp 166-167° C.; 1H NMR [(CD3)2SO] δ 8.99 (s, 1H), 8.70 (d, J=1.7 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.5, 1.8 Hz, 1H), 7.97 (d, J=8.9 Hz, 1H), 3.32 (s, 3H), 1.50 (s, 9H). Anal. (C16H18BrNO4S) C, H, N.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([C:7]2[N:11]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of 5-phenyl-1H-tetrazole (50.0 g, 342.1 mmol, 1.00 equiv) in DCM (dried) (150 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. Triethylamine (45.0 g, 444.7 mmol, 1.30 equiv) at 0° C. was added to the mixture, followed by the addition of chlorotriphenylmethane (100.0 g, 358.7 mmol, 1.05 equiv) in several batches at 0° C. The resulting solution was stirred for 3 hours at room temperature. The solids were collected by filtration, and the filtrate cake was washed with cold EtOAc (1×100 mL) and water (3×300 mL). The solid was dried under reduced pressure to yield 125 g (94%) of 5-phenyl-1-trityl-1H-tetrazole as a white solid. ES m/z: [M+H]+ calcd for C26H20N4, 389.1, found 389.1.
Reaction SMILES: C([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15](C)[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.O[C:25]1C=CC(C#N)=C(C)C=1>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[CH:3]=[CH:18][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[C:16]([CH3:25])[CH:15]=1)=[O:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1cc(O)ccc1C#N
Product: Cc1cc(OC[C@@H](O)CNC(=O)CO)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (1.0 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-2-methyl-benzonitrile; LC-MS: tR=0.35 min, [M+H]+=297.99.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:30])[S:9][C:10]=1[NH:11][C:12]([C:14]1[C:19]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:18][CH:17]=[C:16]([CH:27]2[CH2:29][CH2:28]2)[N:15]=1)=[O:13])=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH:27]1([C:16]2[N:15]=[C:14]([C:12]([NH:11][C:10]3[S:9][C:8]([CH3:30])=[N:7][C:6]=3[C:4]([OH:5])=[O:3])=[O:13])[C:19]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[N:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1nc(C)sc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(C(=O)O)c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)s1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 5-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-thiazole-4-carboxylic acid ethyl ester (70 mg, 0.16 mmol) in a THF/ethanol mixture (2.5 ml; 1.5:1) was cooled to 0° C. and treated with lithium hydroxide (0.82 ml; 1N aqueous solution). After 15 min, the cooling bath was removed and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to r.t. and 0.84 ml 1M HCl was added. The suspension was filtered, the solid was washed with water and THF and dried in vacuo to yield 28 mg (43%) of a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: Fc1cccc(C2CCNCC2)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1CCC(c2cccc(F)c2F)CC1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.41 g, 2.08 mmol) in acetonitrile (4 ml), was added potassium carbonate (0.57 g, 4.16 mmol) and 1-iodoethane (0.163 ml, 2.12 mmol) and the mixture was heated to 120° C. in a sealed tube under microwave radiation for 1200 s. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×40 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.31 g). MS m/z (reL. intensity, 70 eV) 225 (M+, 20), 224 (14), 211 (13), 210 (bp), 127 (8).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[Cl:54][C:55]1[N:63]=[CH:62][CH:61]=[CH:60][C:56]=1[C:57](Cl)=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:57]([C:56]2[C:55]([Cl:54])=[N:63][CH:62]=[CH:61][CH:60]=2)=[O:58])[CH2:51][CH2:52]1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccnc1Cl)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-chloronicotinoyl chloride as the starting materials in 30% yield. LCMS for C30H30Cl2N7O2 (M+H)+: m/z=590.0, 592.0.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH:7](C(OC)=O)[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl>CS(C)=O.O>[I:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CC(=O)Nc2cc(I)ccc2C1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCC(=O)c2ccc(I)cc2N1
Temperature: 150 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
A mixture of methyl 8-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (74 g, 0.2 mol) in DMSO (560 mL) and H2O (16 mL) was heated at 150° C. for 4 h. The reaction mixture was allowed to cool to rt, ice (1.0 L) was added, and the mixture was allowed to stir 12 h. To the flask was added 1N HCl (1.0 L) at 0° C. and the mixture allowed to stir for 3 h. The resulting precipitate was filtered and dried under reduced pressure to afford 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (60 g, 97%).
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:8]=[C:9]([S:13]([N:16]2[C:20](=[O:21])[CH2:19][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:28])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)=O.O1CCCC1.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>[C:5]([C:7]1[CH:8]=[C:9]([S:13]([N:16]2[C:20](=[O:21])[CH2:19][N:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17]2=[O:28])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1cccc(S(=O)(=O)N2C(=O)CN(c3ccccc3)C2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C(O)c1cccc(S(=O)(=O)N2C(=O)CN(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
In 10 ml of a 10% solution of formic acid in tetrahydrofuran (THF), were dissolved 400 mg (1.00 mmol) of 3-(3-allyloxycarbonylbenzenesulfonyl)-1-phenyl-imidazolidin-2,4-dione obtained in Example 33. The resultant solution wad deaerated under reduced pressure. To the solution, 50 mg of tetrakis(triphenylphosphine)palladium and 50 mg of triphenylphosphine were added, followed by stirring at room temperature for 2 hours under shielding from the light. After completion of the reaction, the liquid reaction mixture was concentrated under reduced pressure, and crude crystals obtained as residue were collected by filtration, washed with ethyl acetate and then dried, thereby obtaining 350 mg (yield: 97.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][C:14](=[O:15])[C:13](=[O:17])[NH:12]2
Reactant: O=C(O)C(=O)O
Reactant: COc1cc(N)c(N)cc1OC
Product: COc1cc2[nH]c(=O)c(=O)[nH]c2cc1OC

Procedure:
6,7-Dimethoxy-1,4-dihydroquinoxaline-2,3-dione was prepared from 1,2-dimethoxybenzene. Nitration of 1,2-dimethoxybenzene gave 1,2-dimethoxy-4,5-dinitrobenzene, which was reduced to 1,2-diamino-4,5-dimethoxybenzene. Condensation of the diamine with oxalic acid gave 6,7-dimethoxy-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:27])[O:10][CH:9]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]([CH:19]=CC2C=CC=CC=2)[O:6]1>C(Cl)Cl>[CH:19]([CH:7]1[O:6][C:5]([CH3:4])([CH3:27])[O:10][CH:9]([CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]1)=[O:1]
Reactant: CC(C)(C)OC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CC(C=O)OC(C)(C)O1
Reaction time: 18 h

Procedure:
Ozone was bubbled into a solution of 1,1-dimethylethyl 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetate (3.0 g, 9 mmol) in 100 mL of methylene chloride at -78° C. until a blue color persisted. Nitrogen was then bubbled into the solution without cooling until the color disappeared. The temperature had risen to -20° C. Methyl sulfide (3 mL) was added and the solution stirred for 18 hours. The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with 20% ethyl acetate in hexane to give 1.78 g of the title compound. Recrystallization from pentane gave the compound as a white solid; m.p.=71°-73° C.