Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(C(Cl)=O)=O.[O:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=[C:8]1[C:16]([OH:18])=[O:17]>C(Cl)Cl>[CH3:1][O:17][C:16]([C:8]1[O:7][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=1)=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cnccc2o1
Solvent: ClCCl
Product: COC(=O)c1cc2cnccc2o1
Reaction time: 1 h

Procedure:
(COCl)2 (2.5 mL) was added dropwise to a stirred suspension of furo[3,2-c]pyridine-2-carboxylic acid (1.64 g, 10.1 mmol) in anhydrous CH2Cl2 (40 mL). After effervescence had ceased, the mixture was concentrated. Further CH2Cl2 (20 mL) was added, followed by NEt3 (4 mL) and MeOH (20 mL). After 1 h stirring, the mixture was diluted with EtOAc (50 mL) and washed with H2O, saturated aqueous NaHCO3 and brine. The CH2Cl2 solution was dried (MgSO4), filtered, and concentrated to afford furo[3,2-c]pyridine-2-carboxylic acid methyl ester: δH(CDCl3): 3.96 (s, 3H), 7.48 (d, 1H), 7.54 (s, 1H), 8.59 (d, 1H), 9.00 (s, 1H). A solution of this compound (1.10 g, 6.2 mmol) in MeOH was treated with TFA (0.5 mL). The flask was purged with argon, Bz2O2 (1.50 g, 6.2 mmol) added, and the mixture heated to reflux for 8 h. The mixture was cooled, adsorbed onto silica and purified via column chromatography to furnish 4-hydroxymethylfuro[3,2-c]pyridine-2-carboxylic acid methyl ester: m/z (ES+)=208.0 [M+H]+. A solution of this alcohol (0.50 g, 2.4 mmol), tBDMS-Cl (0.47 g, 3.1 mmol), NEt3 (0.5 mL, 3.6 mmol) and DMAP (catalytic) was stirred in THF overnight. The solution was diluted with EtOAc and washed with H2O and brine, before being dried and concentrated. Purification via chromatography afforded 4-(tert-butylmethylsilanyloxymethyl)furo[3,2-c]pyridine-2-carboxylic acid methyl ester: δH (CDCl3) 0.01 (s, 6H), 0.82 (s, 9H), 3.86 (s, 3H), 4.99 (s, 2H), 7.28 (d, 1H), 7.87 (s, 1H), 8.38 (d, 1H). To a solution of 4-(N-hydroxycarbamimidoylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 9, 93 mg, 340 μmol) in THF was added NaH (60% dispersion in mineral oil, 14 mg, 350 μmol). After effervescence had ceased, 4-(tert-butylmethylsilanyloxymethyl)furo[3,2-c]pyridine-2-carboxylic acid methyl ester (100 mg, 311 μmol) was added. After 3 h at 20° C., the reaction was heated to reflux for 50 min. The mixture was cooled, diluted with EtOAc, washed with saturated aqueous NH4Cl, and brine, before being dried and concentrated. Purification via column chromatography afforded the title compound: m/z (ES+)=545.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+:15]>C(Cl)Cl.C1COCC1>[N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+:15]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc([O-])c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A commercially available dinitrophenol (10.0 g, 54.3 mmol) was dissolved in 250 mL of methylenechloride, and water was removed on anhydrous magnesium sulfate. Solvent was removed by filtration under the reduced pressure. After the anhydrous dinitrophenol (10.0 g, 54.3 mmol) was dissolved in anhydrous THF (300 mL), NaH(0.782 g, 32.6 mmol) was added slowly. After all NaH was added, the solution was stirred for 3 hrs. Solvent was removed under reduced pressure to obtain 60 mol % sodium dinitrophenolate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[CH:4]=1.C(OC(=O)C)(=[O:15])C>>[OH:15][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: COc1cc(C)[n+]([O-])cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cnc(CO)cc1OC
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
19 g of 4,5-dimethoxy-2-methylpyridine 1-oxide are metered into 60 ml of acetic anhydride, warmed to 80° C., in the course of 30 minutes in a manner such that the temperature does not rise above 100° C. After a further 45 minutes at 85° C., excess acetic anhydride is distilled off in vacuo and the oily dark residue, which essentially consists of the intermediate 2-acetoxymethyl-4,5-dimethoxypyridine is stirred with 80 ml of 2N sodium hydroxide solution at 80° C. for 1 hour. After dilution with 80 ml of water and cooling, the mixture is extracted eight times with 100 ml of methylene chloride each time, the combined organic phases are washed twice with 1N sodium hydroxide solution, dried and concentrated and the crystalline, brownish residue is recrystallized from toluene. 14 g (74% of theory) of 2-hydroxymethyl-4,5-dimethoxy-pyridine of m.p. 122°-124° C. are obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>CC(C)=O>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:15]([CH3:20])([CH3:16])[O:13][CH2:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Yield: 6402.1 %

Procedure:
2-Bromo-4'-hydroxy-3'-hydroxymethylacetophenone (17.7 g), 124 mg of p-toluenesulfonic acid monohydrate and 256 ml of acetone dimethyl acetal were dissolved in 256 ml of acetone and the mixture was heated under reflux for 30 minutes. After cooling, an aqueous saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=7/1) to give 11.9 g of 2-bromo-1-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-1-ethanone having a melting point of 52 to 54° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.CCOC(C)=O>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
N-(t-Butoxycarbonyl)glycine 14-3 (Aldrich) was coupled with 3(R)-methyl-β-alanine benzyl ester 0.5 H2SO4 11-7 (Celgene) according to the procedure described for the preparation of 14-5. The title product 15-1 was then obtained by chromatography (silica, hexane/EtOAc 2:3).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1)[C:2]#N.[CH2:26](I)C>>[CH3:26][N:5]1[CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:11]=[C:12]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:13]([OH:20])=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:15]=2)[CH:8]=[C:4]1[S:1][CH3:2]
Reactant: CCI
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2)cc(C(C)(C)C)c1O
Product: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1C

Procedure:
Similarly, by following the procedure of part A above and substituting N-methyl-2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole for 2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole, and substituting methyl iodide for ethyl iodide, there is obtained N-methyl-2-methylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole [mp 173°-175° C.; 1H nmr: 1.50s (18H), 2.3s (3H), 3.73s (3H), 5.6s (OH), 6.81m (1H), 7.38m (1H), 7.76s (2H)].
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:22]([Cu])#[N:23].O>CN(C=O)C>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([CH:16]=2)[C:22]#[N:23])=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Temperature: 120 °C
Yield: 43.3 %

Procedure:
A mixture of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.37 g, 0.925 mmol) and CuCN (0.12 g, 1.39 mmol) in DMF (5 ml) was heated at 120° C. for 3 hours. Water (100 ml) was added, and the precipitate was collected. The residue was triturated with methanolic dichloromethane (10% CH3OH in CH2Cl2 with 0.1% NH4OH) to release the product from its copper complex and filtered. The filtrate was concentrated and purified via flash chromatography (3%CH3OH in CH2Cl2 with 0.1% NH4OH) to give 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile as white solid (0.12 g, 44%): M+H 300.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@@H:19]([CH3:21])[OH:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C(O)(C(F)(F)F)=O.[NH:46]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@H:47]([C:52]([OH:54])=O)[CH2:48][CH:49]([CH3:51])[CH3:50].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:46]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@H:47]([C:52]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@@H:19]([CH3:21])[OH:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:54])[CH2:48][CH:49]([CH3:50])[CH3:51]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Boc-Nle-Asn-Thr-OBzl (3.50 g) was treated with TFA (30 ml) and the solvent was evaporated. The residue was triturated with ether to give powders, which were dissolved in DMF (30 ml) together with TEA (1.2 ml). To this was added Boc-Leu-ONB which was prepared from Boc-Leu-OH (1.66 g), HONB (1.41 g) and DCC (1.63 g). The mixture was stirred at room temperature for 15 hours and the solvent was evaporated. The residue was triturated with water (50 ml) to give powders, which were collected by filtration and washed with ethyl acetate. Yield 3.60 g (83.8%); m.p. 200°-201° C. [α]D21.5 -22.7° (c=0.8, DMF), Rf1 0.60
Reaction SMILES: CN(C=O)C.[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:21](Br)[C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>O.CCOCC>[CH2:28]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][N:6]1[CH:7]([CH:8]([CH3:10])[CH3:9])[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1C(Br)Br
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C(=O)O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 20 ml DMF is added valine (1.17 g, 10 mmol) and potassium carbonate (5.5 g, 40 mmol) followed by α,α-dibromo-o-xylene (2.63 g, 10 mmol). The reaction mixture is stirred for about 20 hours at RT under nitrogen and then poured into ether and water. The aqueous layer is separated, acidified to about pH 3 with aqueous HCl and extracted thoroughly with ether. The organic layer is washed with water and brine, dried and solvent removed under vacuum to give 2-(2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][CH2:44][C:45]1[CH:46]=C(C=C[CH:51]=1)N.CC[N:54]([CH:58]([CH3:60])[CH3:59])C(C)C>CN(C=O)C>[I:43][C:44]1[CH:60]=[C:58]([NH:54][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH:59]=[CH:51][C:45]=1[CH3:46]
Reactant: O=C(O)c1ccoc1
Reactant: Nc1cccc(CI)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Furoic acid (2.4 g) and HATU (8.15 g) in DMF (25 ml) were stirred at room temperature for 15 min. HOBT (2.9 g), 3-iodomethylaniline (5.0 g) and DIPEA (11.2 ml) were added and the mixture was stirred at room temp for 16 h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases were washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a silica column and eluted with cyclohexane/ethyl acetate (3:1) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH:5]2[C:9]3([CH2:18][C:19]4[C:24]([N:4]2[C:3]1=[O:33])=[CH:23][CH:22]=[C:21]([NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]3=[O:17].[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[NH2:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:4]1[C:3](=[O:33])[CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH:5]1[C:9]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:18]2
Reactant: CC1OC(C)C2N(C1=O)c1ccc(NC(=O)OC(C)(C)C)cc1CC21C(=O)NC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1OC(C)C2N(C1=O)c1ccc(N)cc1CC21C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A suspension of tert-butyl 1,1′,2,3′,4,4′,4a,6′-octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H), 5′(2′H)-pyrimidin]-8-ylcarbamate (from Example 15) (7.4 g, 16.65 mmoles) in 250 mL of CH2Cl2 at room temperature is treated via pipette with a solution of 4.0 N HCl in dioxane (20 mL, 80 mmoles). The resulting slurry is stirred at room temperature for 2 days and then concentrated. The residue is dissolved in hot 1:1 EtOAc/methanol (˜300 mL) and recrystallized from heptane. After cooling to room temperature and then stirring at 0° C. for 30 minutes, the solid is isolated by filtration and dried (20 torr, 60° C., for 18 h) to give 6.31 g (99%) of the title compound as a beige solid. 1H NMR (DMSO-d6): δ 11.78, 11.47, 9.83, 7.06, 6.92, 6.87, 4.03, 3.67, 3.60, 3.50, 3.41, 2.90-2.82, 1.13, 0.91.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[C:13]([Cl:19])[CH:14]=[C:15]([Cl:18])[CH:16]=3)[CH2:11][N:10]([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:41].CN([CH:45]=[O:46])C.C1C=CC=CC=1>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.Cl[Pd]Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([Cl:19])[CH:14]=1)[CH2:11][N:10]([CH3:20])[CH2:9][CH:8]2[C:5]1[CH:6]=[CH:7][C:2]([C:45]([OH:46])=[O:41])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: [C]=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
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: c1ccccc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(C(=O)O)cc2)C1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
5.57 g (15 mmol) of 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3) was dissolved in 150 ml of abs. DMF/benzene (1:1). After the solution was degassed, under argon 1.18 g (4.5 mmol) of triphenylphosphine and 1.17 g (9 mmol) of Ca(HCO2)2 were added. After renewed flushing with argon, 867 mg (0.75 mmol) of Pd(PPh3)4 was added and carbon monoxide was passed into the solution. The mixture was stirred at 120° C. After six hours at 120° C. and standing overnight under argon, a further 867 mg (0.75 mmol) of Pd(PPh3)4 was added and stirring at 120° C. and passing carbon monoxide into the solution was continued for eight hours. After again standing overnight, 135 mg of PdCl2 was added and reaction was allowed to take place under the same conditions. For workup, the solvent was removed in vacuo and the residue was taken up in ethyl acetate. Three extractions with 2 N NaOH were carried out. The combined aqueous phases were adjusted to pH 6 with 6 N HCl and extracted three times with ethyl acetate. The organic phases were dried with MgSO4 and freed of solvent. The residue was purified on silica gel using a dichloromethane/methanol mixture, resulting in 420 mg of the title compound (Rt=4.025 min (method A); MS(Cl+)=336.1/338.1).
Reaction SMILES: C(O)CCC.[OH-].[Na+].[CH2:8]([P:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:16])[O:11]CCCC)[CH3:9].S(=O)(=O)(O)O>O>[CH2:8]([P:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:11])[OH:16])[CH3:9]
Reactant: CCCCOP(=O)(CC)CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCOCCP(=O)(O)CC
Temperature: 120 °C
Yield: 78.5 %

Procedure:
A stirred apparatus is initially charged with 150 g of butanol, 65 g of water, 150 g (3.75 mol) of sodium hydroxide and 278 g (1.25 mol) of butyl ethyl(2-ethoxyethyl)-phosphinate (produced as in Example 7). The efficiently stirred mixture is heated to about 120° C. and reacted at that temperature for about 6 hours. Then, 250 ml of water were added and the butanol was removed from the reaction mixture by distillation. Following the addition of a further 500 ml of water, the mixture is neutralized by addition of about 184 g (1.88 mol) of concentrated sulfuric acid. The water is then distilled off in vacua. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to obtain 163 g (98% of theory) of ethyl(2-ethoxyethyl)phosphinic acid as oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:8][CH2:9][O:10][CH3:11])[CH2:4][CH2:5][O:6][CH3:7].C(=O)([O-])O.[Na+].[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.[Cl-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:11][O:10][CH2:9][CH2:8][C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])([CH2:4][CH2:5][O:6][CH3:7])[CH2:2][NH:1][C:25](=[O:41])[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COCCC(CN)(CCOC)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COCCC(CCOC)(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a suspension of tert-butyl (3-(aminomethyl)-1,5-dimethoxypentan-3-yl)carbamate (G21, 275 mg) and sodium hydrogencarbonate (400 mg) in 1,4-dioxane (4 mL) and water (4 mL), 9-fluorenylmethyl succinimidyl carbonate (261 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours, and then stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and saturated aqueous sodium chloride were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain (9H-fluoren-9-yl)methyl tert-butyl (4-methoxy-2-(2-methoxyethyl)butane-1,2-diyl)dicarbamate (G22, 269 mg).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][O:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1C(N2CCCC2=O)c2sccc2OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.1 g, 4.11 mmol) was added to a mixture of sodium hydride (60% in mineral oil, 0.172 g, 4.32 mmol) in N,N-dimethylformamide (20ml) at 0° C. and stirred for 1.5h. Methyl iodide (0.28 ml, 4.52 mmol) was added to the resultant mixture and the mixture stirred at rt for 1 h. The mixture was poured into ice Water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from dichloromethane and hexanes to give the product 0.825 g (71%) as a colorless solid; mp 117°-118° C.; IR(KBr): 2979, 1677, 1572 and 1420 cm-1 ; MS: m/z 282 (MH+); 1H NMR (CDCl3): δ 1.27 (s,3 H), 1.48(s,3H), 2.05(m,2H), 2.50(m,2H), 3.33(m,2H), 3.41(d,J=8.8 Hz, 1H), 3.51(s,3H), 5.33(d,J=8.8 Hz, 1H), 6.55(d,J=5.4 Hz, 1H) and 7.09 (d,J=5.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH3:39])[CH2:38][O:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:39][C:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:37])[CH3:38])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(C)(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2 g), 2-(4-fluorophenyl)-2-methyloxirane (1.2 g), potassium carbonate (1.4 g) and DMF (20 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.8 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>CCO.CC(C)=O>[Cl-:19].[N+:26]([C:23]1[CH:22]=[C:21]([N+:29]([O-:31])=[O:30])[CH:20]=[CH:25][C:24]=1[N+:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:18][CH:17]=1)([O-:28])=[O:27]
Reactant: CCOc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CC(C)=O
Product: CCOc1cc(-c2cc[n+](-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc2)ccc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 102 °C
Yield: 88.1 %

Procedure:
To 4-[3-(ethyloxy)-4-nitrophenyl]pyridine (2.2 g, 9.0 mmol) in 80 mL of EtOH was added, 1-chloro-2,4-dinitrobenzene (14.6 g, 72.06 mmol). The mixture was heated to 102° C. for 72 h. The mixture was cooled and rotovaped down. The product was taken up in acetone. The resulting slurry was filtered and washed with acetone. The product was dried under vacuum to give the title compound of step B (3.7 g, 7.93 mmol, 92%). MS (ESI): 411 [M+H]+.