Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 42.3 %

Procedure:
Benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-1a) (517 mg, 1 mmol) was stirred a 10/1/2 solution of 6N NaOH (aq)/THF/MeOH (27 mL) at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 (ca. 50 mL), and the aqueous phase was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (15 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes) in three 5 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in 15 mL of absolute ethanol and evaporated on the rotovap (4×) to provide pure 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (174 mg, 42%) as a white solid. M.p 161-163° C. 1H NMR (CDCl3, 400 MHz): δ 3.78 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.99(d, J=8.8 Hz, 2H), 709-7.07 (m, 2H), 7.27-7.24 (m, 3H), 7.93 (d, J=8.8 Hz, 2H), 8.24 (d, J=8 Hz, 2H). MS 412 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CC(C)Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a mixture of 10 g of 6,7-dichloro-5-hydroxy-2-isobutylbenzo[b]thiophene and 200 ml 2-butanone is added a mixture of 6.9 g of ethyl bromoacetate in 50 ml of 2-butanone and by 6.6 g of potassium carbonate and 3.4 ml sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and 100 ml of ether. The organic layers are combined, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 12 g of ethyl[ (6,7-dichloro-2-isobutylbenzo[b]-thien-5-yl)oxy]acetate, mp 75°-76°.
Reaction SMILES: C(N(CC)CC)C.O[C@@H]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[NH:13][C:12]1=[O:32])C.C(C1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(O)=O>C(#N)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([C:17](=[N+:45]=[N-:46])[C:16](=[O:31])[CH2:15][CH:14]2[NH:13][C:12](=[O:32])[CH2:11]2)=[O:19])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (263 mg, 2.6 mmol) is added by syringe to a mixture of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (253 mg, 0.72 mmol) and p-carboxybenzene sulfonylazide (196 mg, 0.84 mmol) in dry acetonitrile (6 ml) at 0° C. When addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is then diluted with ethyl acetate (50 ml) and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed on a short silica gel column (ethyl acetate) to yield 222 mg, (81% overall from (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyl dimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one) of (3S,4R)-3-(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one as a white solid m.p. (dec.) 163° C. IR(CHCl3, CM-1) 3410, 2132, 1756, 1718, 1650, 1350, 1280, 1120; n.m.r. (CDCl3) δ7.9(2d-aromatic, 4), δ5.4(s, 2), δ6.2(brs, 1), δ4.1(m, 2), δ2.6-3.6(m, 4), δ1.32(d, 3, J=6.2).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1ccccc1
Yield: 84.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.58 ml (4.96 mmol) of benzoyl chloride under ice-cooling with stirring and the mixture stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 960 mg of the desired compound (84.9%, colorless needles), mp: 120.0°-121.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[NH2:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:5]2[C:6](=[O:8])[N:14]([CH:15]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:10])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)cc1
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 4.5-dichlorophthalic anhydride (0.91, 4.19 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid in 10 mL acetic acid was stirred under nitrogen for 6 hours. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 1.20 g (61%) of 3-(4,5-dichlorophthalimido)-3-(4-methoxyphenyl)propionic acid as a white powder. mp 182°-185° C; 1H NMR (DMSO-6, 250 MHz) δ8.19(s, 2H), 7.34 (d, 2H, J=8.7), 6.90 (d, 2H, J=8.7), 5.61 (t, 1H, J=7.8), 3.72 (s, 3H), 3.50-3.20 (m, 2H). 13 C NMR (DMSO-d6) δ171.6, 165.8, 158.8, 137.6, 131.0, 130.4, 128.4, 125.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14 N2O7. Theoretical: pending
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH:5]=[C:4]([NH:14][CH3:15])[N:3]=1.C1C(=O)N([Br:23])C(=O)C1>CC#N>[Br:23][C:5]1[C:6]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:7][C:2]([Cl:1])=[N:3][C:4]=1[NH:14][CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1cc(C(=O)N(C)OC)nc(Cl)n1
Solvent: CC#N
Product: CNc1nc(Cl)nc(C(=O)N(C)OC)c1Br
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (959 mg) in MeCN (21 mL) was added NBS (814 mg), and the reaction mixture was heated at 60° C. for 8 h. The solvent was removed, and the residue was purified by Biotage eluting with 50%-70 EtOAc/Hexanes (1.2 L) to give the title compound as a white solid (1.1 g). LC-MS (M+H)+=310.95.
Reaction SMILES: [C:1]([CH:3]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[N:2].[NH2:26][OH:27]>CO>[NH2:2]/[C:1](=[N:26]\[OH:27])/[CH:3]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CN(C(=O)OC(C)(C)C)C(C#N)CCC(C)(C)COC1CCCCO1
Reactant: NO
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CCC(C)(C)COC1CCCCO1)/C(N)=N/O
Temperature: 60 °C

Procedure:
To a stirred solution of tert-butyl [1-cyano-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]methylcarbamate (8.5 g, 23.98 mmol), in methanol (5 mL) was added 50% hydroxylamine (1.543 mL, 25.2 mmol). The mixture was heated to 60° C. for 3 hours (LC-MS indicates complete conversion) cooled and concentrated. Removal of excess hydroxylamine azeotropically with methanol gave tert-butyl [1-[(Z)-amino(hydroxyimino)methyl]-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]methylcarbamate: MS (ES+): 388.26 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]#[N:23])(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:24][NH:25][CH3:26])[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.8 %

Procedure:
To a solution of tert-butyl ({5-(2-chloropyridin-3-yl)-1-[(3-cyanophenyl)sulfonyl]-4-fluoro-1H-pyrrol-3-yl}methyl)methylcarbamate (489 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound as a pale-yellow oil (yield 152 mg, 39%). A solution of the obtained free base in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (44 mg) in ethanol (4 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 127 mg, 28%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccccc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 91.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.15 g of 2-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(2-fluorophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (63)).
Reaction SMILES: C1(S([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:11][C@H:12]2[O:17][C@@H:16]([O:18][CH3:19])[CH2:15][C@H:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13]2)(=O)=O)C=CC=CC=1.P(O)([O-])([O-])=O.[Na+].[Na+].O>CO.[Na].[Hg]>[CH2:21]([O:20][C@@H:14]1[CH2:13][C@H:12]([CH2:11][CH2:10][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[O:17][C@@H:16]([O:18][CH3:19])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CC(c2ccc(Cl)cc2Cl)S(=O)(=O)c2ccccc2)O1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@H]1C[C@H](OCc2ccccc2)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Yield: 92 %

Procedure:
To a mixture of 1-(2,4-dichlorophenyl)-2-(4(R)-benzyloxy-2(R)-methoxy-3,4,5,6-tetrahydro-2H-pyran-6(S)-yl)ethyl phenyl sulfone (0.06 g, 0.11 mmole) and anhydrous disodium phosphate (0.065 g, 0.45 mmoles) in dry methanol (5 ml) was added pulverized 5% sodium amalgam (0.2 g). The mixture was stirred at room temperature for twenty hourss, during which time an additional 0.4 g of 5% sodium amalgam was added in three portions. The reaction mixture was poured into water and extracted with ether. The ether solution was dried (MgSO4), filtered, and the solvent evaporated in vacuo to give the title compound as a colorless viscous oil (0.04 g); 'H NMR (CDCl3) δ 1.53 (1H, ddd), 1.58-1.88 (4H, m), 2.06 (1H, m), 2.70 (1H, ddd), 2.95 (1H, ddd), 3.42 (3H, s), 3.76 (1H, p), 4.16 ;l (1H, d), 4.52 (1H, d), 4.65 (1H, d), 4.78 (1H, dd), 7.13-7.40 (8H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].O=CC1C=CC(O)=C(OC)C=1>C(OCC)(=O)C.CCCCCC>[CH:19]([NH:22][C:16](=[O:18])[C@@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COc1cc(C=O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)NC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
Reaction of N-benzyloxycarbonyl-D-valine with isopropylamine by the method of Example 20, Part A afforded a quantitative yield of N-benzyloxycarbonyl-D-valine isopropylamide of Rf 0.61 (TLC, ethyl acetate/hexane, 1:1, vanillin spray).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].S(Cl)([Cl:28])(=O)=O.S(=O)=O>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([Cl:28])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Agent: O=S=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1cc(Cl)c(O)c(C(C)(C)C)c1)OCC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
71.2 g of 3,5-di-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester are dissolved in 200 ml of carbon tetrachloride. After addition of a few drops of pyridine, 40.5 g of sulphuryl chloride are added dropwise, with stirring, at about 0° C in the course of 45 minutes. The reaction mixture is then further stirred for 10 hours at room temperature, in the course of which the formation of sulphur dioxide is observed. After the reaction is terminated, the solvent is removed as far as possible completely in vacuo. The semi-crystalline residue is digested with water and washed neutral and finally recrystallised from aqueous isopropanol in order to purify it. Instead of isopropanol it is also possible to use ethylene glycol monomethyl ether. Toluene is also suitable for effecting recrystallisation, but the crude product must in this case be freed from water beforehand. The 3-chloro-5-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester is obtained in the form of colourless crystals (stabiliser 1) with a melting point of 116° C.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[C:6]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:20][C:21]1[C:26]([C:2]2[S:19][C:5]3[C:6]4[N:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:7]=4[O:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1cccnc1F
Reactant: COC(=O)c1cnc2c(c1)OCCc1cc(Br)sc1-2
Product: COC(=O)c1cnc2c(c1)OCCc1cc(-c3cccnc3F)sc1-2
Yield: 61 %

Procedure:
Methyl 9-bromo-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate was coupled with 2-fluoropyridin-3-ylboronic acid under Suzuki conditions to give methyl 9-(2-fluoropyridin-3-yl)-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate. Yield 61%. MS (ESI+): 357.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.54 g), 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (173 mg, 0.72 mmol) and potassium carbonate (0.25 g, 1.8 mmol) were combined in THF/H2O (20 mL/10 mL) and heated at reflux for 48 hours. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was separated, dried over MgSO4, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting sequentially with 1% methanol in dichloromethane, 2% methanol in dichloromethane, 3% methanol in dichloromethane, 6% methanol in dichloromethane, and 10% methanol in dichloromethane to give the title compound: Rf =0.48 (silica gel, 10% methanol in dichloromethane). Exact mass (FAB+): calculated for C32H36Cl2N3O3 calculated 580.2133. Found 580.2131.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([Cu])#[N:38]>CN1CCCC1=O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:9]2[C:10]3[N:11]([C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:16]=3)[CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:37]#[N:38])=[CH:3][CH:4]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2c(-c3ccc(C#N)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Temperature: 250 °C

Procedure:
Into a microwave reaction vial were placed 7-(4-chlorophenyl)-8-(4-methoxyphenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (51 mg, 0.10 mmol), CuCN (89.5 mg, 1.0 mmol), and 1-methylpyrrolidin-2-one (1.0 mL, dry). This mixture was heated to 250° C. in a microwave reactor for 8 h. HPLC/MS analysis indicated 55% conversion to desired product. The reaction mixture was cooled to room temperature and poured into 10% aqueous ammonium hydroxide solution. The resulting mixture was stirred at room temperature for 1 h. Solid was filtered off and purified by reverse phase preparative HPLC (without TFA). The title compound (8.6 mg) was obtained as a light yellow solid. HPLC/MS: retention time=3.5 min, [M+H]+=502.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH2:36])[CH:27]=[CH:28][C:29]=1[C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:36][C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=[CH:28][C:29]=1[C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: COc1cc(Nc2nc(-c3ccc(C(F)(F)F)cc3)cc(C(C)(C)O)n2)ccc1-c1cnc(C)s1
Yield: 24 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) was reacted with 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (66 mg, 0.3 mmol) to give the title compound as light yellow solid (36 mg, 24%). MS ISP (m/e): 501.1 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.98 (s, 1H), 7.77 (m, 3H), 7.54 (d, 1H), 7.34 (2 s, 2×1H), 7.10 (dd, 1H), 3.98 (s, 3H), 3.87 (s, 1H), 2.73 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C@:14]1([O:48][CH2:47][C@@H:37]([O:38]C(=O)C2C=CC=CC=2)[C@@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:17]1[O:18]C(=O)C1C=CC=CC=1)[O:15][CH3:16])(=O)C1C=CC=CC=1>CO>[CH3:16][O:15][C@@:14]1([O:48][CH2:47][C@@H:37]([OH:38])[C@@H:27]([OH:28])[C@@H:17]1[OH:18])[CH2:13][OH:12]
Reactant: CO[C@]1(COC(=O)c2ccccc2)OC[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CO[C@]1(CO)OC[C@@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A solution of sodium methoxide (0.5 M in methanol, 10.0 ml) was added to a vigorously stirred solution of 1,3,4,5-tetra-O-benzoyl-2-O-methyl-β-D-fructopyranose (10.0 g, 16.4 mmol) in anhydrous methanol. After stirring for 1.5 hrs at room temperature the reaction was complete. The pH was adjusted to 7.0 with Amberlite IRC-50 (˜4.0 g). The solids were removed by filtration and the filtrate was concentrated in vacuo. Purification on a silica gel column (methanol:dichloromethane, 4:1 and 3:1) provided the product as white foam 2.70 g (81%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A stirred solution of 6.9 g (0.03 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 60 ml of methylene chloride was treated with 10.8 g (0.06 mole) of 1-benzylpiperazine, added dropwise. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and stirred for an additional 1 hr. The methylene chloride portion was separated and the aqueous portion was extracted with 2×25 ml of methylene chloride. The methylene chloride portions were combined, dried and concentrated in vacuo, yielding 12 g of oil residue. This oil solidified when triturated with ligroin and was recrystallized from benzene/ligroin to yield 10.1 (91%) of tan crystals. A 500 mg portion was recrystallized from benzene/ligroin to yield 250 mg of fine white crystals, m.p. 109°-111° C.