Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31](Cl)(=[O:33])=[O:32])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:33])=[O:32])([CH3:17])[CH3:18]
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1OC

Procedure:
As described under 1.2, 8.25 g (0.04 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 13.3 g (0.044 mol) of 2,4,6-tris(isopropyl)benzenesulfonyl chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/-hexane, 14.25 g (75%) of α-(2,4,6-tris(isopropyl)phenylsulfonyl-oxyimino)-3,4-dimethoxy-benzyl cyanide are obtained in the form of beige crystals having a melting point of 90.5-93.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 352 nm (ε=11000) that extends to 433 nm. Elemental analysis: C25H32N2O5S (472.6)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=O.[OH-].[Na+].S(Cl)(Cl)=O>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.ClCCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=3)=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2cccc(F)c2)nc2cccc(Cl)c12
Yield: 99.9 %

Procedure:
When 42.9 g of 6-chloroanthranilic acid, 39.6 g of 3-fluorobenzoyl chloride, 20 g of 50% strength sodium hydroxide solution, 0.45 g of benzyltriphenylphosphonium chloride, 620 g of 1,2-dichloroethane and 32.7 g of thionyl chloride are used as starting materials and the procedure described in Example 1 is employed, 68.8 g of 5-chloro-2-(m-fluorophenyl)-4H-3,1-benzoxazin-4-one of melting point 120°-123° C. are obtained. The yield is virtually quantitative and the purity is 98% according to HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(C)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(p-tolyloxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 2-(p-tolyloxy)-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:36][CH2:37][C:38]#[N:39])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>C(O)C.O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:36][CH2:37][C:38]#[N:39])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OCCSCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#CCSCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.1 %

Procedure:
In a mixture of 40 ml of ethanol and 5 ml of dioxane is suspended 2.78 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-cyanomethylthioethoxyimino)acetate, followed by addition of 5 ml of 2N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 2 hours, at the end of which time 40 ml of ethanol and 80 ml of tetrahydrofuran are added. The mixture is further stirred at room temperature for 19 hours. The reaction mixture is concentrated under reduced pressure and 500 ml of ether is added to the residue (about 50 ml). The resulting crystals are collected by filtration and washed with ether. The crystals are dissolved in a mixture of water, tetrahydrofuran and ethyl acetate (1:1:2) and the solution is adjusted to pH 2 and shaken. The organic layer is separated, washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and a mixture of ether and petroleum ether (2:1) is added to the residue. The resulting powders are collected by filtration to give 2.14 g of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-cyanomethylthioethoxyimino)acetic acid as light yellow powders.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36]([OH:38])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: C1CCNC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (400 mg) and pyrrolidine (59 mg) were dissolved in DMF (10 ml), WSC.HCL (217 mg) and HOBt (150 mg) were added, and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was poured into 10% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extracts were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (420 mg).
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11](Cl)([S:26]([CH2:28][CH3:29])=[O:27])[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCCC1C=NCCC2>C(OCC)(=O)C>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11]([S:26]([CH2:28][CH3:29])=[O:27])=[C:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS(=O)C1(Cl)CC2C(Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)C(Cc3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
A solution of benzyl 6-benzyl-3-chloro-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (79) (0.020 g) in ethyl acetate (2 ml) was treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.0069 g). It was stirred for 15 mins. at room temperature and then the solution was washed with brine and dried over sodium sulphate. Concentration of the solution gave benzyl 6-benzyl-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (80) (0.016 g) as a colourless gum; νmax (CHCl3) 2990, 1790, 1725 and 1590 cm-1 ; λmax (ethanol) 308 nm; τ (CDCl3) 2.5-2.9 (10H, m, phenyls), 4.66 and 4.82 (2H, ABq J 12 Hz, OCH2), 5.99 (1H, ddd J 10, 8 and 3 Hz, C5-H), 6.39 (1H, ddd J 9 6 and 3 Hz, C6-H), 6.6-7.2 (4H, m, C4-H2 and C8-H2), 7.20 (2H, q J 71/2 Hz, SCH2) and 8.76 (3H, t J 71/2 Hz, CH3); (M+ at m/e 409.1333 C23H23NO4S requires 409.1348).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39]([C:5]3[CH:6]=[C:7]([NH:8][S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=4)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=3)[CH:38]=[CH:37][C:35]=2[N:36]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3cccc(OC(F)F)c3)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)cc2s1
Temperature: 100 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a 50 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (98 mg, 213 μmol), 2-amino-6-bromobenzothiazole (49 mg, 213 μmol), tetrakis(triphenylphosphine)palladium (25 mg, 21 μmol), sodium carbonate (213 μl, 425 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(5-(2-aminobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (48 mg, 47% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H13ClF2N4O3S2: 482.0. found 483.0.1H NMR (300 MHz, MeOH) δ ppm 6.88 (t, J=73.08 Hz, 1H) 7.38-7.71 (m, 5H) 7.91 (d, J=1.17 Hz, 1H) 8.17 (d, J=2.19 Hz, 1H) 8.46 (d, J=2.34 Hz, 1H)
Reaction SMILES: P(=O)(O)O.N[C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[CH:8][N:7]=1.Br[Si](C)(C)C>>[N:7]1[CH:8]=[C:9]2[C:13]([NH:12][CH:11]=[N:10]2)=[N:14][CH:6]=1
Reactant: Nc1ncc2[nH]cnc2n1
Agent: C[Si](C)(C)Br
Agent: O=[PH](O)O
Product: c1ncc2nc[nH]c2n1
Yield: 35 %

Procedure:
Example 1 describes preparation of 2-amino-9-[CR(-)-1-hydroxymethyl-3-diethylphosphono)-1-propyloxymethyl]- 9H-purine 1-5 as shown in Scheme 1. Briefly, the synthesis set forth in Scheme 1 involves, regiospecifically opening 2-(benzyloxymethyl) oxirane 1-1 with lithiated diethyl methylphosphonate in the presence of boron trifluoride etherate to afford 1-2 in 94% yield (Example 1, section (a.)). Compound 1-2 was then transformed to the corresponding chloromethyl ether and condensed with 2-amino-6-chloropurine in the presence of sodium hydride to give the nucleoside phosphonate 1-3 in 53% yield (Example 1, section (b.)). Treatment of 1-3 with 10% palladium/carbon and ammonium formate gave the 2-aminopurine phosphonate 1-4 in 66% yield (Example 1, section (c)). Finally, compound 1-4 was treated with excess bromotrimethylsilane to give the desired nucleoside phosphonate 1-5 in 35% yield (Example 1, section (d.)). Optical purity of compounds was determined by HPLC using a chiral column.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[Cl:17]N1C(=O)CCC1=O.CN(C)C=O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[C:5]([Cl:17])=[C:4]([Cl:16])[N:3]=1
Reactant: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c(Cl)c(NCC2(CO)CCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl)methyl]amino]pyrimidine (0.24 g, 2.0 mmol) were added N-chlorosuccinimide (0.27 g, 2.0 mmol) and dimethylformamide (1.5 ml), and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give colorless prism crystals (0.3 g, 54.2%), m.p. 179-181° C. (acetone).
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17]Br.C(Cl)Cl>C(#N)C.O>[CH3:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17][O:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cccc(O)c2[nH]1
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1nc2cccc(OCc3c(C)cc(F)cc3C)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.1 %

Procedure:
4-hydroxy -2-methylbenzimidazole (0.57 g, 3.8 mmol) was dissolved in acetonitrile (4 ml). To the solution were added sodium hydroxide (0.17 g, 43 mmol) (dissolved in 1 ml water) and 2,6-dimethyl-4-fluorobenzylbromide (0.82 g, 3.8 mmol) dissolved in acetonitrile (6 ml) and the reaction mixture was refluxed for 80 min. and was stirred for 20 h. at ambient temperature. To the reaction mixture was added methylene chloride (25 ml) and water (25 ml). The organic layer was separated, washed three times with 2 M NaOH, dried over sodium sulfate and was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and was then purified twice by column chromatography on silica gel a) methylene chloride: methanol (10:1) b) ethyl acetate: methanol:acetic acid: water (96:6:6:4). There was obtained 0.066 g (6%) of the title compound.
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][N+:8]=1[O-])[CH3:6].[OH-].[Na+]>C(Cl)Cl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][N:8]=1)[CH3:6]
Reactant: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous trichloride (7.2 mL, 82 mmol) in CH2Cl2 was added to a cooled 0° C. solution of 2-ethyl-4-nitro-pyridine 1-oxide (3 g, 17.8 mmol) in CH2Cl2. The reaction was stirred for 2 hours and then warmed up to rt. After 3 hours the mixture was poured into ice, made basic with 15% NaOH and extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated to a yellow oil that solidified on standing (2.56 g, 95%). 1H NMR (400 MHz, CDCl3): δ 1.40 (t, J=7.6 Hz, 3H), 3.14 (d, J=7.6 Hz, 2H), 8.04 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 8.92 (d, J=5.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: S=C(Cl)Cl
Reactant: C=CCNCCCNc1ccc(Cl)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CCN1CCCN(c2ccc(Cl)cc2C)C1=S
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of the diamine of Step C (5.6 g) and triethylamine (6.6 mL) in dry chloroform (70 mL) under nitrogen was added thiophosgene (1.79 mL). After 30 minutes at ambient temperature, additional thiophosgene (0.6 mL) was added. After 15 minutes, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title compound (3.1 g, 47.0%) as a white solid, m.p. 101-103° C.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[OH:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:31]([O-])(=[O:33])[CH3:32].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(O)(=O)C.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.CCCC(C)C.O>[C:31]([O:30][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:33])[CH3:32]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc2ccccc2c1O
Agent: [Pb+4]
Solvent: CCCC(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc2ccccc2c1OC(C)=O
Temperature: 55 °C
Yield: 95.1 %

Procedure:
cb) 2-octadecyloxy-1-naphthol 594 g (1.5 mol) 2-octadecyloxynaphthalene and 397 g (0.75 mol) lead tetraacetate are added to a mixture of 3 l glacial acetic acid and 600 ml acetic anhydride in a 10 l three-neck flask with stirrer, Claisen attachment, thermometer and cooler with a calcium chloride tube and it is heated to 55° C. Over a period of 4 days a further 400 g lead tetraacetate are added in portions (each of 100 g) at intervals of 24 hours while stirring. Afterwards the yellow solution which is formed is cooled to room temperature, stirred again for 30 minutes after addition of 1.5 l water, the crystal slurry which forms is aspirated and washed in portions with 2 l water. The wet crude product is dissolved in 4 l toluol and shaken three times with 1 l portions of water, three times with 1 l saturated sodium hydrogen carbonate solution and then again three times with 1 l water. After drying the toluol phase over sodium sulphate, aspiration and concentration by evaporation, 635 g brown crude product are obtained which is purified chromatographically as follows: the crystallizate obtained is dissolved in a mixture of 1.3 l toluol/isohexane 5:2 and the solution is applied to a silica gel 60 (Merck) column, inside diameter 11.5 cm, filling height 1.2 m. Toluol/isohexane 5:2 is used as the mobile solvent and fractions of ca 300 ml are taken. Fractions 9-52 are combined and concentrated by evaporation until constancy of weight. One obtains 324.2 g 2-octadecyloxy-1-naphthol acetate, mp 67°-68° C. This is dissolved without further purification in 1.8 l methanol while heating and cooled to 20° C. 93 ml concentrated sulphuric acid are added dropwise to the suspension which formed within 15 minutes without cooling and while stirring, whereby the temperature increases to 35° C. Subsequently it is heated for 2 hours under reflux, then cooled with an ice bath and stirred for a further 30 minutes while cooling on ice. The crystals which form are aspirated, washed with 150 ml ice-cold methanol and dried at 35° C. in a drying cupboard over diphosphorus pentoxide. One obtains 294.4 g (47.5% of the theoretical yield) 2-octadecyloxy-1-naphthol, colourless crystals, Fp 58°-59° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+]>CO>[C:13]1([S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])(=[O:12])=[O:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCCNS(=O)(=O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Then, 5.43 g of 6-aminocaproic acid methyl ester hydrochloride, 6.78 g of 1-naphthalenesulfonyl chloride and 3.03 g of triethylamine were dissolved in 50 mL of dichloromethane and stirred for 12 hours. The reaction mixture was washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 5.50 g of 6(1-naphthalenesulfonyl)aminocaproic acid methyl ester. The resulting 6-(1-naphthalenesulfonyl)aminocaproic acid methyl ester (3.35 g) was dissolved in methanol, and the solution was added with 20 mL of 1 N sodium hydroxide, and stirred for 3 hours. Then, the methanol was evaporated under reduced pressure, and the residue was made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.02 g of 6-(1-naphthalenesulfonyl)aminocaproic acid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[CH:12][S:13][C:6]=12.Cl.C([O-])(O)=O.[Na+]>CO.[Fe]>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[CH:12][S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of 3 (660 mg, 2.27 mmol) in MeOH (10 ml) was added conc. HCl (1 ml) and Fe (1.91 g, 34.8 mmol), and the reaction mixture was stirred at 0° C. for 3 hrs, neutralized with aqueous NaHCO3 solution and extracted with EtOAc, producing 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)-phenylamine (4) as a dark oil (500 mg, 83%), which was used directly in the next step. To a solution of the amine 4 (200 mg, 0.69 mmol) in DMF (10 ml) was added 3-oxo-3-(phenylamino)propanoic acid (1, 155 mg, 0.89 mmol), HOBT (121 mg, 0.89 mmol) and EDC (198 mg, 1.035 mmol). The reaction mixture was stirred at room temperature overnight, evaporated to dryness and the residue was dissolved in EtOAc and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc:hexane 3:1) to afford the title compound 5a (30 mg, 10% yield) as a white solid (after trituration with Et2O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.5 (s, 1H), 10.2 (s, 1H), 8.49 (d, J=5.48 Hz, 1H), 8.14 (d, J=5.48 Hz, 1H), 7.85 (dd, J=2.35 and 13.01 Hz, 1H), 7.59 (m, 3H), 7.42 (m, 2H), 7.30 (dt, J=1.96 and 7.43 Hz, 2H), 7.05 (t, J=7.24 Hz, 1H), 6.65 (d, J=5.28 Hz, 1H), 3.51 (s, 2H).