Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([CH:15]([OH:17])[CH3:16])[C:9]1=[O:18])[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:39](O)=[O:40].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:2]([CH3:1])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([O:17][CH:39]=[O:40])[CH3:16])[C:9]1=[O:18])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1[C@@H](C(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H]([C@@H](C)OC=O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 1:3 mixture of methyl 3-methyl-2-[(3S,4R)-3-[(1RS)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (55 mg) was dissolved in tetrahydrofuran (2 ml) and triphenylphosphine (135 mg) and formic acid (19.4 μl) were added to the mixture. This mixture was cooled to 0° C. and a solution of diethyl azodicarboxylate (81 μl) in tetrahydrofuran (1 ml) was added. After stirring at the same temperature overnight, the mixture was diluted with ethyl acetate (30 ml), washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (5 g) eluting with hexane and ethyl acetate (10:1-2:1) to give 25 mg of methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:25])[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][C:61]1[CH:65]=[C:64]([Sn](C)(C)C)[S:63][N:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:25][C:4]1[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=[C:2]([C:64]2[S:63][N:62]=[C:61]([CH3:60])[CH:65]=2)[CH:3]=1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Reactant: COc1ccc2c(OCc3nnc4c(F)cc(Cl)cn34)ccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)ns5)cn34)ccnc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were added and stirring was continued at 80° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and urified by MPLC (CH2Cl2/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH: 9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]+. Calc'd for C21H16FN5O2S: 421.46
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH3:8].[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C1=C(c2ccccn2)CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 6 h
Yield: 179.1 %

Procedure:
A mixture of 3.2 g (12.8 mmol) of 1-benzyl-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine and 1.2 g of Pd(OH)2/C in 25 mL of MeOH was hydrogenated at 50 psi for 6 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by chomatography [CH2Cl2:MeOH:(2M NH3 in MeOH), 100:8:4) to give 1.86 g of the title compound.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Mg]Cl.C([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:19])[CH:12]=1)(=O)C.[O:20]1[CH2:24][CH2:23]CC1>>[F:19][C:13]1[C:12]([C:24]([OH:20])([CH3:23])[CH3:5])=[CH:11][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: C1CCOC1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C#N)c(F)c1
Agent: [Ce+3]
Agent: [Cl-]
Product: CC(C)(O)c1cccc(C#N)c1F
Temperature: 0 °C

Procedure:
To a stirred suspension of cerium (III) chloride (4.7 g, 15.0 mmol) in tetrahydrofuran (30 mL) at 0° C. was added drop-wise a solution of 3.0 M methyl magnesium chloride in tetrahydrofuran (6.0 mL, 19 mmol). The reaction mixture was stirred at 0° C., after which a solution of 4-acetyl-2-fluorobenzonitrile (2.5 g, 15.0 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then quenched with 5 mL of 2N acetic acid added drop-wise. The reaction mixture was thereafter poured into water (200 mL), acidified to a pH of 2 with 2N acetic acid, and then extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with water and brine, dried over magnesium sulfate (MgSO4), and then concentrated to give an oil. The oil product was purified using chromatography on silica gel, eluting with ethyl acetate/hexane (1:1) to yield 1.95 g of 2-fluoro-(1-hydroxy-1-methyl-ethyl)-benzonitrile final product as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].CS(O[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.2 g) is heated at 70° C. for 10 minutes in dimethyl sulfoxide (50 ml), to which is added 1,4-butanediol (4.5 g). The mixture is heated for one further hour. To this reaction mixture is added dropwise a solution of 3-(octadecyloxy)propyl methanesulfonate obtained in Reference Example 1 (4.06 g) in dimethyl sulfoxide (15 ml), and the mixture is stirred at 70° C. for one hour. The reaction mixture is poured into cold water, and the mixture is subjected to extraction with a mixture of hexane and ethyl acetate. The extract is washed with water and then dried, and the solvents are then distilled off under reduced pressure. The residue is subjected to purification by means of silica gel column chromatography to obtain the above-titled compound (2.2 g).
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][CH2:7][S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])([F:4])[F:3].[F:14][C:15]([S:18][CH2:19][CH2:20]OS(C(F)(F)F)(=O)=O)([F:17])[F:16].[C:29]([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:29][C:11]([S:8]([CH2:7][CH2:6][S:5][C:2]([F:1])([F:4])[F:3])(=[O:9])=[O:10])([CH2:20][CH2:19][S:18][C:15]([F:17])([F:16])[F:14])[C:12]#[N:13]
Reactant: N#CCS(=O)(=O)CCSC(F)(F)F
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C#N)(CCSC(F)(F)F)S(=O)(=O)CCSC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2-trifluoromethylsulfanyl-ethanesulfonyl)-acetonitrile (190 mg, 0.81 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (340 mg, 1.22 mmol) and K2CO3 (340 mg, 2.44 mmol) in 1,2-dimethoxyethane (10 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient of EtOAc/cyclohexane) to afford compound II-26 (20 mg, 7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[OH:16][N:15]=[C:9]([C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccccn1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl picolinoylacetate (0.500 g, 2.6 mmol) in acetic acid (0.5 mL) was added a solution of sodium nitrite (0.238 g, 3.4 mmol) in water (0.5 mL), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (0.5 mL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353 g, 1.6 mmol, 61%) as a white solid. 1H NMR (DMSO) δ 1.17 (3H, t), 4.22 (2H, q), 7.74 (1H, m), 8.04-8.11 (2H, m), 8.74 (1H, m), 12.87 (1H, s). LCMS (2) Rt: 1.09 min; m/z (ES+) 223.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1Cl>C1(C)C(C)=CC=CC=1.[Cu]>[C:1]1([O:11][C:21]2[CH:20]=[CH:19][C:18]([N+:23]([O-:25])=[O:24])=[CH:17][C:16]=2[Cl:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Oc1cccc2ccccc12
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 144 g (1 mol) of α-naphthol in 1 liter of xylene were added 65 g (1 mol) of finely powdered 88% potassium hydroxide. The mixture thus obtained was boiled under N2 -atmosphere in an apparatus equipped with an effective water trap under constant stirring until no water was separating any more and the head temperature had risen to 137° C. Then, 500 ml of dimethylformamide were added, The solution thus obtained was boiled for a further two hours under nitrogen in the apparatus equippped with an effective water trap; then, 500 ml of solvent were distilled therefrom. The residue was allowed to cool off under nitrogen to 100° C., and 211 g (1 mol) of 3,4-dichloronitrobenzene and 1 g of copper powder were added. Then it was refluxed under nitrogen while stirring for 8 hours (approx. 140° C. bottom temperature). Afterwards it was allowed to cool off to ~50° C., approx. 30 g of kieselguhr were added, the mixture thus obtained was stirred, and the undissolved substance was removed by suction filtration and washed with xylene. The filtrate united with the wash liquid was evaporated in vacuo to dryness. The residue was dissolved in warm toluene. The obtained solution was extracted thrice with separate portions of 500 ml of 1 N sodium hydroxide solution and, subsequently, twice with separate portions of 500 ml of water. Then, the toluene phase was evaporated to dryness in vacuo (crude yield: 290 g, 96% of theory). The residue was stirred with 1.7 liter of gasoline (boiling range 80°-110° C.) at approx. 85° C. Most of the crude product dissolved; some resin remain undissolved. The solution decanted therefrom was allowed to cool off slowly. First, the product precipitated oily; however, by trituration at approx. 50° C., crystals were obtained. Then it was cooled for several hours to 5° C. and the crystalline product was removed by suction filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:15]([OH:16])[CH:14]=[C:13]([CH2:12][Cl:11])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 4-chloroacetoacetate (0.387 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[CH3:28][C:29]1(C)[C:33](C)(C)OB(C(C)=C)O1>COCCOC>[F:16][C:4]1[CH:5]=[C:6]([C:29]([CH3:33])=[CH2:28])[CH:7]=[C:2]([F:1])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2F)n1
Solvent: COCCOC
Product: C=C(C)c1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 90 °C

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3/1, 0.09 M) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.5 equiv.) and PdCl2(dppf)-CH2Cl2Adduct (0.1 equiv.). The reaction was heated to 90° C. in an oil bath for 15 min. The mixture was cooled to rt and partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography (Analogix, eluting with 0-100% ethyl acetate). The pure fractions were concentrated to yield methyl 6-(2,6-difluoro-4-(prop-1-en-2-yl)phenyl)-5-fluoropicolinate. LC/MS=308.2 (M+H), Rt=0.99 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.15 (s, 3 H), 4.01 (s, 3 H), 5.23 (s, 1 H), 5.47 (s, 1 H), 7.11 (d, J=9.39 Hz, 2 H), 7.65 (t, J=8.41 Hz, 1 H), 8.26 (dd, J=8.61, 3.91 Hz, 1 H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)[O:20][C:23]=2[CH:24]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(-c3nc4ccc(Cl)cc4o3)ccc2n1C1CCOCC1
Yield: 1.4 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-5-chlorophenol (0.15 g, 1.05 mmol), anhydrous DMF (10 mL) and WSC (0.22 g, 1.14 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.38 g, 2.00 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (5 mg, 1.4% yield) as an orange solid.
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])CC)([CH3:3])[CH3:2].Cl[PH:11][O:12][CH2:13]N(C(C)C)C(C)C.[O:21]=[C:22]([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(Cl)Cl.C(OCC)(=O)C>[CH:7]([N:4]([CH:1]([CH3:2])[CH3:3])[P:11]([O:12][CH3:13])[O:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:21])[CH3:28])([CH3:8])[CH3:9]
Reactant: CC(C)N(COPCl)C(C)C
Reactant: CC(=O)CCCCO
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COP(OCCCCC(C)=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
To a rapidly stirred solution of diisopropylethylamine (2.3 ml, 13 mmol) and chlorodiisopropylaminomethoxyphosphine (1.4 ml, 6.5 mmol) in CH2Cl2 (15 ml) was added dropwise to a solution of 5-oxo-1-hexanol (0.58 g, 5 mmol) in CH2CL2 (7 ml) over 10 min. The reaction was stirred at room temperature for an additional 10 min, diluted with ethyl acetate (100 ml) and extracted with saturated aqueous NaCl (with 5% NaHCO3 5, 3×75 ml). The ethyl acetate layer was dried over MgSO4, filtered, concentrated and distilled in vacuo to yield 0.65 g of the methyl ketone phosphoramidite (50%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[CH:27]=[N:28]3)=[CH:23][C:22]=2[O:40][CH3:41])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9213.9 %

Procedure:
Triphenylphosphine (1.7 g, 6.5 mmol) was added under nitrogen to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.53 g, 5 mmol) in methylene chloride (20 ml), followed by the addition of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (1.29 g, 6 mmol), (prepared as described for the starting material in Example 1), and by a solution of diethyl azodicarboxylate (1.13 g, 6.5 mmol) in methylene chloride (5 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was poured onto a column of silica and was eluted with ethyl acetate/petroleum ether (1/1 followed by 6/5, 6/4 and 7/3). Evaporation of the fractions containing the expected product led to an oil that crystallised following trituration with pentane. The solid was collected by filtration and dried under vacuum to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (232 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8](OC)=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH:24]([O-])([O-])OC.C([O-])(=O)C.[NH4+:33]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]2[C:6](=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:13]=[CH:24][NH:33][C:8]2=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(OC)c(OCCCN2CCCCC2)cc1N
Reactant: COC([O-])[O-]
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 mg (3.1 mmol) of methyl 5-methoxy-4-(3-piperidinopropoxy)anthranilate, 0.99 g (9.3 mmol) of methyl orthoformate, 0.72 g (9.3 mmol) of ammonium acetate, and 5.0 mL of methanol. The reaction was carried out at 120° C. for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 0.89 mg (reaction yield: 90%) of 6-methoxy-7-(3-piperidinopropoxy)quinazolin-4-one.
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:21]>O>[Cl:21][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2onc(O)c2c1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
3-Hydroxy-5-methyl-1,2-benzisoxazole (15.0 g, 100.6 mmol; preparation: Australian Journal of Chemistry (1977), 30(8), 1847-50) were suspended in triethylamine (15.4 ml, 110.6 mmol), and phosphorus oxytrichloride (37.0 g, 22.5 ml, 241.4 mmol) was added dropwise with cooling to this mixture at room temperature. Since stirring of the reaction mixture became almost impossible after about half the amount of phosphorus oxytrichloride had been added dropwise, the temperature was raised to 50° C. After dropwise addition of the total amount of phosphorus oxytrichloride, the reaction mixture was heated at 130° C. for 5 h, after which the reaction was complete according to TLC. After cooling, the mixture was slowly added dropwise to water (200 ml) while cooling, the aqueous phase was extracted 3 times with MtB ether, the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. This resulted in 14.6 g of 3-chloro-5-methyl-1,2-benzisoxazole (yield: 87%) as viscous oil which solidified overnight. MS (MSD) m/z 168 [M+H+].
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([SH:16])[CH2:14][SH:15]>>[C:1]1([CH:11]2[S:16][CH2:13][CH2:14][S:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: SCCS
Reactant: O=Cc1cccc2ccccc12
Product: c1ccc2c(C3SCCS3)cccc2c1
Yield: 95.9 %

Procedure:
Following the general procedure as in Example 1, 38.27 gm (0.245 moles) of α-naphthaldehyde and 23.58 gm (0.25 moles) of 1,2-ethanedithiol gave, after evacuating the volatiles, 54.56 gm (0.235 moles) of an orange colored oil (96% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(NC(=O)c1cc3ccccc3cn1)n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a solution of 0.031 g (0.18 mmol) of isoquinoline-3-carboxylic acid in DMF (1 mL) was added 0.085 g (0.22 mmol) of HBTU and 0.1 mL of DIEA. The mixture was stirred for 5 min, then added 0.04 g (0.18 mmol) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester in one portion. The reaction mixture was stirred for 1 h. After usual workup, 45 mg (73%) of 1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was isolated after purification by column chromatography eluting with DCM/methanol (v/v from 15:1 to 10:1). LCMS: 437 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 12.8 (s, 1H), 9.41 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.84 (t, 1H), 7.77 (m, 3H), 7.51 (d, 2H), 7.32 (m, 4H), 5.63 (s, 2H), 3.99 (s, 3H) ppm.