Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1.F[B-](F)(F)F.C1(C2C=C(C3C=CC=CC=3)C=C(C3C=CC=CC=3)[O+]=2)C=CC=CC=1.[N-:48]=[N+:49]=[N-].[Na+]>C(O)C.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][N:14]=[N+:48]=[N-:49])=[CH:11][C:10]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
A stirred solution of 4-(4-chlorophenylthio)-3,5-dichlorobenzylamine (3.59 g, 11.3 mmol) in absolute ethanol (30 ml) at ambient temperature was treated in one portion with 2,4,6-triphenylpyrylium tetrafluoroborate (3.58 g, 9.06 mmol). The mixture was stirred 30 minutes, diluted with dimethylformamide (30 ml), and stirred 16 hours. The solvent was evaporated under vacuum at 60° C. and the residue was triturated with diethyl ether (2×25 ml). The residual solid was dissolved in dry dimethylformamide (23 ml), dry sodium azide (2.27 g, 34.9 mmol) was added, and the mixture was stirred at 130° C. for 6 hours and ambient temperature for 4 days. The mixture was diluted with water (250 ml) and extracted twice with diethyl ether. The combined extracts were washed with water (2X) and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was disolved in dichloromethane, silica gel (60 g) was added, and the mixture was dried under vacuum, placed on a column of silica gel (600 ml), and eluted in 50 ml fractions with 1:2 (v/v) dichloromethane-hexane. After a forerun, fractions 8-14 were combined and evaporated under vacuum to provide 320 mg oily 4-(4-chlorophenylthio)-3,5-dichlorobenzyl azide. Fractions 15-22 were combined, evaporated under vacuum, and the residue was chromatographed on one 20 cm×20 cm 1500μ silica gel preparative thick layer chromatography plate developed with 1:2 (v/v) dichloromethanehexane. Product was eluted with dichloromethane and solvent was evaporated under vacuum to provide an additional 62 mg of oily azide (total yield: 382 mg [10%]).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](N)=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].C[N:29](C)C=O>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N:29]=[CH:22][N:23]([CH3:25])[CH3:24])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(N)ccc1S(=O)(=O)NC(C)(C)C
Product: COC(=O)c1ccc(N=CN(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 55 °C

Procedure:
A mixture of 3.15 g of N-tert-butyl4-amino-2-methoxycarbonylbenzenesulfonamide, 2.2 ml of N,N-dimethylformamide dimethyl acetal and 60 ml of N,N-dimethylformamide is stirred at 50-60° C. until the reaction has ended. The volatile components are then distilled off under reduced pressure. The residue is washed with a little diisopropyl ether. This yields 3.52 g of the desired amidine derivative.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([O:20][CH3:21])[O:18][C:17](=[O:22])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:23]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:23][C:16]1[C:17](=[O:22])[O:18][CH:19]([O:20][CH3:21])[C:15]=1[CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrBr
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1OC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC(O)C1=C(Br)C(=O)OC1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.3 g. of 4-(1-hydroxytridecyl)-5-methoxy-2(5H)-furanone and 0.5 ml of carbon tetrachloride is cooled to 0° and 0.55 ml of a 3.1M solution of bromine in carbon tetrachloride is added dropwise over 15 minutes. Two drops of glacial acetic acid are added and the mixture is allowed to warm to room temperature. The reaction is monitored by TLC. After one hour, the mixture is cooled to 0° and 25 ml of pyridine is added over 5 minutes. The mixture is stirred for one hour, filtered to remove pyridine hydrobromide and solvent removed to give a residue which is purified by flash chromatography to give 3-bromo-4-(1-hydroxytridecyl)-5-methoxy-2(5H)-furanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:16][CH:17]([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][CH:17]([F:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cccc(OCC(F)F)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (3.506 g; 16.40 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 17 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2,2-difluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[CH2:21][C:22]([OH:24])=O)[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:48][O:49][CH2:50][CH2:51][NH:52][CH3:53]>ClCCl.O>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[CH2:21][C:22]([N:52]([CH2:51][CH2:50][O:49][CH3:48])[CH3:53])=[O:24])[CH3:2]
Reactant: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)O
Reactant: CNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)N(C)CCOC
Temperature: 25 °C
Reaction time: 14 h
Yield: 13.2 %

Procedure:
2-Ethyl-3,5-dihydroxy-6-(4-methoxybenzoyl)phenyl-acetic acid (0.18 g, 0.53 mmol) obtained in Example 10, Step 1 was dissolved in dichloromethane (2.0 mL). To the solution were added 1-hydroxybenzotriazole hydrate (0.11 g, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g, 0.72 mmol) and 2-methoxy-N-methylethylamine (0.12 mL, 1.1 mmol), followed by stirring at room temperature for 14 hours. To the reaction mixture was added water (10 mL), and the mixture was extracted with chloroform (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (methanol/chloroform=1/9) to obtain Compound 10 (28 mg, 13%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:10]2=[O:20])=[CH:5][CH:4]=1.B(Br)(Br)Br.CCCCCC>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
4.10 g (15.2 mM) of (5R)-3-(4-methoxyphenyl)-5-phenyl-2-oxazolidinone synthesized in Example 1 was dissolved in 100 ml of methylene chloride and cooled to -75° to 70° C. on a dry ice-acetone cooling bath. To the solution, 31.5 ml of 1.0M-solution of boron tribromide in methylene chloride was added dropwise in 43 minutes, followed by stirring for 1 hour at -75° to -70° C. and further stirring for 2 hours at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by evaporation under reduced pressure to obtain a residue. To the residue, an appropriate amount of hexane was added to precipitate a crystal. The crystal was recovered by filtration, thus obtaining 3.13 g of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 80.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[CH3:19][O:18][C:16]([C:10]1[C:9]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:14][CH:13]=[C:12]([O:30][CH2:29][C:28]([F:32])([F:31])[F:27])[N:11]=1)=[O:17]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(OCC(F)(F)F)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (500 mg, 1.16 mmol), 2,2,2-trifluoroethanol (84 μl, 1.16 mmol), cesium carbonate (415 mg, 1.27 mmol) and dry DMSO (5 ml) was stirred at r.t. for 3 h. The reaction mixture was poured into ethyl acetate (100 ml) and extracted with saturated sodium bicarbonate (aqueous solution). The organic layer was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried, evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as white solid (456 mg, 87%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12]Cl)=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12][O:2][CH3:1])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: ClCc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COCc1cnc(Cl)c(Cl)c1
Temperature: 60 °C

Procedure:
Under argon and at room temperature, 4.14 g (23 mmol) of sodium methoxide (30 percent strength solution in methanol) was added dropwise within 5 minutes to a solution of 4.11 g (20.9 mmol) of 2,3-dichloro-5-(chloromethyl)-pyridine [prepared from 2,3-dichloro-5-(hydroxymethyl)-pyridine by reaction with thionyl chloride] in 40 ml of methanol. The reaction mixture was subsequently heated to 60° C. for 3 hours. After the reaction had ended, the solvent was distilled off and the residue was admixed with 100 ml of water and extracted with dichloromethane (3×75 ml). The organic phase was dried over magnesium sulfate and evaporated. The yield of the product was 4.06 g (90.4 percent) of a yellow oil, purity (GC) 90.8 percent.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][OH:42])[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@H:28]([OH:40])[C@@H:27]([CH2:41][O:42][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of t-butyldiphenylsilyl chloride (8.66 g, 31.53 mmol), 4-dimethylaminopyridine (5.12 g, 42.04 mmol) and methyl 2-azido-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) (7.21 g, 21.02 mmol) in dry 1,2-dichloroethane (100 mL) was stirred at 80° C. for 2 hours. The resulting clear solution was cooled to room temperature, diluted with CHCl3 (300 mL), washed with H2O (3×200 mL), brine solution (200 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—ether 2:1 as the mobile phase to give methyl 2 -azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl-1-thio-β-D glucopyranoside (10) (9.73 g, 80%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.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>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
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: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.9 %

Procedure:
To a mixture of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, mmol) in dioxane (3.3 mL) and water (3.3 mL), were added 2-chloro-4-methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85° C. for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR=2.96 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31]CN=C=NCCCN(C)C.Cl.C(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:22]3[C:16]4[O:15][C:14]([NH:13][C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[CH:24][C:25]=2[N:30]=[CH:31]1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)c(N)c4)c3o2)cc(OC)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.16 g (0.228 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine, 0.068 g (0.346 mmol) EDC-HCl, 0.043 g (0.345 mmol) DMAP, 0.012 g (0.27 mmol) formic acid), and 7 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=9:1) to afford ca. the title compound. 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-1,2-diamine as described in Example 1.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:30]=[CH:29][CH:28]=[C:27]([NH2:26])[CH:32]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc(N)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-aminophenyl boronic acid. Mass spectrum (ESI) 407.2 (M+1)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26])(=[O:22])[CH3:21].CC[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][S:26][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])(=[O:22])[CH3:21]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: O=C(O)CCCBr
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CSC(=O)CCCBr)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 4-bromobutyric acid (5.1 g, 30.6 mmoles) and 1,1′-carbonyldiimidazol (5.61 g, 34.6 mmoles)) in chloroform (50 ml) is left at room temperature under stirring for 1 hour. To the reaction mixture N-acetyl cysteine (5 g, 30.6 mmoles) dissolved in N,N-dimethylformamide (5 ml) and sodium ethylate (50 mg) is added under stirring. After 24 hours the solution 2 is washed with HCl 1% and brine, the organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel column, eluting with ethyl acetate/chloroform 7/3. N-acetyl-S-(4-bromobutyroyl) cysteine is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(O)(C)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=1
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Solvent: CC(C)O
Product: CC(C)(C)CNc1nc(Cl)cc(NC(C)(C)C)n1

Procedure:
After dissolving 5.0 g of 2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reaction mixture is boiled under reflux for 20 hours. Subsequently, the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The evaporation residue is purified by chromatography on a silica gel column by using a 9:1 mixture of hexane/ethyl acetate as eluent. After recrystallizing the eluted product from hexane, the title product is obtained in a yield of 4.05 g (65.9%), m.p.: 115°-119° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[O:51])=[CH:48][N:47]=1>C1COCC1.C(Cl)Cl.O>[OH:51][CH:50]([C:49]1[CH:48]=[N:47][C:46]([C:45]([F:55])([F:44])[F:54])=[CH:53][CH:52]=1)[C:11]1[C:6]2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:3](=[O:35])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(OC(F)(F)F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)nc3)c(Oc3cccc(OC(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (156 mg, 0.32 mmol) in THF (6 mL) at −78° C. was added LDA (0.8 mL, 1.6 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 6-(trifluoromethyl)nicotinaldehyde (112 mg, 0.64 mmol) in THF (3 mL) was added dropwise. The reaction was stirred at −78° C. for 45 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:6) to give 5-(hydroxy(6-(trifluoromethyl)-pyridin-3-yl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 18.6% yield) as a solid. LCMS: [M+-THP-OH—H] 569 and TR=2.162 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:33][O:34][CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:37][CH2:36][CH2:35][O:34][CH3:33])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)NCCOC
Yield: 88 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (120 mg, 0.25 mmol), methoxyethylamine (45 μL, 0.52 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 117.9 mg of the title compound as a white solid (88%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 72% of theory, C35H42N6O5 (626.8) Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1) ##EQU95##
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[S:7].[Br:8][CH2:9][CH2:10][CH2:11]Cl>C(O)C>[Br-:8].[S:1]1[C:2]2[S:7][CH2:9][CH2:10][CH2:11][N+:3]=2[CH2:4][CH2:5][CH2:6]1
Reactant: ClCCCBr
Reactant: S=C1NCCCS1
Solvent: CCO
Product: C1CSC2=[N+](C1)CCCS2
Product: [Br-]

Procedure:
A mixture of 66.5 g. of tetrahydro-1,3-thiazin-2-thione and 83 g. of 1-bromo-3-chloropropane in 200 ml. of ethanol is refluxed for 24 hours. The solvent is removed under vacuum and the residue triturated with ether, then acetone. The product is recrystallized from ethanol yielding 2,3,6,7-tetrahydro-(1,3)-thiazino-[2,3-b]-(1,3)-thiazinium bromide.