Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=2[NH2:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=2[NH:17][C:25](=[O:26])[CH2:24][Cl:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (1.79 g, 5.51 mmol) in 20 mL of EtOAc and 20 mL of saturated NaHCO3 solution at 0° C. was added chloroacetyl chloride (1.09 mL, 13.8 mmol). After one hour, the solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-4-yl)butanoate (1.1 eq., prepared in Synthetic Example 8) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 213 to 214° C./DMF-EtOH.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:2]=1[O:21][C:18]1[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncccc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
To a 50 mL round-bottomed flask was added 2-chloro-3-(pyridin-4-yl)pyridine (0.75031 g, 3.9 mmol), 4-aminophenol (0.4302 g, 3.9 mmol), cesium carbonate (0.38 ml, 4.7 mmol) in DMSO at 80° C. Upon completion, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3 15 mL). The organic extract was washed with water (1 10 mL), brine (1 10 mL), dried with magnesium sulfate, filtered and concentrated. The residue was taken up in DCM and was loaded onto a SCX cartridge. The impurities were filtered off with DCM and MeOH. 4-(3,4′-Bipyridin-2-yloxy)aniline was filtered from cartridge using 2.0M ammonia in MeOH (MS 264.0).
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.Cl.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=[O:24])[CH2:22][NH2:23])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[C:1]([NH:23][CH2:22][C:21]([C:20]1[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:24])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCC(=O)NCC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 22.0 g (108 mM) of undecanoyl chloride in 185 ml of pyridine, 22.2 g (110 mM) of 4-methoxyphenacylamine hydrochloride was gradually added in 30 minutes under cooling and stirring below -5° C., followed by stirring for 30 minutes below -5° C. and heat-refluxing of 1 hour under stirring. After the reaction, the reaction mixture was cooled to room temperature and poured into 1 liter of cool water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from ethanol to obtain 13.9 g of decanoyl-4-methoxyphenacylamine (Yield: 38.8%).
Reaction SMILES: ClC(OC(Cl)C)=[O:3].[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][CH:27]=2)[C:16]1=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1ccc(CC2CN(Cc3ccccc3)CCO2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(CC2OCCN(Cc3ccccc3)C2=O)cc1

Procedure:
1-Chloroethyl chloroformate (2.98 ml, 27.7 mmol) was added in a steady stream to a stirred solution of the N-benzyl-2-(4-tert-butylphenylmethyl)morpholine (8.94 g, 27.7 mmol) obtained in (ii) in 1,2-dichloroethane (100 ml) at 0° C. The reaction was stirred for 20 minutes and then heated under reflux for 135 minutes before cooling and evaporation in vacuo. Methanol (100 ml) was then added and the reaction heated under reflux for 1 hour before cooling, evaporation in vacuo and dissolution in chloroform (about 200 ml). This solution was washed with saturated aqueous sodium hydrogen carbonate (20 ml), dried with sodium sulphate and evaporated in vacuo. The resulting gummy solid was recrystallised from chloroform/diethyl ether to afford the desired product as a white solid, 1.5 g, M.pt. 190°-193° C., M+ --HCl found: 233.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>CO>[N+:11]([C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1/[CH:1]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccccc2)s1
Yield: 67 %

Procedure:
A solution (0.33 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate in MeOH, was treated with benzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution a catalytic amount of pyrrolidine (0.01 eq.) was added. After 18 h at reflux additional pyrrolidine (0.01 eq.) was added. The reaction was heated to reflux for 40 h. After cooling down, evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (67%) as a solid.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([O:12][C:13](=[O:30])[CH2:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([OH:27])[C:21]([CH3:29])([CH3:28])[CH2:20]2)=[O:17])[CH2:6][C:5]1([CH3:32])[CH3:31].S([O-])([O-])=O.[Na+].[Na+].[C:39]([OH:43])([CH3:42])([CH3:41])[CH3:40]>>[OH:43][C:39]([CH3:42])([CH3:41])[CH2:40][O:27][N:22]1[C:21]([CH3:29])([CH3:28])[CH2:20][CH:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]([O:12][CH:7]2[CH2:6][C:5]([CH3:32])([CH3:31])[N:4]([O:3][CH2:40][C:39]([OH:43])([CH3:42])[CH3:41])[C:9]([CH3:11])([CH3:10])[CH2:8]2)=[O:30])[CH2:24][C:23]1([CH3:26])[CH3:25]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl)succinate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[Na+]>OS(O)(=O)=O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:16])([C:14]([NH2:15])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-Benzyl-4-hydroxy-piperidine-4-carbonitrile (5 g, 23.12 mmol) is dissolved in a mixture of H2SO4 (18 mL) and H2O (2 mL) at 0° C. The mixture is warmed to room temperature for 14 hours, transferred into cold 2 N NaOH and adjusted to pH>8. The solid is filtered and washed with H2O, and dried over sodium sulfate to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2449.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:15]([OH:29])=[C:16]([S:21]([N:24]([O:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22])[C:17]([Cl:20])=[CH:18][CH:19]=1>C(O)C>[Cl:20][C:17]1[C:16]([S:21]([N:24]([O:27][CH3:28])[CH2:25][CH3:26])(=[O:22])=[O:23])=[C:15]([OH:29])[C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:19][CH:18]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (0.30 g, 1.76 mmol) in ethanol (5 ml) was treated with TEA (250 μl, 1.80 mmol) and the reaction mixture was heated to 45° C. A solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (0.58 g, 2.07 mmol) in EtOH (5 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at 45° C. for 1 hour and then concentrated in vacuo. The residue was purified using flash chromatography (50% EtOAc in iso-hexane) to furnish a solid [M+H]+ 405.2.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([CH:7]=[O:8])=[O:6].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.C[O:29]S([O-])(=O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH2:1]([OH:12])[C@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([C:7]([OH:29])=[O:8])=[O:6]
Reactant: COS(=O)(=O)[O-]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 1 h

Procedure:
A reaction mixture containing the purified aldehyde dehydrogenase (0.04 mg protein, and prepared according to Example 1), L-sorbosone (4 mg) and phenazine methosulfate (0.2 mg) in 1.0 ml of 0.5M potassium phosphate buffer (pH 7.0) was incubated for 1.0 hour at 25° C. with gentle shaking. As a result, 2-keto-L-gulonic acid was formed at the rate of about 2.3 mg/hour.
Reaction SMILES: CS(O[CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][O:21][C:14]=12)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[I-:22].[Na+]>C(C(C)=O)C>[CH2:20]1[O:19][C:15]2[C:14](=[C:13]([CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][I:22])[CH:18]=[CH:17][CH:16]=2)[O:21]1
Reactant: CCCCCC(COS(C)(=O)=O)c1cccc2c1OCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCC(CI)c1cccc2c1OCO2
Yield: 86.6 %

Procedure:
Thus obtained 8.76 g (27.9 mmol) of 2-(2, 3-methylenedioxyphenyl)heptyl methanesulfonate was dissolved in 70 ml of methyl ethyl ketone, and the solution was mixed with 6.6 g of sodium iodide. The resultant mixture was refluxed under heating for 10 hours. After cooling, the precipitated salt was filtered off, and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent; ethyl acetate/hexane=1/20) to give 8.36 g of 2-(2, 3-methylenedioxyphenyl)heptyl iodide as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1.[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]([N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])[C:7]([OH:8])([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Reactant: O=c1ccccn1Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccccn1C(c1ccc(F)cc1)C(O)(c1cccnc1)c1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of dipyridin-3-ylmethanone (1 g, 5.9 mmol) and 1-(4-fluorobenzyl)pyridin-2(1H)-one (1 g, 4.9 mmol) in THF (50 mL) was cooled to −78 C. To the resulting white suspension was added in a dropwise manner, LiHMDS (1M in THF, 6 mL). The resulting cream suspension was stirred for 30 min then allowed to warm up gradually to −30 C over 1 h. The reaction mixture was quenched with saturated NaHCO3 and then it was extracted once with ether and once with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. The resulting yellow oil was purified by normal phase Gilson chromatography eluting with 98% DCM, 2% methanol. The product was isolated as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=4)[C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)C)(C)(C)C.Cl[CH2:35][C:36]([NH:38][CH3:39])=[O:37].Cl>>[F:32][C:15]1[CH:16]=[C:17]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:35][C:36]([NH:38][CH3:39])=[O:37])[CH:26]=3)[C:21]2=[O:31])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][C@@H:9]([NH:7][CH3:6])[CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1
Reactant: CNC(=O)CCl
Agent: Cl
Product: CNC(=O)COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O

Procedure:
According to Method K, {(R)-1-[2-fluoro-4-(6-hydroxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester was alkylated with 2-chloro-N-methyl-acetamide and the product was treated with hydrogen chloride (5 N in 2-propanol), releasing the amine. In this way the product was obtained with molecular weight 426.50 (C23H27FN4O3); MS (ESI): 427 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:21]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[C:16](=[CH2:21])[CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-(2,3-Dichloro-4-butyrylphenoxy)propionic acid (6.65 g, 0.022 mole), dimethylamine hydrochloride (12 g, 0.15 mole), paraformaldehyde (2.3 g, 0.077 equiv.) and acetic acid (1 ml) were mixed and stirred while heating on a steam bath for 2.5 hours. N,N-dimethylformamide (25 ml) was added to the mixture and stirring and heating continued for another 1.5 hours. The mixture was poured into ice water (600 ml) and the precipitate that formed removed by filtration, washed with water and dried. After recrystallization from butyl chloride, 58 g 3-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid remained.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:23]2[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2.[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30].C(=O)(O)[O-].[Na+]>O>[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:32][CH2:33][N:34]([CH2:7][CH2:8][CH2:9][N:10]2[C:23]3[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:35][CH2:36]1)=[O:30]
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(Cl)cc3Cl)CC1)c1ccccc1S2
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To 75 ml of dry dimethylformamide was added 2.0 g of 10-(3-chloropropyl)-2-methylthiophenothiazine, 1.7 g of 4-(2,4-dichlorobenzoyl)piperidine, and 5.0 g of sodium bicarbonate. The reaction mixture was stirred at 90° for five hours, poured into 200 ml of water, and extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. This oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate/dichloromethane (1:2 by volume) as the eluent. Concentration of the appropriate fractions yielded 2.7 g of 4-(2,4-dichlorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.
Reaction SMILES: [Cl-].C([Li])CCC.[CH2:7]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[Cl-].[Na+].[CH2:21]([O:23][CH2:24]C)C>>[CH2:7]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:21][O:23][CH3:24])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Product: CCCCc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.1 g of methoxymethyltriphnylphosphonium chloride is introduced into 280 ml of diethyl ether under nitrogen. At 0° C., 29.6 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 10 g of 4-butylbenzaldehyde in 40 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate, 6.7 g of 2-(4-butylphenyl)-1-methoxyethene 48 (E,Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and is stirred under nitrogen with 10 ml of 2N hydrochloric acid overnight. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 3.9 g of title compound 49 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17]C)=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:15](=[O:17])[CH2:14][CH2:13][C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)=[CH:29][CH:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: COC(=O)CCc1ccc(NS(C)(=O)=O)c(F)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CNC(=O)CCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Yield: 58 %

Procedure:
The compound 26-2 (30 mg) prepared in Step 2 was dissolved in toluene (4 ml) and to the solution was added 4-t-butylbenzylamine (150 μl), followed by refluxing for 3 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was chromatographed on silica gel column (ethyl acetate/hexane=1/1) to yield the compound 26-3 (28 mg, 58%).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:26]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: OCC(c1ccccc1)c1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (2.52 mmol) of 2,2-diphenylethanol was dissolved in 10 ml of toluene. 382 mg (3.78 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature for 1 hour. 386 mg (3.03 mmol) of diketene was added to the obtained mixture under cooling with ice, and then they were stirred under heating at 100° C. for 2 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the unpurified title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])C)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][SiH:28]([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[C:3]1[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[N:6]=[C:5]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:4]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
100 mg of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid (example 55), 35.5 mg of copper(II) acetate and 20 mg of imidazole are dissolved in dry pyridine, and the solution is stirred at 80° C. for 3 hours. For workup, it is diluted with 20 ml of water and extracted several times with ethyl acetate, the organic phases are dried using a silica gel cartridge, and the volatile components are distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).