Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23]([OH:25])=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:38]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:39]C([O-])=O.C([Mg]Cl)(C)C>C1COCC1>[Br:1][C:2]1[C:3]([CH2:22][C:23](=[O:25])[CH2:39][C:38]([O:44][CH2:45][CH3:46])=[O:43])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A flask was charged with 2-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)acetic acid (0.576 g, 1.377 mmol) and THF (20 mL), and carbonyl diimidazole (0.3014 g, 1.859 mmol) was added. The mixture was heated at 50° C. for 2 hours. In a separate 50 mL scintillation vial, mono-ethyl malonate (0.2845 ml, 2.410 mmol) was dissolved in THF (15 mL) and cooled to 0° C., and isopropyl magnesium chloride (2.410 mL, 4.819 mmol) was added. This second mixture was stirred at ambient temperature for 30 minutes, then heated to 50° C. and stirred another 30 minutes. Both solutions were cooled to 0° C. and the second mixture was added to the first mixture. The combined mixture was stirred at ambient temperature overnight, then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate/hexane to provide the desired product (0.337 g, 46-10% yield) as white solid.
Reaction SMILES: BrC1C=CC=CC=1.[Li].O1CCCCC1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.CN(C)[CH:30]=[O:31]>CCOCC>[OH:15][C:16]1[C:17]([CH:30]=[O:31])=[C:18]([O:26][CH3:27])[C:19]([O:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(OC2CCCCO2)cc1OC
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: CCCOc1ccc(O)c(C=O)c1OC
Temperature: 25 °C

Procedure:
1 ml of bromobenzene (11.88 ml) was added to a mixture of lithium chips (1.63 g) and anhydrous ether (90 ml) under nitrogen. When the reaction had commenced the remainder of the bromobenzene was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing. After the addition was complete the mixture was stirred and refluxed (1 hr) and then cooled to room temperature. 3-Methoxy-4-n-propoxyphenol tetrahydropyranyl ether (30.03 g, 0.113 M) was added dropwise to the stirred mixture and then stirred at room temperature (3 days). A solution of anhydrous dimethyl formamide (8.5 ml) in anhydrous ether (8.5 ml) was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing, and then stirred for an extra hour. The reaction mixture was poured into 2 N sulphuric acid/ice (200 ml) and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (175 ml) and 2 N hydrochloric acid (210 ml) was added. After stirring at room temperature (2 hr) the mixture was diluted with water (500 ml) and extracted with ethyl acetate/ether (1:1). The combined extracts were extracted with 2 N sodium hydroxide solution, the combined aqueous phases acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was chromatographed on silica (MFC) eluting with chloroform-methanol (98:2) to give 6-hydroxy-2-methoxy-3-n-propoxybenzaldahyde as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N:6]1([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[Cl:1][CH2:2][C:3]([N:9]1[CH2:10][CH2:11][N:6]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH2:7][CH2:8]1)=[O:4]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
Chloroacetyl chloride (1.16 ml, 14.62 mmol) is added to an ice-cooled solution of 2-(1-piperazinyl)pyrimidine (2.0 g, 12.18 mmol) in dichloromethane (20 ml) and triethylamine (5.09 ml, 36.54 mmol), and the mixture is stirred for 5 minutes and then warmed to room temperature. After 30 min at RT, water (50 ml) is then added to the mixture, which is extracted twice with methylene chloride (50 ml). The organic phase is washed with saturated sodium chloride solution. Drying of the organic phase over sodium sulphate, filtration, concentration under reduced pressure and silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=10:1 to 1:1) gives 2.05 g (70%) of product as a colourless solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:28]>C(Cl)Cl>[NH2:28][CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: COc1nc(Cl)ccc1CCO
Reactant: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(Cl)ccc1CCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.20 g (0.8 mmol) of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2Cl2 cooled to -50° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78° C. before a rapid addition of 30 ml of cold (-78° C.) NH3 (l). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-methoxypyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CNCCN(C)C>>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: CNCCN(C)C
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In another embodiment the compounds can be prepared as shown in Scheme IV. A bromo-nitrobenzene (1) can be reacted with N1,N2,N2-trimethylethane-1,2-diamine to give N1-(nitrophenyl)-N1,N2,N2-trimethylethane-1,2-diamine (2). A solution of (2) in can be subjected to hydrogenation, passed through a short pad of celite, washed with MeOH and evaporated under reduced pressure. Thiocarbodiimidazole can then be added to (2) to give the N1-(isothiocyanato-phenyl)-)-N1,N2,N2-trimethylethane-1,2-diamine (3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: OCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 54 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a N,N-dimethylformamide (125 mL) solution of 4-bromobenzyl alcohol (25 g, 130 mmol) was added potassium tert-butoxide (15.8 g, 141 mmol) at room temperature, which was stirred at 54° C. for 10 minutes. To the reaction solution was added 2-fluoropyridine (15 mL, 154 mmol) was added at a temperature from 40° C. to 58° C., which was stirred at 65° C. for 30 minutes. The reaction solution was cooled to room temperature, and partitioned into water and ethyl acetate. The water layer was further extracted with ethyl acetate (twice). The ethyl acetate layers were combined, washed with water (3 times) and aqueous sodium chloride (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. To the residue was added diethyl ether, which was then concentrated under a reduced pressure to obtain the title compound (34 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][P:13]([CH3:17])[O:14]CC)[CH3:11]>[Hg]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[P:13]([CH3:17])(=[O:14])[O:12][CH2:10][CH3:11]
Reactant: CCOP(C)OCC
Reactant: Clc1ccc(Cl)c(I)c1
Agent: [Hg]
Product: CCOP(C)(=O)c1cc(Cl)ccc1Cl

Procedure:
Using a high pressure 450 watt mercury lamp, 20 grams of 2,5-dichloroiodobenzene and 30 grams of diethylmethylphosphonite are combined and irradiated for approximately 31/2 hours. After concentration and distillation, a clear oil is obtained, which then solidified. The solid is recrystallized from ethyl ether to give 8.5 g. of white needles having a melting point between 90° and 91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21](Cl)=[O:22]>N1C=CC=CC=1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[O:22]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-2-thiophenecarboxylate (0.82 g, 5.2 mmol) and 2-quinoxalinecarbonyl chloride at 0° C. was added pyridine (1 mL) dropwise. The resulting solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with saturated NH4Cl, and NaHCO3. The organic layer was the dried and concentrated in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]([C:7]1[O:8][CH2:9][C:10](=[O:17])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:6].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCC[C@H]1C(O)=O>C(O)C>[CH:12]([OH:14])=[O:13].[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:9]2[O:8][C:7]([N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])[CH3:6])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2=[O:17])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N(C)CCN(C)C)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N(C)CCN(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Product: O=CO
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a solution of ethyl 2-{[2-(dimethylamino)ethyl]-N-methylamino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.78 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.78 mmol) in ethanol (6.0 mL), L-proline (0.0093 mg, 0.078 mmol) was added at ambient temperature. The mixture was refluxed for 20 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.035 g, y. 12%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][NH:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]OS(OC)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:25])[C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)c1nc[nH]c(=O)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c1=O

Procedure:
Using a procedure described in U.S. Patent Publication No. 2005/0090668, a solution of 5-benzyloxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester was first treated with NaH (1.3 equiv.) in DMF followed by the addition of dimethylsulfate (1.3 equiv.) to give mainly the desired product after 2 h at room temperature. The reaction mixture was quenched with cold HCl (1N, 30 vol.) and extracted with EtOAc (3×30 vol.). The combined organic extracts were washed with dilute HCl and brine, dried and concentrated to an oil. Chromatography of the crude product (eluted with 40-60% EtOAc/hexane) gave 88% yield of the N-methylated compound (Synthon A).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20]C)=O)[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C.C(#N)C>[NH:23]([C:18]([C:16]1[N:17]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][CH:15]=1)=[O:20])[NH2:24]
Reactant: NN
Reactant: COC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The methyl 6-(benzyloxycarbonylamino)picolinate from step 1 was dissolved in ethanol (0.5 M), and hydrazine hydrate (15 mL, 310 mmol, 5.0 eq) was added. The solution was heated to reflux and stirred for 2 hours, then cooled to room temperature. The solvent was removed under reduced pressure to provide a yellow solid, which was suspended in acetonitrile, filtered, and the solid washed with acetonitrile to yield benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (17.5 g) as a white solid. The filtrate was concentrated and the precipitated solid filtered off and washed with acetonitrile to provide more benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate. A total of 17.5 g of pure material was obtained.
Reaction SMILES: [CH2:1]([N:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([Cl:17])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH-].[Na+:27]>C(O)C>[CH3:2][CH2:1][N:3]([C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:17])[C:14]=2[C:15]=1[O-:16])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[Na+:27]
Reactant: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 2.5 °C
Yield: 75.4 %

Procedure:
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide (35 gm) was suspended in ethanol (140 ml) at 20-25° C. under stirring followed by the addition of freshly prepared sodium hydroxide solution (4.13 gm of sodium hydroxide in 11 ml of water) at 20-25° C. and then stirred for 15-30 minutes at 25-30° C. The resulting solution was filtered through a hyflow super cell bed and the bed was washed with ethanol (105 ml) at 25-30° C. The resulting filtrate was seeded with pure laquinimod sodium (0.175 gm) and then stirred for 4 hours at 25-30° C. The resulting mass was cooled to 0-5° C. followed by stirring for 2 hours at the same temperature. The resulting white colored solid was filtered, washed with chilled ethanol (38 ml) and then dried under vacuum at 60-65° C. to yield 28 gm of laquinimod sodium in crystalline Form A1 (HPLC Purity: 99.9%; Bulk density: 0.333 g/ml; Tapped density: 0.476 g/ml; and Particle size distribution: d(0.9)=26.3 microns).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[CH:3][C:4]([O:6][CH3:7])=[O:5].[C:17]1([C:23](=O)[CH:24]=[CH:25][CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:26][C:25]1[CH:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:1]=[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C=C(N)c1cccc([N+](=O)[O-])c1
Reactant: CC=CC(=O)c1ccccc1
Solvent: CCCCO
Product: COC(=O)c1c(C)cc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A mixture of methyl 3-amino-3-(3-nitrophenyl)acrylate (45 g) and 1-phenyl-2-buten-1-one (44 g) in n-butanol (450 ml) was refluxed for 4 hours. After allowing to cool at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (500 g) eluting with benzene. The fractions containing the object compound were combined and concentrated under reduced pressure to give methyl 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.10 g).
Reaction SMILES: Cl.Cl.Cl.C1(NC(C2C3C=C(C4C(Cl)=CN=C([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)N=4)SC=3C=CC=2)=O)CC1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH:54][C:55]([C:57]2[C:65]3[CH:64]=[C:63]([C:66]4[C:71]([Cl:72])=[CH:70][N:69]=[C:68](Cl)[N:67]=4)[S:62][C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:56])[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1>>[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH:54][C:55]([C:57]2[C:65]3[CH:64]=[C:63]([C:66]4[C:71]([Cl:72])=[CH:70][N:69]=[C:68]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)[N:67]=4)[S:62][C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:56])[C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)=[CH:41][CH:40]=1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4Cl)cc23)c2ccc(OC)cc2)cc1
Agent: Cl
Product: CN1CCN(CCCN)CC1
Product: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(NCCCN5CCN(C)CC5)ncc4Cl)cc23)c2ccc(OC)cc2)cc1
Yield: 65 %

Procedure:
Using the method of Preparation E of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is prepared from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxy-phenyl)-methyl]-amide and 1-(3-aminopropyl)-4-methylpiperazine as a white solid (65% yield).
Reaction SMILES: [FH:1].N[C:3]1[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.[N+]([O-])([O-])=O.[Na+]>>[Cl:9][C:7]1[CH:8]=[C:3]([F:1])[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1
Reactant: F
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A vessel is charged with 400 g (20 moles) of hydrogen fluoride and 167.4 g (0.518 mole) of methyl 2-[4-(3-amino-5-chloropyridin-2-yl-oxy)phenoxy]propionate are added in portions at a temperature from -8° to 0° C. 37.3 g (0.540 mole) of sodium nitrate are added over one hour and the mixture is stirred for two hours before it is slowly heated in an autoclave to 55° C. Excess hydrogen fluoride is removed by distillation and the residue is taken up in a mixture of 200 ml of methylene chloride and ice-water and the solution is neutralised with concentrated ammonia. The neutralised solution is extracted three times with methylene chloride and the organic extracts are washed with water, dried and concentrated by evaporation, affording 81.0 g (48% of theory) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate with a melting point of 63°-64°.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C1COCC1>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:20](=[O:21])[CH2:19][CH2:18][Cl:17])[C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=C(Cl)CCCl
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
The synthesis was performed according to the below synthetic scheme. To a solution of 11-Oxo-10,11-dihydro-5H-dibenzo[b,e][1,4] diazepin (0.376 gr., 1.79 mmol) in dry THF, (10 ml) NaNH2 (0.132 gr., 3.39 mmol) was added. The mixture was cooled to 0° C., and 0.2 ml 3-chloropropionyl chloride (2.09 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C., allowed warming to room temperature, washed with 5% aq. potassium bicarbonate and extracted with CH2Cl2 (20 ml). The resulting organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was crystallized from ether, resulting in 0.467 gr. (87% yield) of 11-Oxo-10,11-dihydro-5-[(3-chloro)1-oxopropyl] 5-H-dibenzo[b,e] [1,4] diazepin in the form of a yellow solid, mp 241-242° C. 1H NMR (CDCl3): 8.78 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.4-7.26 (m, 6H), 3.77 (m, 4H). FAB/MS: 301(M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:12](=[O:13])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 250 mL round-bottom flask under N2 was dissolved 2-amino-6-chlorobenzoic acid (11.69 g, 68 mmol) in 100 mL of 1,4-dioxane. The solution was cooled to 0° C. and to this solution was added phosgene (36 ml, 68 mmol) via a dropping funnel. The reaction mixture was stirred for 24 hours allowing to warm to 23° C. (rt). The resulting white solid was filtered off and washed with 1,4-dioxane and Et2O. Yield=12.5 g, 93%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:7]=1
Reactant: O=C1CCCCC1Cl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OC1CCCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclohexanone (108.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IId-a (138.5 g, 78.3%) as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:37]=[CH:36][C:25]2[C:26](=[O:35])[CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:29][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:30]([C:28]1[O:29][C:24]2[CH:23]=[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)[CH:37]=[CH:36][C:25]=2[C:26](=[O:35])[CH:27]=1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1cc(=O)c2ccc(CBr)cc2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(=O)c2ccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)cc2o1
Temperature: 70 °C
Yield: 58.7 %

Procedure:
0.8 g of 2-(4-hydroxyphenoxy)methylquinoline, 0.99 g of 7-bromomethyl-2-carboethoxy-4-oxo-4H-1-benzopyran and 0.44 g of potassium carbonate are combined in 15 ml of dimethylformamide and heated at 70° C. for 18 hours. The mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The organic solution is dried and evaporated and the resulting crude product is purified by column chromatography on silica gel to give 0.9 g of 2-carboethoxy-7-(4-(quinolin-2-ylmethoxy)phenoxy-methyl)-4-oxo-4H-1-benzopyran.