Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.C(O)(=O)C.C([BH3-])#[N:29].[Na+]>CO.C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][CH:20]([NH:29][C@@H:8]([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[CH2:19][CH2:18]2
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: [BH3-]C#N
Agent: O=C1CCc2cccc(Br)c2C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC1CCc2cccc(Br)c2C1)c1ccccc1
Reaction time: 3 h

Procedure:
Initially, 8-Bromo-2-tetralone was prepared by substituting 2-bromophenylacetylchloride in the procedure described in A. H. Horn, C. J. Grol, D. Dijkstra, A. H. Mulder, J. Med. Chem. 21, 825 (1978). Next, 8-bromo-2-tetralone (25 g, 111.1 mmol), S-(-)-alpha-methylbenzylamine (71.5 ml, 5 eq.), acetic acid (80 ml), 4 A molecular sieves (15 ml), THF (125 ml) and methanol (125 ml) were introduced into a flask and cooled to 0°. Sodium cyanoborohydride (15.1 g, 2 eq.) was added in portions over a 15 min period. The slurry was allowed to stir for 3 hr. The slurry was filtered and the solvent reduced to a syrup by evaporation in vacuo. The residue was partitioned between ether and 2N aqueous sodium hydroxide. The ether layer was washed with water (3×) and brine. After drying over anhydrous sodium sulfate the solvent was removed in vacuo. The viscous oil was placed on a flash silica gel column (5 cm×50 cm) and eluted with ethyl acetate/hexane (8%) to separate the higher Rf (+)-diastereomer (solidifies upon standing, 17g). The solvent was raised to 12% to elute the lower Rf (-)-diastereomer (an oil, 16g). In this manner the 8-bromo-N-[(S)-alpha-methylbenzyl]-2-aminotetralin was obtained.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:18][O:19][CH:20]=[O:21].O>O1CCCC1>[CH3:18][O:19][C:20]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: NCCc1ccccc1
Reactant: O=COCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NCCc1ccccc1
Yield: 97.6 %

Procedure:
To a cold solution consisting of phenethylamine (20g,0.16mol) in tetrahydrofuran (900 mL) was added triethylamine (23 mL, 0.16 mol). To this solution was added dropwise chloromethylformate (64 mL, 0.8 mol). The reaction mixture was then stirred overnight water (450 mL) was added and the layers were separated. The organic layer was washed successively with water (1×200mL) and brine (1×200mL). The organic solvent was dried (anhydrous magnesium sulfate), filtered and concentrated to give the title compound (28 g, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:25]=[CH:24][C:12]([C:13]([N:15]3[CH2:20][CH2:19][C:18]4[O:21][CH:22]=[CH:23][C:17]=4[CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:22]1[O:21][C:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]3[CH:24]=[CH:25][C:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[CH:10][CH:11]=3)[CH2:16][C:17]=2[CH:23]=1)[CH3:30]
Reactant: C=O
Reactant: CNC
Reactant: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4occc4C3)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4oc(CN(C)C)cc4C3)cc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.350 g (0.968 mmol) of 5-[4-(4-methoxybenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.131 ml (1.45 mmol) of 50% aqueous dimethylamine and 0.118 ml (1.45 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 90 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1 to 25/1). This was washed with diethyl ether to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]([OH:20])[C:18]1[CH:21]=[CH:22][C:15]([S:14][CH3:13])=[CH:16][CH:17]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: CSc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (32 mmol) and 4-(methylthio)benzaldehyde (30 mmol) using the procedure described for compound (96) (9.4 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccc(O)cc1

Procedure:
Prepared from 2-(2-aminophenyl) indole and 4-hydroxybenzoic acid in 35% overall yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 95.6% Purity by LC/MS (230 DAD) Mass-spec (M+H+)=329.8 1H NMR (MeOH-d4): 6.65 s (1H), 6.83 m (2H), 7.01 t, 7 Hz (1H), 7.12 td, 7.1 Hz (1H), 7.34 td, 7.1 Hz (1H), 7.39–7.43 m (2H), 7.51 d, 7 Hz (1H), 7.66 dd, 8.1 Hz (1H), 7.76 m (2H), 7.91 dd, 8.1 Hz (1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Sc1ccc2ccccc2n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CC#N
Product: COc1cc2nccc(Sc3ccc4ccccc4n3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
2-Quinolinethiol (87 mg) and 4-chloro-6,7-dimethoxyquinoline (100 mg) were suspended in acetonitrile (3 ml), and the suspension was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate and was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (15 mg, yield 10%).
Reaction SMILES: C[Si](C)(C)C#CC=C1CC[NH:9][CH2:8]C1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:22][C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36]#[CH:37])[CH2:31][CH2:30]2)[C:26]([N+]([O-])=O)=[CH:25][CH:24]=1>>[F:14][C:15]1[CH:16]=[C:17]([C:37]#[C:36][CH:35]=[C:32]2[CH2:33][CH2:34][N:29]([C:27]3[N:28]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=3[C:8]#[N:9])[CH2:30][CH2:31]2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: C[Si](C)(C)C#CC=C1CCNCC1
Reactant: Fc1cccc(I)c1
Product: Cc1ccc(C#N)c(N2CCC(=CC#Cc3cccc(F)c3)CC2)n1

Procedure:
The title compound was prepared in the same way as the Compound of Example 274 but replacing 1-bromo-3,5-difluorobenzene with 1-fluoro-3-iodobenzene and Compound 274c with Compound 284a. The residue coming from the work-up procedure was purified by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording the title compound as a colourless oil. Yield: 20.4%
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.[NH2:14][CH2:15][CH:16](O)[CH3:17]>O1CCCC1>[CH3:17][C:16]1[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:10]=2[NH:14][CH:15]=1
Reactant: CC(O)CN
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1cccs1)C2
Temperature: 150 °C
Reaction time: 7 h
Yield: 30.2 %

Procedure:
A mixture of 5-thienylcyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (1.0 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the mixture were added 2-bromomesitylene (2.1 g), tetrakistriphenylphosphine palladium (0.30 g) and potassium carbonate (2.8 g), and the mixture was stirred at 150° C. for 7 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydroindol-4-one (0.72 g).
Reaction SMILES: [CH2:1]1[O:15][C:14]2[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9](O)=[O:10])[NH2:8])=[CH:4][C:3]=2[O:2]1.Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:18].Cl.C1(NCC([Cl:34])=O)C=CC=CC=1>>[ClH:18].[CH2:1]1[O:15][C:14]2[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([Cl:34])=[O:10])[NH2:8])=[CH:4][C:3]=2[O:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccc2c(c1)OCO2)C(=O)O
Reactant: O=C(Cl)CNc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccc2c(c1)OCO2)C(=O)Cl

Procedure:
The compound 3,4-methylenedioxyphenylalanine, Ber., 59, 2952 (1926), is treated with hydrogen chloride and phosphorous pentachloride in accordance with the procedure described by Hartcastle et al., J. Org. Chem., 31, 897 (1966) for the preparation of phenylglycyl chloride hydrochloride to yield 3,4-methylenedioxyphenylalanyl chloride hydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)C1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
276 g (1 mole) of 1-(p-carboxyphenyl)-3-ethoxycarbonyl-2-pyrazolin-5-one and 122 g (1 mole) of p-hydroxybenzaldehyde were dissolved in 1000 ml of acetic acid. The reaction mixture was refluxed for 3 h. The dye crystallized partially. After cooling to room temperature the dye was filtered with suction and rinsed with acetone.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])O[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:19]=1[CH2:20][NH:21][CH2:22]C(O)=O>CC1C=CC(C)=CC=1>[CH3:16][O:17][C:18]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:19]=1[CH2:20][N:21]1[C:11](=[O:12])[C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[CH2:22]1
Reactant: CC(C)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(C(C)C)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-isopropyl-1H-benzo[d][1,3]oxazine-2,4-dione (3.0 g, 15 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (3.7 g, 16 mmol) in p-xylene (40 mL) was heated under reflux (150° C.) for 2.5 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2×20 ml). Yield: 4.9 g (90%). m/z 367 (M—H−).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].CO.O.[OH-].[Li+]>C1COCC1>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:18]([C@H:20]2[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)C2CCC(=O)CC2)c(C(=O)O)s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (519 mg, 1.13 mmol) was dissolved in a mixture of 3:2:1 THF:MeOH:H2O (25 mL). Lithium hydroxide (5 mL, 1.0N aqueous solution) was added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was neutralized with 5% citric acid(aq), and thrice extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to afford 505 mg of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid which was carried on without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1>CN(C)C=O.C(OCC)(=O)C>[C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)#[N:12]
Reactant: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-chloro-5-cyano-3-nitropyridine (3.5 g)(obtained according to International Patent Application No.WO9410171) in N,N-dimethylformamide (35 mL) was added trans-4-aminocyclohexanol (4.39 g) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 45 minutes and diluted with ethyl acetate. The mixture was washed with water (3 times) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (3.38 g) as a yellow sold.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:17]1([C:23]([CH:25](Br)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]2[N:16]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:12][CH:11]=3)[S:15][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccccc4)c(-c4ccccc4)s3)cc2)cn1
Yield: 88.2 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (example 72c)) and 130 mg (0.47 mmol) desyl bromide. 155 mg (88%) of the product was isolated as a colorless solid. MS ISP (m/e): 409.3 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.74 (s, 1H), 9.50 (s, 1H), 8.00-7.90 (m, 3H), 7.73 (d, 2H), 7.49 (d, 2H), 7.40-7.30 (m, 8H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][N:7]([CH3:29])[CH:8]1[C:22]2=[CH:23][CH:19]([O:20][C:21]2=[O:24])[CH:18]2[CH:14]([O:15][C:16](=[O:26])[CH:17]2[CH3:25])[CH2:13][C:12]2([CH3:27])[CH:10]([O:11]2)[CH:9]1[OH:28]>CC(C)=O>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[OH:28][CH:9]1[CH:8]([NH+:7]([CH3:6])[CH3:29])[C:22]2=[CH:23][CH:19]([O:20][C:21]2=[O:24])[CH:18]2[CH:14]([O:15][C:16](=[O:26])[CH:17]2[CH3:25])[CH2:13][C:12]2([CH3:27])[CH:10]1[O:11]2
Reactant: CS(=O)(=O)O
Reactant: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Solvent: CC(C)=O
Product: CC1C(=O)OC2CC3(C)OC3C(O)C([NH+](C)C)C3=CC(OC3=O)C21
Product: CS(=O)(=O)[O-]
Yield: 55.4 %

Procedure:
A solution of methanesulphonic acid (0.1 mmol; 1 ml; 0.1N in acetone) is added to a solution of the compound of Example 5 (0.1 mmol; 34 mg) in acetone (2 ml). The precipitate is filtered, washed with acetone and dried under reduced pressure. 24 mg of the expected product is obtained in the form of a white powder. Melting point: 220° C.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.Cl.Cl.[NH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)=[C:29]([Cl:44])[CH:28]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=[CH:18]1.[C:45](=O)([O-])[OH:46].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:44][C:29]1[CH:28]=[C:27]([NH:26][C:24]2[C:25]3[N:17]([CH2:16][CH2:15][NH:14][C:45]([NH:4][O:3][CH3:2])=[O:46])[CH:18]=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:32]=[CH:31][C:30]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1
Reactant: O=C([O-])O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CON
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N′-carbonyldiimidazole (187 mg) in N,N-dimethylformamide (2 mL) were added O-methylhydroxylamine hydrochloride (96 mg) and triethylamine (0.27 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. A solution of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred at room temperature for 22 hrs, aqueous sodium hydrogen carbonate and brine were added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→80:20) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (116 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18](O)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18]([Cl:29])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoic acid in DCM (8 mL) was added oxalyl chloride (208 μL, 2.34 mmol) followed by 3 drops of DMF. After 30 minutes, additional oxalyl chloride (2 mL, 22.5 mmol) was added. After 30 minutes stifling at ambient temperature the reaction was concentrated under reduced pressure and dried under high vacuum to afford the title compound as an oil. The crude product was used without further purification in the next step.
Reaction SMILES: N#N.Cl[C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1>O.O1CCOCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[C:4]([C:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a N2 purged solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (4.891 g, 16.37 mmol), potassium acetate (6.54 g, 66.6 mmol), dioxane:water (160 mL, 10:1), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (6.03 g, 19.50 mmol) was added A-Phos (1.5 g, 2.118 mmol). The vial was capped and placed in a preheated oil bath (120° C.) and stirred for 1.5 hours. The solution was allowed to cool to room temperature and poured into water. The aqueous solution was extracted with EtOAc (3×70 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with 0% to 50% EtOAc in hexane, to provide tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow foam. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) 0.01298.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>C(#N)C>[Br-:10].[Cl:1][C:2]1[N:3]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:4][NH+:5]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:6]=1[Cl:7]
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: ClC1=C(Cl)[NH+](Cc2ccc3ccccc3c2)CN1Cc1ccc2ccccc2c1
Product: [Br-]
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
4,5-dichloroimidazole (10.0 mmol, 1.370 g) and KOH (11.0 mmol, 0.617 g) were placed in a 50 mL round bottom flask with 10 mL acetonitrile. The mixture was brought to reflux (85° C.) and stirred 1 h until KOH was consumed. 2-Bromomethylnapthalene (10.00 mmol, 2.211 g) was added and the solution was stirred 2.5 hours. KBr was removed by vacuum filtration and a second equivalent of bromomethylnapthalene was added to the filtrate. The mixture was stirred at reflux for 1.5 hours. The white precipitate was collected by filtration and analyzed. Yield: 92.0% 1H NMR (500 MHz, d6-DMSO): δ 5.71 (s, 4H), 7.57-7.62 (m, 6H), 7.95-8.06 (m, 8H), 9.75 (s, 1H) ppm. 13C NMR (500 MHz, d6-DMSO): δ 51.8, 117.9, 119.3, 125.5, 136.7, 136.8, 127.7, 127.8, 128.8, 130.1, 132.7, 132.8, 136.9 ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:11][C:4]2[CH:5]=[CH:9][CH:10]=[CH:2][CH:3]=2)=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Yield: 165.7 %

Procedure:
4-Hydroxyphthalic acid (3.50 g, 19.2 mmol) and K2CO3 (23.9 g, 173 mmol) in acetone (100 mL) and water (50 mL) were stirred at rt for 15 min. Benzyl bromide (20.6 mL, 173 mmol) was added and the mixture was heated under reflux for 3 d. Vacuum distillation (45°-50° C./1.1 mm) removed residual benzyl alcohol and the distillation residue was purified by gradient flash chromatography (10-30% ethyl acetate:hexane) to give dibenzyl 4-benzyloxyphthalate (7.20 g, 83%) as a pale yellow oil. TLC Rf 0.65 (25% ethyl acetate:hexane). ##STR413## Step 2