Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([O-])=[O:24])[N:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na+].[C:28](Cl)(=O)C(Cl)=O.CN(C)C=O.C[N:40]1[CH2:45][CH2:44]O[CH2:42][CH2:41]1>O1CCOCC1.ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([N:40]4[CH2:41][CH2:42][CH2:28][C@H:45]4[CH3:44])=[O:24])[N:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CC(=O)[O-]
Reactant: CN1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CC(=O)N1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of Sodium {2-[6-(4-methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-acetate (See Intermediate 20) (1.0 mmol) and oxalyl chloride (3.0 mmol) in dioxane (0.10M), add a catalytic amount of dimethylformamide and heat to reflux for 30 minutes. After this time, remove the heat and concentrate in vacuo. Take the resulting solid into dichloromethane (0.10M) and slowly add a solution of (R)-methyl-pyrrolidine hydrochloride (1.0 mmol) and n-methylmorpholine (2.0 mmol) in dichloromethane. Stir at room temperature for 1 hour. After this time, the reaction appears complete. Wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Concentrate the organic layer in vacuo and purify via radial chromatography eluting with methanol and dichloromethane. MS (m/e): 440.2(M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A solution of nickel(II) chloride hexahydrate (36.6 mg, 0.154 mmol) and (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (302 mg, 0.77 mmol) in methanol (8 mL) was cooled to 0° C. and then treated with sodium borohydride (87 mg, 2.29 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with ethyl acetate (50 mL). The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (280 mg, 93%) as a viscous oil: EI-HRMS m/e calcd for C18H23F3O4S (M+) 392.1269, found 392.1276.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:10]=3)[C:5]([CH2:31][CH:32]=[CH2:33])([CH2:28][CH:29]=[CH2:30])[C:4]=2[CH:3]=1.C([Li])CCC.[N:39]1[C:46](F)=[N:45][C:43](F)=[N:42][C:40]=1F>C1COCC1.C1(C)C=CC=CC=1.O>[C:22]1([N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:7]=[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][C:2]([C:40]5[N:42]=[CH:43][N:45]=[CH:46][N:39]=5)=[CH:3][C:4]=4[C:5]3([CH2:31][CH:32]=[CH2:33])[CH2:28][CH:29]=[CH2:30])=[CH:10][CH:9]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: Fc1nc(F)nc(F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1(CC=C)c2cc(-c3ncncn3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
To a solution of 2-bromo-7-(diphenylamino)-9,9-diprop-2 -enylfluorene (22.16 g, 0.045 mol), in THF (200 mL), cooled in a dry ice-acetone bath, a solution of n-butyl lithium in hexanes (1.6M, 30 mL, 0.048 mol), was added by syringe over 5 minutes. After 25 minutes, over a 30 minute period, a solution of cyanuric fluoride (2.025 g, 0.015 mol), in THF (100 mL) was added to result in a greenish fluorescent solution, which turned orange at the end of additon. The mixture was allowed to warm up slowly to room temperature, diluted with toluene and water, and the organic phase was dried and concentrated. The residue was chromatographed over alumina (eluted with 1:3 toluene-heptane), rechromatographed over silica gel (eluted with 1:3 toluene-heptane), and then crystallized from 1:3 toluene-heptane. The desired product was obtained as a bright yellow solids, 11.84 g, 60% yield, m.p. 235-237° C. Recrystallization from 2:1 heptane-toluene raised its m.p. to 236-238° C. Mass Spec: m/z 1314 (M+). Anal. Calcd. for C96H78N6: C, 87.64%; H, 5.90%: N, 6.3%. Found: C, 87.59%; H, 6.06%; N, 6.15%.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.COC(=O)[C@@H](C(C)C)N.COC(=O)[C@@H](C)N>O1CCOCC1.C(Cl)Cl>[N:12]1([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)[C@@H](C)N
Agent: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of methyl 2-(R)-[(4-tert-butoxycarbonylpiperazine-1-sulfonyl)amino]propionate (3.6 g, 10.7 mmol) [prepared by proceeding as described in Example 2, but substituting 4-(5-chloropyridin-2-yloxy)piperidine and D-valine methyl ester with 1-tert-butoxycarbonyl-1,4-piperazine and D-alanine methyl ester, respectively] in 10% dioxane/methylene chloride (100 ml) for 10 min. The reaction was stirred at RT for 4 h and concentrated in vacuo to give methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (91%) as a white solid that was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH2:50].[H-].[Na+]>CN(C=O)C>[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH:50][C:37](=[O:38])[C:36]([NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=1)=[O:34])([CH3:40])[CH3:41]
Reactant: Nc1nncs1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nncs4)c3)cc12
Reaction time: 8 h
Yield: 47 %

Procedure:
DIEA (44 μL, 0.253 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169 mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and the slurry became a clear solution after 10 min. It was allowed to stir overnight. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (22 mg, 45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1H, br. s.), 8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3H, m), 7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d, J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=11.23 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=10.56 min, purity=96%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CN(C)C=O.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ncc(/C=C\c2ccc([N+](=O)[O-])cc2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Yield: 26.7 %

Procedure:
A mixture of N-{5-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1 g) and 10% palladium carbon (1.04 g) in ethyl acetate (100 ml) and N,N-dimethylformamide (20 ml) was stirred under 4 atm hydrogen at ambient temperature for 4hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl ether to give N-{5-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (240.9 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reactant: Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: COc1c(-c2ccc(C)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20 g, 80 mmol), prepared as described in Example 361B, and 4-methylphenylboronic acid (13 g, 96 mmol) in toluene (300 mL) at RT under argon was added (Ph3P)4Pd (1.85 g, 1.8 mmol) and 2 M aqueous Na2CO3 solution (160 mL, 320 mmol). The resulting suspension was heated at 100° C. for 5 h with stirring. HPLC/MS indicated complete reaction. After cooling the reaction mixture to room temperature, it was extracted with CH2Cl2 (200 mL×2), then dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to give the title compound, 2-benzyl-4-methoxy-5-p-tolylpyridazin-3(2H)-one, (21.9 g, 89%) as a white foam. MS [M+H]+ 307; HPLC retention time=3.78 min.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:27])[C:19]2([S:25][CH3:26])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=O)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:30][C@:6]12[C@@H:5]([OH:4])[CH2:22][C@@:20]3([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:27])[C:19]3([S:23][CH3:24])[S:25][CH3:26])[C@@H:15]1[CH2:14][CH2:13][C:12]1[C@:7]2([CH3:29])[CH:8]=[CH:9][C:10](=[O:28])[CH:11]=1
Reactant: CSC1(SC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CSC1(SC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a stirred solution of 1.7 g (3.76 mmole) of 11β-(acetyloxy)-9-fluoro-17,17-bis(methylthio)androsta-1,4-diene-3,16-dione in a mixture of methanol (70 ml), tetrahydrofuran (50 ml) and water (5 ml) was added 10% potassium carbonate solution dropwise until the pH of solution was about 10. The solution was allowed to stir at room temperature under nitrogen for 2 hours and quenched with a slight excess of concentrated acetic acid. The solvent was evaporated in vacuo to give a slurry. This was diluted with water and extracted with dichloromethane. The dichloromethane solution was dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.35 g of the title compound. Recrystallization of this from acetone-hexane gave 720 mg of an analytical specimen, melting point 293°-294° C., dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(F)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (174 mg, 0.524 mmol) in THF (1967 μl)/H2O (656 μl) was added LiOH (37.7 mg, 1.573 mmol) and the reaction was allowed to stir for 2 h. THF was removed by rotovap before the solution was diluted in EtOAc (10 mL) and aqueous phase was acidified to pH 3 using a 1N aqueous HCl solution. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product, (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a yellow gum (0.183 mg, 99%).
Reaction SMILES: O.O.[C:3]([OH:8])(=O)[C:4](O)=[O:5].C(O)(=O)C(O)=O.Cl.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>O>[OH:5][C:4]1[C:3]([OH:8])=[N:23][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:22]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Oc1nc2ccccc2nc1O
Temperature: 90 °C
Yield: 95.8 %

Procedure:
To a 2 L flask were added 280.0 g of oxalic acid dihydrate (2.221 moles) and then 1 L of distilled water. Then the mixture was heated to 90° C. After complete dissolution of oxalic acid, 400 mL of concentrated hydrochloric acid was added, followed by addition of 220.0 g of o-phenylenediamine (2.034 moles). The temperature was maintained at 90° C. for 30 minutes with continuous stirring. Off-white crystals were formed. After cooling to room temperature, the off-white crystals were collected by filtration, washed first with water, then with methanol and dried under reduced pressure to give 315.8 g (96%) of off-white needles: mp>350° C.
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cc(CN(C2CCNCC2)C2CC2)ccn1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccncc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidine-4-yl-pyridin-4-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (19%, yellow oil). HPLC-MS m/z=(M+1), Rt: 2.82 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>CC(N(C)C)=O.CS(C)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:32]([NH:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.96 g, 2.47 mmol) in 10 mL of DMA was added 2,4-difluoro phenyl isocyanate (0.42 g, 2.71 mmol), and the mixture was stirred at ambient temperature overnight The reaction mixture was diluted with DMSO and was purified by RP-HPLC. The fractions containing the product were pooled and evaporated to a small volume. The aqueous solution was neutralized with 1N NaOH to a pH of 9.0 and the product was extracted with ethyl acetate (2×, 50 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea as a colorless solid in 59% yield. LCMS m/z (%)=520 (M+H 79Br, 100), 522 (M+H 81Br, 98). 1H NMR (400 MHz. DMSO-d6) δ: 9.03 (bs, 1H), 8.49 (bs, 1H), 8.01-8.1 (m, 1H), 7.61 (s, 1H), 7.51 (dd, J=8.96 and 2.73 Hz, 1H), 7.35 (d, J=2.72 Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, J=9.04 Hz, 1H), 7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, 3H), 2.51-2.73 (m, 2H), 2.34-2.38 (bs, 4H), 1.59-1.63 (bs, 4H).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Yield: 38.9 %

Procedure:
7-Fluoro-1-methylamino-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Example 1 but starting from 1.93 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[ b][1,8]naphthyridine-3-carboxylic acid, 2.4 g of 1-methylpiperazine and 20 cm3 of pyridine. After recrystallizing twice from 15 cm3 of dimethylformamide each time, 0.9 g of 7-fluoro-1-methylamino-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 263°-264° C.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CN(C)[CH:23]=[O:24]>>[Br:1][C:2]1[C:3]([O:24][CH3:23])=[CH:4][C:5]([O:11][CH3:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Agent: [Cs+]
Solvent: CI
Product: COc1cc(OC)c(C(=O)O)cc1Br

Procedure:
1.1 A solution of 15 g of 5-bromo-2,4-dihydroxybenzoic acid, 14.4 ml of iodomethane and 62.9 g of caesium carbonate in 100 ml of N,N-dimethylformamide (DMF) is heated under reflux for 16 hours. The mixture is subjected to conventional work-up, giving 16.7 g of 5-bromo-2,4-dimethoxybenzoic acid (“1”).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-hydroxymethylphenyl)propionic acid ethyl ester (P5, 2.9 g, 13.9 mmol) in triethylamine (4.0 mL, 27.8 mmol) and dichloromethane (30 mL) was slowly added at 0° C. mesyl chloride (1.6 mL, 20.9 mmol). The solution was stirred at room temperature for 18 hours, then the solution was washed with 1N aqueous hydrochloric acid. The organic phase was dried (anhydrous magnesium sulfate) and concentrated to afford the title compound as an oil.