Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](Cl)=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[C:20]([NH:21][C:22]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].O>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]2[O:9][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)=[O:23])[C:12]=3[N:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Nc1c(NC(=O)c2cnccn2)cccc1C(=O)O
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)o2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
2,4-dimethylthiazole-5-carbonyl chloride 17 (104 mg, 0.58 mmol) was added to a suspension of 2-amino-3-(pyrazine-2-carboxamido)benzoic acid 16 (100 mg, 0.39 mmol) in pyridine (5 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O (30 mL). The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 18 (110 mg, 81% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[NH2:22][C:23]1[C:24]([C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=3)[C:31](=[O:41])[O:30][N:29]=2)=[N:25][O:26][N:27]=1.[CH2:42]([N:45]([S:53]([N:56]([CH2:60][CH:61]=[CH2:62])[CH2:57][CH:58]=O)(=[O:55])=[O:54])[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH:43]=[CH2:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:42]([N:45]([S:53](=[O:55])(=[O:54])[N:56]([CH2:60][CH:61]=[CH2:62])[CH2:57][CH2:58][NH:22][C:23]1[C:24]([C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=3)[C:31](=[O:41])[O:30][N:29]=2)=[N:25][O:26][N:27]=1)[C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])[CH:43]=[CH2:44]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: C=CCN(CC=O)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(CCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
To a 50-mL flask was added sodium triacetoxyborohydride (1.06 g, 5.0 mmol, 1.0 equiv.), trifluoroacetic acid (TFA, 2.0 mL, 26 mmol) and tetrahydrofuran (THF, 1.0 mL) at ambient temperature. This mixture was cooled to −5° C. under N2 and stirred at 0-5° C. for 10 min. To this solution was added 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.171 g, 5.0 mmol; Step D) and tert-butyl allyl{[allyl(2-oxoethy)amino]sulfonyl}carbamate (0.398 g, 2.5 mmol, 0.5 equiv.) in THF (1.5 mL) drop-wise at 0-5° C. over 5 min. The resulting reaction mixture was stirred under N2 at 0-5° C. At 20 min, 40 min, and 2.5 h time points, a solution of tert-butyl allyl{[allyl(2-oxoethy)amino]sulfonyl}carbamate (0.040 g, 0.125 mmol, 0.25 equiv.) in THF (0.20 mL) was added drop-wise at 0-5° C. At 2.5 h, a solution of sodium triacetoxyborohydride (0.211 g, 1.0 mmol, 0.2 equiv.) in trifluoroacetic acid (TFA, 1.5 mL, 9.5 mmol) was added at 0-5° C. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was then poured into an ice-cold saturated solution of sodium carbonate (50 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was then purified on silica gel (0-75% ethyl acetate/hexane gradient elution) to give the desired product (0.239 g, 74.2%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.71 (m, 1H), 7.58 (t, 1H, J=8.7 Hz), 6.62 (m, 1H), 5.77 (m, 2H), 5.19 (m, 4H), 4.17 (m, 2H), 3.89 (m, 2H), 3.44 (m, 2H), 3.38 (m, 2H), 1.42 (s, 9H); C23H27BrFN7O7S (MW 644.47), LCMS (EI) m/e 544/546 (M+-Boc+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:23]([CH:26]=1)[C:24]#[N:25].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:14]([C:11]2[C:10]([CH3:17])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:20]=[CH:21][C:22]=1[O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])#[N:25]
Reactant: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
1-(4-Fluorophenyl)-3,5-dimethylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.7 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.6 g), melting point: 174–175° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:17](=O)[CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH2:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCN1CCCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of methyl 14-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate (prepared as described in Example 8, Step 7) in THF (0.1 M), BH3.Me2S (20 eq, 2 M solution in THF) was added. The solution was stirred overnight at RT. MeOH was carefully added to the mixture to quench the reaction, followed by an excess of 1 N NaOH (>10 eq). The mixture was heated at 60° C. for 12 h. The solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (24% over three steps).
Reaction SMILES: C(Cl)Cl.[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:27]=[C:26]([CH2:28][NH:29][CH3:30])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5].CCN(CC)CC.[F:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>O>[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:27]=[C:26]([CH2:28][N:29]([CH3:30])[S:45]([C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5]
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To an anhydrous DCM (50 mL) solution of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((methylamino)methyl)phenoxy)acetate (22) (28 g, 72 mmol), was added Et3N (8.6 g, 85 mmol) followed by portionwise addition of 4-fluoro-benzenesulfonyl chloride (16.6 g, 85 mmol). The mixture was stirred at room temperature for 20 min and water (20 mL) was added. The organic layer was separated, dried and concentrated in vacuo. The crude was purified by column chromatography to give t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (23) (24 g, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Temperature: 150 °C
Reaction time: 14 h
Yield: 36.2 %

Procedure:
To a suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.53 g, 6.53 mmol) and potassium carbonate (3.72 g, 26.9 mmol) in N,N-dimethylformamide (50 mL) were added 1-fluoro-3-nitrobenzene (1.08 g, 7.65 mmol) and 18-crown-6 (1.07 g, 4.05 mmol), and the mixture was stirred at 150° C. for 14 hr. The reaction mixture was cooled to room temperature, and added to a mixed solvent (1:1, 300 mL) of ethyl acetate and hexane. The mixture was washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was collected by filtration, and the residue was subjected to silica gel column chromatography using ethyl acetate and hexane (1:1) as an eluent to give the title compound (840 mg, 36%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([OH:18])=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:19][N:20]([CH:22]=O)[CH3:21].S(Cl)(Cl)=O.[O:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([NH:4][C:10]2[CH:11]=[CH:12][C:13]([CH2:22][N:20]([CH3:19])[CH:21]3[CH2:31][CH2:32][O:28][CH2:29][CH2:30]3)=[CH:14][CH:9]=2)=[O:18])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid (320 mg) was dissolved in tetrahydrofuran (15 ml), and DMF (0.3 ml) was added to the solution. Then, thionyl chloride (0.23 ml) was added thereto at 0° C., and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. The solvent and excess thionyl chloride were evaporated under reduced pressure, and the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (275 mg) and triethylamine (1.27 g) in tetrahydrofuran (10 ml) at 0° C. The temperature was returned to room temperature, and the mixture was stirred overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8) to give 1-allyl-7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (266 mg) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[C:13]([Cl:19])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16].N1C=CC=CC=1>C(OCC)(=O)C>[ClH:19].[C:13](=[O:18])([O:1][CH2:2][CH2:3][NH:4][CH3:5])[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)OC(C)C
Product: Cl
Reaction time: 3.5 h
Yield: 69.6 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g) obtained in Reference Synthetic Example 1 and ethyl acetate (20 mL) were added isopropyl chlorocarbonate (1.23 g) and pyridine (1.94 mL) under ice-cooling. After stirring for 3.5 hrs under ice-cooling, isopropyl chlorocarbonate (1.23 g) was further added, and stirred at room temperature for 2.5 hrs. To the reaction solution was added ethyl acetate (120 mL), and washed with water (50 mL), and saturated saline (50 mL), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and to the residue was added 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 2 hrs, the depositting solid was collected by filtration. The solid was washed with ethyl acetate (15 mL), and dried at 60° C. under reduced pressure to give title compound as white solid (1.38 g).
Reaction SMILES: [F:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13].CN1CCOCC1.C(OC(Cl)=O)C(C)C>CCOCC.C1COCC1>[CH2:6]([O:5][C:3]([CH:2]([F:1])[C:12]([CH:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13])=[O:4])[CH3:7]
Reactant: CCOC(=O)CF
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(F)C(=O)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl fluoroacetate (2.0 g, 18.9 m mol) in ether (25 ml) was added dropwise with stirring to a suspension of NaH (50 percent oil dispersion)(0.91 g, 18.9 m mol) in ether (20 ml). The reaction mixture was stirred three hours at room temperature, then cooled to -15°. The mixed anhydride of Boc-Pro-OH [prepared from Boc-Pro-OH (4.1 g, 18.9 m mol) in the THF (50 ml) containing N-methylmorpholine (2.1 ml, 18.9 m mol) at -15°, by the addition of isobutylchloroformate (2.45 ml, 18.9 m mol) and stirred 5 minutes] was filtered into the chilled enolate suspension and stirred at -15° for 10 minutes. The reaction was then allowed to warm to room temperature for one hour. The solution was poured onto ice containing 2.5N H2SO4. The organic solvents were removed by evaporation and the aqueous residue extracted with ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3, saturated with NaCl, and dried over anhydrous MgSO4. The ethyl acetate was removed by evaporation and the residue was applied to a silica gel column. The product was eluted with chloroform. The solvent was removed by evaporation yielding 1.08 g of an oil. The 1H nmr (CDCl3) showed peaks shifted from TMS by ##STR5##
Reaction SMILES: [CH2:1]([NH:8][C:9](SC)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23]1>C(#N)C>[CH2:1]([NH:8][C:9]([NH:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23]1)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C#N)=C(NCc1ccccc1)SC
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(NCc1ccccc1)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
To a solution of ethyl 3-benzylamino-3-methylthio-2-cyanoacrylate (1.07 g, 3.87 mmol) in acetonitrile (10 ml) was added 2-aminomethyl-4-(p-fluorobenzyl)morpholine (0.90 g, 4.02 mmol) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as white crystals (0.70 g) from the fraction from hexane-ethyl acetate (1/1). Yield=40%.
Reaction SMILES: [C:1]([P:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][P:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O.[Ru:28]([Cl:31])(Cl)Cl.[CH2:32]([OH:34])C>>[C:23]([P:18]([CH2:17][C:13]1([C:32]([Ru:28][Cl:31])=[O:34])[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:12]1)[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCO
Reactant: CC(C)(C)P(Cc1cccc(CP(C(C)(C)C)C(C)(C)C)c1)C(C)(C)C
Reactant: Cl[Ru](Cl)Cl
Solvent: O
Product: CC(C)(C)P(CC1=CC=CC(CP(C(C)(C)C)C(C)(C)C)(C(=O)[Ru]Cl)C1)C(C)(C)C

Procedure:
Refluxing 1,3-bis((ditertiarybutylphosphino)methyl)benzene with ruthenium(III)chloride hydrate in ethanol produced the known complex 1,3-bis((ditertiarybutylphosphino)methyl)benzene(carbonyl)chlororuthenium(II). The carbonyl ligand is formed by decarbonylation of the ethanol solvent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CN(C=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([NH:25][CH:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(NC1CCCC1Br)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC2CCCC2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
A mixture of 2.5 g (15 mmoles) of methyl 4-hydroxybenzeneacetate, 4 g (30 mmoles) of K2CO3 and 30 ml of DMF is heated to 80° C. A solution of 5 g (14.8 mmoles) of N-(2-bromocyclopentyl)-4-chlorobenzenesulfonamide as in example 5a is added dropwise thereto, in 50 ml of DMF. The mixture is stirred 5 h at 80° C. After cooling, the solid which is present is filtered and rinsed with ethyl acetate. The filtrate which is diluted with water is extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue which is purified by chromatography on a column of silica (eluant:hexane-ethyl acetate 1/1) gives 6.2 g (yield=99.5%) of a yellow liquid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][O:33][CH3:34].Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[N:20]=[CH:19][N:18]=2)[CH:23]=1
Reactant: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred solution of 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.05 g, 0.12 mmol) in DMF (2 mL) were added MeNH—OMe.HCl (0.0084 g, 0.12 mmol), EDCI HCl (0.0361 g, 0.18 mmol), HOBT (0.0084 g, 0.062 mmol) and DIPEA (0.023 g, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h and was quenched with water. A white solid was isolated by filtration and dried under vacuum to give N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.025 g, 44.5%) as a white solid.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:3][N:4]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2C1CCOC1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[3,2-c]pyridine (60.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (74.0 mg), tetrakis(triphenylphosphine)palladium(0) (20.1 mg) and potassium carbonate (48.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.6 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1
Reactant: CCC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 5.0 ethyl 4,6-dichloroquinoline-3-carboxylate (1.08 g, 4 mmol, 1 equiv.) in 1,4-dioxane (10 mL) at room temperature was added compound 5.1 1-(4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.2 g, 4 mmol, 1 equiv.). The resulting solution was heated to 80° C. and stirred 4 h before cooling to room temperature. NaOH ON aqueous solution, 3 mL) was added. The solution was diluted with EtOAc (30 mL) and washed with water (30 mL×2) and brine (30 mL). The organic phase was dried over Na2SO4. After removal of solvents, the residue was purified via flash chromatography (CH2Cl2: MeOH=20:1) to afford the desired product 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (2 g; 93%). LC-MS: (M+H): 622.20