Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[F:10][C:11]([F:16])([F:15])[C:12](O)=[O:13].Cl>CCOCC>[CH:4]1[C:5]([C:12]([C:11]([F:16])([F:15])[F:10])=[O:13])=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
In a three-neck flask, 52.5 g of 4-fluoro-1-bromobenzene are charged with 60 ml ether, then 7.3 g magnesium turnings. The walls of the flask are rinsed with a few ml ether. Small crystals of iodine are added thereto and the mixture is heated to reflux until all the magnesium has reacted with the same. The mixture is left to revert to room temperature, then a solution of 11.4 g trifluoro acetic acid in 15 ml ether is very slowly added in about 20 minutes. The inner temperature is kept at about 20°-30° by external cooling. The mixture is kept aside at room temperature for 15 minutes and then heated to reflux for three hours. The mixture is thereafter kept in a cool place for 12 hours. The cooled mixture is poured on a mixture of crushed ice and chlorhydric acid. The etherous phase is separated. The aqueous phase is extracted twice with 100 ml ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1cc(Cl)ccc1C(=O)Cl

Procedure:
A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.0 g of the desired product as a residue.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:35]([CH:36]=O)=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1>CO.N1CCCCC1>[Br:26][C:27]1[CH:28]=[C:29]2[C:35](/[CH:36]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncc(Br)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (1.0 mL) was added with 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.044 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was suspended in methylene chloride and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.018 g, 56%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:29][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:30])([F:31])[F:21])=[CH:28][CH:27]=3)=[O:19])[CH2:16][CH2:17]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
A solution of 29.3 g of trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarbonyl chloride in 120 ml of toluene is added dropwise in the course of 2 hours with stirring to a boiling solution of 16.2 g of p-trifluoromethylphenol and 10 ml of pyridine in 120 ml of toluene. The reaction mixture is refluxed for a further 3 hours and then evaporated. The residue is worked up as conventional. p-Trifluoromethylphenyl trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarboxylate is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[CH3:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Reaction time: 0.42 h
Yield: 84.9 %

Procedure:
2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H NMR (CDCl3): δ8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H) , 2.50 (s, 3H).
Reaction SMILES: [OH-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C:19]([CH3:21])=[O:20]>C1(C)C=CC=CC=1>[O:3]([C:10]1[CH:11]=[C:12](/[CH:13]=[CH:18]/[C:19](=[O:20])[CH3:21])[CH:15]=[CH:16][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
6.7% w/v aqu. NaOH (12 ml) was added to a solution of 3-phenoxybenzaldehyde (40 g, Aldrich) in acetone (200 ml). The mixture was stirred for 1/2 hour and then poured into 2 M aqu. HCl and extracted with ether/pet.ether (1:1). The extract was washed with satd. aqu. NaCl, dried over MgSO4 and stripped to give the aldol product. The latter was taken up in toluene (100 ml) p-toluenesulphonic acid (1 g) was added and the mixture heated on a steam-bath for 1 hour. The mixture was then cooled, washed with satd. aqu. NaHCO3 and satd. aqu. NaCl. dried over MgSO4, and stripped to give the desired product (39.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C[CH2:33][N:34](C(C)C)C(C)C.CN>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([NH:34][CH3:33])=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)cn34)ccnc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)s1
Yield: 18.8 %

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig's Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added. The solution was concentrated in vacuo and purified via flash chromatography eluting with 3-8% MeOH:NH4OH in DCM. There remained an impurity, so the product was triturated with MeCN, filtered and washed with DCM to yield 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylthiophene-2-carboxamide (0.0276 g, 19% yield) as an amorphous tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[F:19][C:20]([F:30])([F:29])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH:25]3[CH2:26][CH2:27][N:22]([CH2:21][C:20]([F:30])([F:19])[F:29])[CH2:23][CH2:24]3)=[O:15])=[CH:11][N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cc(F)cc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2cc(F)cc(F)c2)nc1
Yield: 7.2 %

Procedure:
6-(3,5-Difluoro-phenyl)-nicotinic acid (50 mg, 0.21 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (48 mg, 0.22 mmol) N,N-diisopropylethylamine (0.296 mL, 1.69 mmol), HATU (101 mg, 0.26 mmol) in acetonitrile (5 mL) was shaken at room temperature for 12 h. The reaction mixture was concentrated and the crude reaction mixture purified by automated reversed phase chromatography to provide 6 mg (7%) of the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.08 (1H, s), 8.47 (1H, d, J=7.0 Hz), 8.30 (1H, dd, J=8.4, 2.2 Hz), 8.19 (1H, d, J=8.1 Hz), 7.88 (2H, d, J=7.0 Hz), 7.36 (1H, t, J=10.1 Hz), 3.82 (1H, br. s.), 3.11-3.23 (2H, m), 2.95 (2H, d, J=11.0 Hz), 2.42-2.48 (2H, m), 1.76-1.87 (2H, m), 1.56-1.66 (2H, m).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(CCc1ccc(-c2ccc(Oc3ccc(C)cc3)cc2F)cc1)(COC(C)=O)COC(C)=O
Yield: 77.4 %

Procedure:
A solution of N-[1,1-bis(acetoxymethyl)-3-(2′-fluoro-4′-hydroxybiphenyl-4-yl)propyl]acetamide (278 mg), 4-methylphenylboronic acid (175 mg), copper(II) acetate (117 mg), pyridine (255 mg) and molecular sieves 4A (500 mg) in methylene chloride (5 mL) was stirred at room temperature for 9 hr. 2% Aqueous citric acid solution (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].N1C=CC=CC=1.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>O1CCCC1>[C:11]([C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:20]#[N:21])[CH:23]=3)(=[O:30])=[O:29])[CH:3]=[CH:4][C:5]=2[CH3:13])[NH:9][CH:8]=1)#[N:12]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(N)c2[nH]cc(C#N)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccc(C#N)c2)c2[nH]cc(C#N)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.4 %

Procedure:
To a solution of 7-amino-3-cyano-4-methyl-1H-indole (10 g, 58.4 mmol) in tetrahydrofuran (200 ml) were added pyridine (20 ml) and 3-cyanobenzenesulfonyl chloride (12.5 g), followed by stirring at room temperature for 3.5 hours. After further adding 2N hydrochloric acid (100 ml), extraction was performed with ethyl acetate. The organic layer was washed with water (twice) and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-3:2). A mixed solvent of ethanol-hexane (1:2) was added thereto, and after sonication, the precipitate was collected by filtration and washed with a mixed solvent of ethanol-hexane (1:3). The mixture was dried overnight under reduced pressure to give the title compound (9.33 g, 27.7 mmol, 47% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].P([O-])([O-])([O-])=O>C1COCC1>[Si:7]([O:3][CH2:2][CH2:1][OH:4])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
Ethylene glycol (2.00 g) in anhydrous THF (60 ml) under nitrogen was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.29 g) and the mixture stirred at 20° C. for 45 min. Tert-butyl dimethylsilyl chloride (4.86 g) was added and the mixture stirred at 20° C. for 45 min. Phosphate buffer (60 ml, pH6.5) was added and the mixture stirred for 20 min before extracting with ether (60 ml). The organic layer was then washed with water (60 ml) and brine (60 ml), before drying over Na2SO4, filtering, and removing the solvent in vacuo. This was purified by flash chromatography on silica. Elution with 1:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (3.82 g). TSP+ve 194 MNH4+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[S:10][CH:11]=[CH:12][C:13]=3[C:14]([NH2:15])=[N:16][C:4]=2[CH:3]=1
Reactant: N#Cc1ccsc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2cc(Cl)ccc2Nc2sccc21
Yield: 142.2 %

Procedure:
Suspend 2-(4-chloro-2-nitro-phenylamino)-thiophene-3-carbonitrile (4.85 g, 17.35 mmol) in ethanol (40.0 ml). Dissolve tin(II) chloride dihydrate (11.75 g, 52.06 mmol) in 5N HCl (40.0 ml) and then add it to the suspension. Heat the reaction at reflux for 48 hours. Cool the reaction to ambient temperature and then chill it in a refrigerator for 2 hours. Collect the resulting precipitate by vacuum filtration and then dry it under vacuum to give 3.53 g (71%) of the title compound: mass spectrum (ion spray): m/z=250.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(F)(F)F)nc1
Reaction time: 72 h
Yield: 93 %

Procedure:
5-Nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (20.5 g, obtained in example 108, step 1) was dissolved in methanol (160 mL). Palladium on activated charcoal (1.96 g, 10% Pd) was added and an atmosphere of hydrogen was introduced at RT. The mixture was stirred under hydrogen for 72 hours. The reaction mixture was filtered over dicalite speed plus (Acros Organics), washed with ethyl acetate and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a brown liquid (16.49 g, 91%). MS (m/e): 193.1 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCl)NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCO
Yield: 94 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[bis(4-fluorophenyl)methyl]-1- piperaziny]pentanesulfonamide (905.6 mg) as a pale yellow oil (94.0%).
Reaction SMILES: [CH3:1][CH:2]([O:4]/[N:5]=[C:6](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:7]([OH:9])=O)[CH3:3].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:41][CH:42]1[C:67](=[O:68])[N:44]2[C:45]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])=[C:46]([CH2:49][Cl:50])[CH2:47][S:48][C@H:43]12>ClCCl.C(OCC)(=O)C>[Cl:50][CH2:49][C:46]1[CH2:47][S:48][C@@H:43]2[CH:42]([NH:41][C:7](=[O:9])/[C:6](=[N:5]\[O:4][CH:2]([CH3:3])[CH3:1])/[C:10]3[N:11]=[C:12]([NH:15][C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:13][CH:14]=3)[C:67](=[O:68])[N:44]2[C:45]=1[C:51]([O:53][CH:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
A mixture of (Z)-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IVc) (707 mg, 1.5 mmoles) and phosphorus pentachloride (344 mg, 1.65 mmoles) in dichloromethane (14 ml) was stirred at room temperature for 1 hour and poured into a solution of Compound V (677 mg, 1.5 mmoles) and BSA (1.1 ml, 4.5 mmoles) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate (100 ml) and water (3×100 ml), dried over sodium sulfate and evaporated to give 1.4 g (100%) of Compound VIc.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]([CH3:40])[CH2:31][C:32]([NH:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:33])[CH:26]=[CH:25][CH:24]=1>>[CH:35]1([NH:34][C:32](=[O:33])[CH2:31][N:30]([CH2:29][C:27]2[N:28]=[C:23]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=2)[CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CN(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CN(CC(=O)NC1CCCC1)Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N2-[(6-bromopyridin-2-yl)methyl]-N-cyclopentyl-N2-methylglycinamide (0.11 g, 0.34 mmol) as the starting materials.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(O)(=O)C.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)=[C:22]([O:37][CH2:38][CH3:39])[CH:21]=2)=[CH:14][N:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:38]([O:37][C:22]1[CH:21]=[C:20]([CH2:19][C:15]2[C:16]([NH2:18])=[N:17][C:12]([NH2:11])=[N:13][CH:14]=2)[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][CH:30]=1)[CH3:39]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C=O)cc1
Reactant: NCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(CNCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 2,2,2-trifluoroethylamine (0.477 ml; 6 mmol) in 4 ml methanol is adjusted to pH 6 with glacial acetic acid, and 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-2′,6′-diethoxy-biphenyl-4-carbaldehyde (392 mg; 1 mmol) is added. The reaction mixture is then cooled to 0° C. and sodium cyanoborohydride (38 mg; 0.6 mmol) is added. After half and hour at 0° C., the mixture is stirred for 3 h at room temperature. After evaporation of the reaction mixture, the residue is stirred in 20 m water and the mixture is adjusted to pH 8 with 1 N aqueous sodium hydroxide solution. The substance which has precipitated out is filtered off with suction and dried under a high vacuum. The residue is stirred in 20 ml methylene chloride and filtered off with suction again and dried. 105 mg (22%) 5-{2,6-Diethoxy-4′-[(2,2,2-trifluoro-ethylamino)-methyl]-biphenyl-4-ylmethyl}-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[N+]([O-])([O-])=[O:18].[K+]>>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:18])[NH:5]2
Reactant: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
To a stirred solution of 6-bromo-7-chloro-5-nitroquinoxaline-2(1H)-one (0.025 g, 0.082 mmol) in conc. H2So4 (0.5 mL) was added KNO3 (0.011 g, 0.11 mmol) and the resulting dark red solution was stirred at r.t. for 65 h. The solution was then cooled in an ice-bath and diluted with ice to a total volume of 5.0 mL. The precipitated solid was filtered, washed with water (2.0 mL) and dried under vacuum to give 0.019 g (72%) of crude product. It was purified as follows. Crude product (0.016 g) was taken up in 1N NaOH (1.1 mL). The mixture was centrifuged and the supernatant liquid was acidified with conc. HCl to pH~2. The precipitated solid was filtered, washed with water (1.0 mL) and dried under vacuum to furnish 0.010 g (50%) of pure title compound as a cream colored powder; m.p. 338°-343° C. (decomposed); 1H NMR (DMSO-d6): 7.351 (s, 1H), 12.251 (s overlapped by a br s, 2H).