Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8])=[CH:13][CH:12]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a rapidly stirring solution of 22.5 g (0.56 mole) of sodium hydroxide in 400 ml of water was added, dropwise, 73.8 g (0.52 mole) of freshly distilled 1,4-dichloro-2-butanol. The mixture was stirred for 15 min at ambient temperature. To this mixture was added, over a 45 min period, a solution obtained by adding 75.0 g (0.43 mole) of 4-bromophenol to a solution of 18.0 g (0.47 mole) of sodium hydroxide in 430 ml of water. The mixture was stirred vigorously for 30 hr and then cooled in an ice bath. The suspended solid was collected by filtration, rinsed with water several times and air dried. Recrystallization from ethyl ether-petroleum ether (b.p. range 30°-60° C.) gave 44.2 g (37%) of white solid, m.p. 75°-78° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.33 mmol) to afford the desired product (41 mg, 28%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.46 (d, J=8.0 Hz, 1H), 8.96 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.64-7.57 (m, 2H), 4.13-4.07 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.22-2.15 (m, 2H), 2.13 (s, 6H), 1.87 (d, J=12.9 Hz, 2H), 1.57-1.42 (m, 3H), 1.16-0.99 (m, 5H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC 98.5% (AUC), tR=8.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Yield: 84.4 %

Procedure:
4.78 g of (E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5-hexen-2-one was dissolved in 30 ml of tetrahydrofuran, and 14.3 ml of a 1M tetrahydrofuran solution of lithium tri-sec-butyl borohydride was added at -78° C. under cooling with stirring, followed by stirring at the same temperature for 2 hours. To the reaction solution, 10 ml of a 2N sodium hydroxide aqueous solution was added under cooling with ice with stirring, and then, 15 ml of a 30% hydrogen peroxide aqueous solution was gradually dropwise added, followed by stirring at room temperature for one hour. The reaction solution was extracted by an addition of ethyl ether and water. The organic layer was washed with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1→5/1) to obtain 4.06 g of the above-identified compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.C1(C=CC(O)=CC=1)O.[CH3:19][O:20][CH:21]=[CH:22][C:23]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH2:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:24][C:23]([O:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[CH:22][CH:21]2[O:20][CH3:19]
Reactant: COC1=CC(=O)C=CC1=O
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2CC(O[Si](C)(C)C)=CC(OC)C2C1=O
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL round bottom flask, 2-methoxy-1,4-benzoquinone (2.3 g, 16.7 mmol) was suspended in toluene (30 mL). Hydroquinone (95 mg) was added and the resulting suspension was stirred magnetically for 5 min. 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene (Aldrich, used as received, 5.0 g, 4.5 mL, 29.1 mmol) was added in one portion and the reaction was heated under N2 at 60° C. using an oil bath for 18 h. The reaction was removed from the oil bath, allowed to cool to rt and the solvent was removed by evaporation. Crystallization occurred after cooling the mixture to -30° C. for 1 hour. The colorless solid was collected by filtration and washed with hexane (30 mL) giving 4a,5,8,8a-tetrahydro-2,8-dimethoxy-6-trimethylsilyloxynapthalene-1,4-dione ##STR137## as a colorless powder (3.6 g, 11.6 mmol, 70%, >95% pure by 1H NMR, mp 108°-110° C.; 1H NMR (CDCl3) δ0.52 (s, 9H), 2.2-2.4 (m, 2H), 3.18 (s, 3H), 3.47 (t, 1H), 3.80 (s, 3H), 3.92 (m, 2H), 5.20 (d, 1H), 6.12 (s, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][CH2:26][C@H:27]([OH:40])[C:28]#[C:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([CH2:25][CH2:26][C@H:27]([OH:40])[C:28]#[CH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[Si](C#C[C@@H](O)CCc1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#C[C@@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a modified procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)); Tetrabutylammonium fluoride (1.0 M in THF, 25 ml, 25 mmol, 2.5 eq.) was added to a solution of (S)-5-phenyl-1-(triisopropylsilyl)pent-1-yn-3-ol 85 (3.165 g, 10 mmol, 1 eq.) in THF (95 ml). The reaction mixture was stirred for 1 h at r.t. and then quenched by addition of saturated aq. NH4Cl (50 ml). The mixture was extracted with Et2O (3×40 ml), the combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et2O (10:1 to 9:1), giving the title product 86 as a clear, colourless oil (1.6 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([O:15][CH2:16][CH2:17][CH3:18])[CH2:13]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[O:15][CH2:16][CH2:17][CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCOC(C)CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCOC(C)COC(=O)c1ccc(O)cc1
Yield: 90 %

Procedure:
3.2 g of p-hydroxybenzoic acid and 13.8 g of optically active 2-methyl-2-propyloxyethanol were refluxed under heating together with 1 ml of sulfuric acid in benzene for 20 hours. The reaction liquid was condensed and purified by column chromatography to obtain 5.0 g (yield: 90 %) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][OH:19])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]=[O:19])[N:6]2[CH2:13][C:14]([F:16])([F:17])[F:15]
Reactant: N#Cc1ccc2c(cc(CO)n2CC(F)(F)F)c1Cl
Agent: O=[Mn]=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(C=O)n2CC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of 4-chloro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (0.07 g, 0.24 mmol) in MeCN (3 mL) was added activated MnO2 (0.21 g, 2.42 mmol). The mixture was stirred at rt for 2 h. Additional MnO2 (0.11 g, 1.21 mmol) was added and stirred for 1 h. The solids were filtered off and washed with EtOAc, CH2Cl2 and MeOH. The filtrate was concentrated in vacuo and the residue was purified by radial chromatography (2-30% EtOAc-hexanes gradient) to afford the title compound (0.046 g, 67% yield): MS (ES) m/z 285 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A solution of 6.71 (50 mmol) of 2-allylphenol in 50 ml of dimethylformamide was added dropwise to a stirred suspension of 2.20 g (55 mol) of a 60% dispersion of sodium hydride in mineral oil in 30 ml of dimethylformamide. The mixture was stirred at 25° C. for 1 hour and then a solution of 5.95 ml (50 mmol) of benzyl bromide in 20 ml of dimethylformamide was added dropwise. After the resulting mixture was stirred at 25° C. for 18 hours 500 ml of water was added and the mixture was extracted with ether. The ether extracts were washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on a silica gel column, eluting with a 0 to 10% gradient of ethyl acetate in hexane afforded 9.68 g (86.4%) of the product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][C:6]([CH3:12])=[N:7]2.O=P(Cl)(Cl)Cl.C(OC([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=Nc2cccc(Cl)c2C(=O)C1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCNCC2)c2c(Cl)cccc2n1

Procedure:
4,5-Dichloro-2-methylquinoline, obtained by treating 5-chloro-2-methyl-4-quinolone with POCl3 (cf. De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR (CDCl3), δ 2.68 (s, 3H), 7.41 (s, 1H), 7.55 (t, 1H), 7.59 (dd, 1H), 7.95 (dd, 1H)), (125 mg, 0.59 mmol) and 1-tert-butoxycarbonylpiperazine (559 mg, 3.0 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (3 mL) in CH2Cl2 (5 mL) giving 0.18 g of the piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH2:25]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:26]#[CH:27]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:27]#[C:26][CH2:25][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2.3 g; 5.6 mmol), 4-prop-2-ynyl-morpholine (2.1 g; 16.8 mmol), bis(triphenylphosphine)palladium (II) chloride (0.31 g; 0.45 mmol) and copper iodide (0.06 g; 0.34 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.9 g. HPLC-MS: m/z: 456.1 (M+); Rt: 1.53 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)=[CH:21][CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cc(C#N)ccn2)cc1
Yield: 77.6 %

Procedure:
Using a method similar to Example 381, Part A, using 2-chloroisonicotinonitrile (0.500 g, 3.61 mmol) and [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.856 g, 3.61 mmol) gives the title compound (0.947, 77.6%): MS ES+ 340.2 (M+H)+, base peak MS ES+ 284.0 (M+2H—C(CH3)3))+; TLC [silica gel 60 F254, 40% ethyl acetate in hexanes] Rf=0.30.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C@@H:9]([C:14]([OH:16])=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:14]([C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:10]1)=[O:16]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 18 h

Procedure:
(2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1 g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24 mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in CH2Cl2 and stirred vigorously. Triethylamine (9.2 mL, 66 mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol) and EDCl (6.9 g, 36 mmol), and the reaction was stirred overnight. After 18 hours, TLC showed no remaining acid starting material, so the reaction was partitioned between water and CH2Cl2 and the organic layer was washed 3×100 mL of water. The organic layer was washed with 1N HCl, which removed the product into the aqueous layer. This aqueous layer was washed with CH2Cl2 and the organic was discarded. The aqueous solution was then basified and became cloudy with a white precipitate. The basified mixture was extracted with 3×100 mL of CH2Cl2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.BrN1C(=O)CCC1=O.[CH2:31]([SH:34])[CH2:32][SH:33].[OH-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:34][CH2:31][CH2:32][S:33]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Reactant: SCCS
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCS1
Temperature: 25 °C
Reaction time: 3.7 h
Yield: 120.1 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-formyl-1H-pyrazole-3-carbonitrile (5.00 g, 13.7 mmol) in dichloromethane (100 mL) at room temperature was added N-bromosuccinimide (0.74 g, 4.1 mmol) followed by 1,2-ethanedithiol (1.98 g, 20.6 mmol). The resulting mixture was stirred at room temperature for 3.7 hr. It was then worked up by adding 2 N sodium hydroxide. The layers were separated and the organic layer was washed with brine and then dried (sodium sulfate). It was then concentrated to afford a light beige solid (7.0 g). 19F-NMR: −63.791.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:17]Br>C1COCC1.[Cl-].[Na+].O>[Br:17][C:11]1[C:10]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[S:8][C:7]=1[N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1CCCc2cc(N3CCOCC3)sc21
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCc2c1sc(N1CCOCC1)c2Br
Yield: 71.4 %

Procedure:
To a stirred solution of Example 2 (0.83 g, 3.50 mmol) in THF (50 mL) at 0° C. was added, dropwise, Br2 (0.56 g, 3.50 mmol) and the reaction mixture was stirred for 20 minutes. The reaction mixture was then poured into brine (200 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1:5 EtOAc/hexanes) gave the title compound as a pale brown solid (0.79 g, 72%). δH (DMSO-d6) 3.77-3.74 (4H, m), 3.22-3.18 (4H, m), 2.70-2.67 (2H, m), 2.52-2.47 (2H, m), 2.10-2.04 (2H, m). δ 13C (DMSO-d6) 189.7, 160.2, 152.7, 124.6, 97.4, 65.9 (2×CH2), 51.9 (2×CH2), 37.3, 25.9, 23.4. LCMS (ES+) 315.0 and 317.0 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=O>C(O)C>[C:19]1([CH:23]2[C:24]3[N:15]=[C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)[S:14][C:25]=3[CH2:26][CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=1
Reactant: NC(=S)Nc1ccc(-n2cncn2)cc1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: c1ccc(C2CCCc3sc(Nc4ccc(-n5cncn5)cc4)nc32)cc1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A suspension of 4-(1,2,4-triazol-1-yl)phenylthiourea (109.6 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253.1 mg, 1.00 mmol) in ethanol (4 mL) was heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was treated with dichloromethane, diethyl ether and heptane. The product precipitated as a solid and was filtered off to yield the title compound (120 mg, 64%) as a pale-brown solid. MS ISP (m/e): 374.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.4 (s, 1H), 9.38 (s, 1H), 8.29 (s, 1H), 8.02 (d, 2H), 7.56 (d, 2H), 7.30 (t, 2H), 7.10-7.19 (m, 5H), 4.00 (m, 1H), 2.72 (m, 2H), 2.14 (m, 1.70-1.89 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]23[CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]34[CH2:19][N:16]([CH2:15][CH2:14]3)[CH2:17][CH2:18]4)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Clc1ccc(C23CCN(CC2)C3)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1cc(N2CCCC2)ncc1C12CCN(CC1)C2
Temperature: 130 °C
Yield: 41.1 %

Procedure:
0.852 g (11.98 mmol) of pyrrolidine is added to a sealed tube comprising 0.060 g (0.29 mmol) of 4-(6-chloropyridin-3-yl)-1-azabicyclo[2.2.1]heptane obtained in stage 5.1 of Example 5. The mixture is heated at 130° C. for 3 hours, cooled to ambient temperature and diluted with 40 ml of toluene and the combined mixture is concentrated under reduced pressure. The residue thus obtained is diluted with 50 ml of dichloromethane and poured into 300 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted twice with 100 ml of dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 85/15/1.5. 0.029 g of the expected product is obtained in the form of a brown powder.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].Cl[C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:24][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:22]=[C:21]([CH:20]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:9]=1)[O:23][C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1)[CH3:6]
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazol-3-yl)benzamide (0.1 g, 0.29 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (66 mg, 0.35 mmol) and potassium carbonate (81 mg, 0.59 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The resulting mixture was reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The residue was chromatographed on silica, eluting with 10-100% ethyl acetate in isohexane to give the desired compound (52 mg).
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3](B(O)O)[CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:16]=3[C:4]=2[CH:3]=[CH:2][CH:1]=5)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Reactant: Brc1ccc(I)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: Brc1ccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
In the atmosphere of argon, 9.1 g of fluoranthene-3-boronic acid, 10.5 g of 4-bromoiodobenzene, 2.1 g of tetrakis(triphenylphosphine)palladium(0), 186 mL of toluene and 74 mL of an aqueous 2M solution of sodium carbonate were placed in a flask, and stirred at 100° C. for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. After removing an aqueous phase, an organic phase was washed with saturated saline, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and residues were purified by silica gel column chromatography, whereby 9.2 g (yield 70%) of 3-(4-bromophenyl)fluoranthene as an intended product was obtained.