Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:26]([OH:36])=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:24][C:25]1[C:26]([OH:36])=[C:27]([S:32]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:34])=[O:33])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 1-(4′-chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (70 mg, 0.22 mmol) in THF (4 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (61.8 mg, 0.24 mmol) and TEA (0.08 mL, 0.54 mmol). The resulting mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in MeOH and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the title compound (46 mg, 39%) as a glassy solid. 1H NMR (CD3OD) 7.59 (d, J=4.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.36-7.35 (m, 5H), 7.22 (t, J=8.0 Hz, 1H), 7.16-7.09 (m, 5H), 7.05-7.03 (t, J=8.0 Hz, 1H), 6.90-6.85 (m, 2H), 4.46 (s, 2H), 4.41 (s, 2H). MS (ESI): 550.0 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CCCCCO
Solvent: ClCCl
Product: CCOC(=O)CCCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To the suspension of poly(4-methylpyridine) (2.24 g, 2 eq) in newly dried dichloromethane (25 mL ) at 0° C. was added trifluoromethanesulfonic anhydride (5 g, 1 eq) drop wise over 30 mins. Ethyl 6-hydroxyhexanoate (2.76 g, 0.95 eq) was then added in drop wise via a syringe. The mixture was stirred at 0° C. for 4 hrs and the polymer was filtered off by a frit. The solvent was evaporated under reduced pressure (without heating) and the crude product was subjected to a short silica gel pad with 1:4 (v/v) diethyl ether/hexane as the eluent solvent. The solvent was evaporated (without heating) and the product was used directly in the following step. (3.9 g, 75% yield based on ethyl 6-hydroxyhexanoate.) See FIG. 10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][C@H:32]([CH3:34])[C@@H:31]([OH:35])[C@H:30]([NH:36]C(=O)OC(C)(C)C)[CH2:29]3)=[C:20]3[CH2:26][CH2:25][CH:24]([OH:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:44].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:36][C@H:30]1[C@H:31]([OH:35])[C@@H:32]([CH3:34])[CH2:33][N:28]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:44])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH:24]([OH:27])[CH2:25][CH2:26][C:20]=23)[CH2:29]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6 mg, 0.01 mmol) and TFA in DCM (4.0 M; 2.0 mL, 8.0 mmol) was stirred at room temperature for 1 h. After removal of the solvent, the residue was then diluted with MeOH (4 mL) and NH4OH solution (0.5 mL) and filtered. The filtrate was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give two diastereoisomers of the title compound as a white powders.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:20])[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.I[CH3:22]>C1COCC1>[CH3:22][O:20][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Sodium hydride (1.27 g, 31.7 mmole) was added to a solution of 8-(4-fluoro-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.0 g, 10 mmole) in THF (100 ml) and the mixture stirred for 16 hr and heated at reflux for 4 hr. The solution was cooled to 25° C. and iodomethane (6.75 g, 47.6 mmole) was added. The mixture was stirred for 112 hr and concentrated in vacuo. The residue was suspended in water and the mixture extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol methyl ether (98.8%, mp: 52°-54° C.).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([OH:11])[CH3:10]>>[C:1]1([C:10]2[C:9]([OH:11])=[N:7][C:2]3[C:1]([N:8]=2)=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: CCO
Product: Oc1nc2ccccc2nc1-c1ccccc1
Yield: 95 %

Procedure:
Phenylglioxalic acid (26.6 mmol) was mixed with o-phenylenediamine (40 mmol) and stirred in 40 ml of ethanol for 30 min. The reaction mixture was filtered to give, after evaporation of solvent, the crude product. Recrystallization from ethanol gave pure yellow crystalls in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide (0.050 g, 0.152 mmol), morpholine (0.027 mL, 0.305 mmol) and sodium triacetoxyborohydride (0.014 g, 0.228 mmol) in 1,2-dichloroethane (6 mL) was added acetic acid (0.013 mL, 0.228 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo to give a residue that was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(3-(morpholinomethyl)phenyl)oxazole-4-carboxamide (0.022 g, 0.056 mmol, 37%) as a white solid. 1H NMR (DMSO) δ 2.39 (4H, br m), 3.54 (2H, br m), 3.59 (4H, t), 7.38-7.45 (3H, m), 7.50 (1H, t), 7.71-7.78 (3H, m), 8.13-8.17 (2H, m). LCMS (2) Rt: 2.62 min; m/z (ES+) 400.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=2[F:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)cc(F)c1F)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1F)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-3-o-tolyl-1-(2,3,5-trifluoro-phenyl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI−): m/z=446.0 ([M−H]−, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21](Cl)(=[O:23])=[O:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:21]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N3CCOCC3)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (1 g) in DCM is added to a solution of morpholine (2.26 mL) in water (50 mL) and stirred at rt for 5 h. The organic phase is separated and washed water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole (1.3 g, 100%). MS: 439 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (75 g.) is heated with hexadecyl bromide (200 g.) in dry hexamethylphosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (20 ml.). The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the product of the Example.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH:11]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:4]([CH3:26])[CH:3]=1.[CH3:27][N:28](C)C=O>Cl.O>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[O:18][C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:26])[CH:3]=1)#[N:28]
Reactant: Cc1cc(Br)ccc1C(=O)CCC1c2ccccc2Oc2ccccc21
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: Cc1cc(C#N)ccc1C(=O)CCC1c2ccccc2Oc2ccccc21
Reaction time: 24 h

Procedure:
A solution of cuprous cyanide (2.7 g, 30.5 mmol) and 1-(4-bromo-2-methylphenyl)-2-(9H-xanthen-9-ylmethyl)ethanone (10 g, 25.4 mmol) in dry dimethylformamide (80 ml) was heated to reflux under an atmosphere of nitrogen. After 24 h, further cuprous cyanide (2 g, 22.3 mmol) was added and reflux continued for another 20 h. The reaction mixture was cooled and a solution of ferric chloride (8.6 g, 52.9 mmol) in aqueous hydrochloric acid (2M, 200 ml) added. The resulting solution was diluted with water (400 ml) and extracted twice with diethyl ether, the combined extracts were washed with water (5×) and a saturated solution of sodium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to a yellow oil. Purified on flash silica eluting with hexane-dichloromethane (4:1 then 3:2 then 1:1) to give 1-(4-cyano-2-methylphenyl)-2-(9H-xanthen-9-ylmethyl)ethanone as a yellow oil. Sample crystallised from hexane m.p. 138°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:25]=[NH:26])[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15](C1C=CC=CC=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:25][NH:26][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c([nH]c3cccc(-c4ccccc4)c32)c(C=N)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]c3ccccc32)c(CNc2ccccc2)n1
Reaction time: 0.67 h
Yield: 119.3 %

Procedure:
5-phenyl-iminomethyl-beta-carboline-3-carboxylic acid ethyl ester (0.25 g) is hydrogenated in 100 ml of ethanol with addition of Raney nickel at normal pressure and a temperature of 25° C. Taking up of 1 mol of hydrogen takes about 40 minutes. The residue remaining after filtering of the catalyst and evaporation of the filtrate is chromatographed on silica gel with a mixture of 10 parts of dichloromethane and one part of ethanol. Thus, 0.15 g of phenylaminomethyl-beta-carboline-3-carboxylic acid ethyl ester is obtained.
Reaction SMILES: OC[CH2:3][C:4]1[C:5]([NH:18]C(=O)C(C)(C)C)=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Br>O>[C:12]1([C:6]2[C:5]([NH2:18])=[C:4]3[CH2:3][CH2:11][O:10][C:9]3=[CH:8][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1CCO
Agent: Br
Solvent: O
Product: Nc1c(-c2ccccc2)ccc2c1CCO2
Temperature: 95 °C
Reaction time: 12 h
Yield: 28.9 %

Procedure:
A pressure bottle was charged with N-[3-(2-hydroxyethyl)-4-methoxy-[1,1'-biphenyl]-2-yl]-2,2-dimethylpropanamide (10.77 g, 32.9 mmol), 48% HBr solution (200 mL), flushed with nitrogen, capped, and stirred at 95° C. for 12 h. The suspension was cooled to room temperature and poured over 200 g of ice/water. The aqueous phase was washed with Et2O (2×100 mL) and concentrated in vacuo to give a tan solid. The solid was redigested with H2O (200 mL), concentrated in vacuo, and dried (0.5 mm, 18 h). The resultant solid was digested with 1 N NaOH (300 mL), the resultant suspension extracted with CH2Cl2 (3×300 mL), and the combined extracts dried (K2CO3), filtered, and concentrated in vacuo to give the free amine (2.01 g, 21%) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.05 (t, J=8.5 Hz, 2H), 4.64 (t, J=8.5 Hz, 2H), 6.34 (d, J=8 Hz, 1H), 6,91 (d, J=8 Hz, 1H), 7.29-7.45 (m, 7H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B4OCC(C)(C)CO4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)S(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Br:43])[CH:39]=2)[CH:34]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>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.O>[C:1]12([C:11]3[CH:12]=[C:13]([C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[CH:39]=[C:38]([Br:43])[CH:37]=[CH:36]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Reactant: COc1ccc(B2OCC(C)(C)CO2)cc1C12CC3CC(CC(C3)C1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 23.5 %

Procedure:
[3-(1-adamantyl)-4-methoxyphenyl]-5,5-dimethyl-1,3,2-dioxaborinane (100 mg, 0.28 mmol), 6-bromo-2-naphthalenyl trifluoromethanesulphonate (67 mg, 0.19 mmol), K3PO4 (160 mg, 0.75 mmol), THF (2 ml) and H2O (0.4 ml) were introduced in a Schlenk tube. The reaction mixture was deoxygenated (3 froze/thaw cycles). Next, Pd(PPh3)4 (11 mg, 0.009 mmol) was added and the mixture was again deoxygenated (2 froze/thaw cycles). After heating at reflux for 17 h, the mixture was diluted in toluene (5 ml) while it was still hot. The solution was filtered through celite and it was washed with hot toluene (2×5 ml). The joined organic phases were washed with hot H2O (2×5 ml). The organic phase was evaporated and a crude (59 mg) was obtained, which was recrystallized with the minimum volume of toluene at reflux (0.55 ml), giving the title compound (20 mg, 24%) as a pale yellow powder. The spectroscopic data coincide with those of the Example 4.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:40])[C:13]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])([CH3:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]2[CH2:28][NH:27][C:26](=[O:29])[N:25]2[CH3:30])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:9]([O:11][C:12](=[O:40])[C:13]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])([CH3:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]2[CH2:28][N:27]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:26](=[O:29])[N:25]2[CH3:30])=[CH:17][CH:16]=1)[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide (0.02 mL, 0.172 mmol, d=1.438) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.051 g, 0.115 mmol) and sodium hydride (0.011 g, 0.287 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed with 1N HCl, water, and brine. The organic layer is dried and concentrated in vacuo to provide the title compound, which is used in the next step. MS [EI+] 535 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=1)[C:7]2=[O:18])(=[O:3])[CH3:2]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A suspension of 0.250 g of 6-acetyl-2-butyl-4(1H)-quinazolinone, 0.685 g of 5-[4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl) -1H-tetrazole and 0.424 g of anhydrous potassium carbonate in 25.0 ml of dry acetone is heated at reflux for 16 hours. The reaction mixture is alowed to cool to room temperature, filtered and the filtrate evaporated in vacuo to a residue. The residue is purified by column chromatography on silica gel using 1:3 ethyl acetate-hexanes to give 0.43 g of the desired product as a solid, m.p. 104°-105° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([NH:23][C:24]5[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=5)[CH:19]=[C:20]([CH3:22])[CH:21]=4)[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.CCOC(C)=O>[CH3:22][C:20]1[CH:21]=[C:16]([C:14]2[CH:13]=[N:12][N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[CH:15]=2)[CH:17]=[C:18]([NH:23][C:24]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=2)[CH:19]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC(=O)CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-{3-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (62.4 mg, 0.14 mmol) was dissolved in THF (1 mL) and hydrochloric acid (0.45 mL, 2.72 mmol) was added. The reaction mixture was stirred at room temperature for two hours. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-80% EtOAc/hexanes) to afford 4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanone as a colorless foam. MS ESI calcd. for C21H21F3N5O [M+H]+ 416. found 416. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.08 (s, 1H), 4.77-4.68 (m, 1H), 2.61-2.48 (m, 4H), 2.35-2.17 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[C:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1C#CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
The product from step (iii) (3.7 g) was dissolved in EtOH (100 mL) then 5% Pd/C (300 mg) was added. The reaction mixture was hydrogenated at 3 bar for 16 h. The catalyst was removed by filtration and the solvent evaporated to give the subtitle compound 3.8 g.
Reaction SMILES: [Na].O.O.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=O)=[O:12])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:18])(=[O:14])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: -30 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 7 g (30 mmol) of the sodium salt of 4-hydroxybenzenesulfonic acid dihydrate in 40 ml of dimethylformamide is added dropwise to a solution of 15.5 ml (181 mmol) of oxalyl chloride in 120 ml of dichloromethane cooled to −30° C. The reaction medium is slowly brought back to ambient temperature and then stirred at ambient temperature for 18 h. After the addition of 200 ml of ice, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. 6.2 g (100%) of 4-hydroxybenzenesulfonyl chloride are obtained in the form of a colorless oil.