Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:19])/[CH:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OC)c(OC(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-isopropoxy-4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (6.96 g. 20 mmol) in toluene (100 ml) is heated at reflux for 2 hours, cooled to ambient temperature and evaporated. The crude product is taken in to dichloromethane and eluted through a pad of silica to afford (E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLC Rf 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added and the reaction heated at 70° C. for 36 hours. The solvent is evaporated, the residue is taken into ethyl acetate and washed with 2N aqueous HCl, water and brine. After drying over sodium sulfate and evaporation, the crude product is purified by flash column chromatography (4:1 hexane-ethyl acetate elution) to afford 3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 6 2H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). This intermediate is converted into [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin-4-yl]-acetic acid using the general procedure for Intermediate 20. Characterised as the ethyl ester, [MH]+ 496.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C@H:10]([OH:12])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:11][C@H:10]([O:12][C:32](=[O:34])[CH3:33])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of (1S,2S,4S,5R,6R)-2-(tert-butoxycarbonyl)amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.50 g, 4.20 mmol, U.S. Pat. No. 5,958,960), pyridine (0.365 mL, 4.62 mmol) and DMAP (0.513 g, 4.20 mmol) in dichloromethane (40 mL) under nitrogen add acetic anhydride (0.514 mL, 5.0 mmol). Stir at room temperature for 16 hours, dilute with dichloromethane, and pour into 10% aqueous citric acid solution (50 mL). Wash the organic layer with water (50 mL) and brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo, to produce the title compound as a white solid (1.295 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:46][C:47]1[CH:51]=[C:50]([NH2:52])[NH:49][N:48]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:52][C:50]4[NH:49][N:48]=[C:47]([CH3:46])[CH:51]=4)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3cc(C)n[nH]3)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 101 mg, 0.283 mmol) in THF (5 mL) was added triethylamine (34.3 mg, 0.339 mmol), followed by the addition of 2,4,6-trichlorobenzoyl chloride (75.8 mg, 0.311 mmol). The suspension was stirred for 2 hours and then 3-methyl-1H-pyrazol-5-amine (35.7 mg, 0.367 mmol) was introduced. The reaction was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (10 mL). After phase-separation, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified via silica chromatography (EtOAc/MeOH 20:1) to yield the title product (23 mg, 19%). LCMS (apci) m/z=437.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 81.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (202 mg) was obtained.
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.CCOCC>S1(CCCC1)(=O)=O.C1OCCOCCOCCOCCOCCOC1>[Cl:13][C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:1])=[N:7][CH:8]=1
Reactant: Fc1cc(Cl)cnc1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: Fc1cc(Cl)cnc1F
Temperature: 140 °C
Reaction time: 35 h
Yield: 88 %

Procedure:
64.6 g (1.11 mol) of potassium fluoride and 11.25 g (0.074 mol) of caesium fluoride are suspended in 240 ml of sulfolane and the suspension is heated to 140° C. 50 mol of sulfolane are distilled off by decreasing the pressure and then 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine and 1.45 g (0.0055 mol) of 18-crown-6 in 20 ml of sulfolane are added to the suspension. This reaction mixture is stirred for 35 hours at 140° C. and then taken up in ice water. The product is isolated from the aqueous mixture either by extraction with ether or by steam distillation, affording 48.7 g (88% of theory) of 5-chloro-2,3-difluoropyridine, b.p. 65°-66° C. at 133 mbar.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1>CS(C)=O.O.[Cl-].[Na+].O>[CH:7]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1)=[O:5]
Reactant: N#Cc1cc2cc(CBr)ccc2o1
Reactant: C[N+](C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc2cc(C=O)ccc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
Trimethlamine-N-oxide (6.75 g, 90 mmol) was added to a solution of 5-(bromomethyl)benzofuran-2-carbonitrile (4.46 g, 18.89 mmol) in 57 mL of DMSO and 6 mL of H2O. The mixture was stirred at 70° C. for 3 hr. After the reaction was cooled to room temperature, the mixture was diluted with 72 mL of brine, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×20 mL), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-30% Ethyl Acetate/70% Heptane, to give 5-formylbenzofuran-2-carbonitrile (1.5 g). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.7, 1.7 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 8.46 (dd, J=1.6, 0.6 Hz, 1H), 10.11 (s, 1H).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C.O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[N:13]([CH3:35])[C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(S(=O)(=O)c4ccccc4)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(C(=O)c1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
A 0° mixture of 3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodium hydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture is treated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warm to 20–25° under nitrogen over 16 hr. The resultant mixture is diluted with H2O and filtered. The residual solid is triturated with refluxing methanol, isolated, and dried in the vacuum oven at 50° to give the desired indole, mp=254–255°.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH2:8]O)[N:7]=1)[CH3:2].S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][CH2:8][C:6]1[N:7]=[C:3]([CH2:1][CH3:2])[S:4][C:5]=1[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCc1nc(CO)c(C)s1
Solvent: Cc1ccccc1
Product: CCc1nc(CCl)c(C)s1
Yield: 84.7 %

Procedure:
To a solution of (2-ethyl-5-methyl-1,3-thiazol-4-yl)methanol (3.7 g) in toluene (200 mL) was added thionyl chloride (8.5 g) at room temperature, and the mixture was heated under reflux for 30 min. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (10:90-25:75, v/v) to give 4-chloromethyl-2-ethyl-5-methyl-1,3-thiazole as a yellow oil (3.5 g, yield 84%). NMR (CDCl3) δ: 1.35 (3H, t, J=7.6 Hz), 2.44 (3H, s), 2.95 (2H, q, J=7.6 Hz), 4.63 (2H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][Mg]Cl.O>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:12])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)cc1
Temperature: 12.5 °C
Yield: 93.9 %

Procedure:
This was synthesized using a synthesis based on that described by Archer et al., J. Org. Chem., Vol. 42, No. 13, 1977, page 2282, column 2 (see synthesis of (22)). A solution of 4-methoxy acetophenone (151.18 g, 1 mol) in 300 ml of anhydrous THF was added for 1 h to the solution of 1N methyl magnesium chloride (1360 ml, 1.36 mol) in THF while maintaining the internal temperature at 10-15° C. After completion of the addition, the reaction mixture was heated for about 4.5 hrs. After completion of the reaction (as determined by TLC), 0.2 L of water was slowly added during 3 hrs to quench the reaction while maintaining the internal temperature at <15° C. The reaction mixture was decanted from the precipitate and evaporated under vacuum. The remaining white residue was washed with methyl t-butyl ether (MTBE) (2×200 mL) and evaporated. The combined residue was dissolved in 400 mL of MTBE and 200 mL of water was added. The organic layer was extracted and the aqueous layer was washed with MTBE (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to afford 156 g of 2-(4-Methoxy-phenyl)-propan-2-ol as yellow oil (94% yield, 96% purity by HPLC).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Yield: 431.2 %

Procedure:
A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550 mg, 0.230 mmol), K2CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg): 1H NMR (CDCl3) δ 8.15 (s, 1H), 7.47-7.44 (m, 2H), 7.22 (t, 1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 5.53 (b, 1H), 3.23 (b, 6H), 2.80-1.60 (m, 9H), 2.20 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:10]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:10]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Temperature: 25 °C

Procedure:
To (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester (0.742 g, 1.6 mmol) in CH2Cl2 (3 mL) was added 4N HCl in 1,4-dioxane (4 mL), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was then concentrated to give [5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[O:13][C:11](=O)[C:10]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]23)=[CH:4][CH:3]=1.CSC1[NH:23][CH2:24][CH2:25][N:26]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:13])[N:23]3[CH2:24][CH2:25][N:26]=[C:14]23)=[CH:6][CH:7]=1
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(-c2ccc(F)cc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(c2ccc(F)cc2)C2=NCCN12
Reaction time: 4 h

Procedure:
A solution of 5.4 g. of N-(p-fluoro-phenyl)isatoic anhydride, 2.5 g. of 2-methylmercapto-imidazoline and one pellet (about 100 mg.) sodium hydroxide in 75 ml. of dioxane is refluxed with stirring for 4 hours. The resulting mixture is evaporated to dryness, the residue dissolved in methylene chloride, washed with water and extracted twice with 1N hydrochloric acid. The combined aqueous extracts are washed with methylene chloride and then with diethyl ether and made basic with sodium bicarbonate. The resulting precipitate is filtered off, washed thoroughly with water, dried by suction, dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and the methylene chloride exchanged for methanol to crystallize 10-(p-fluoro-phenyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 278°-280°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=3)[CH:22]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.52 g), which was subsequently deprotected.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C@H:21]2[C@H:26]([O:27]CC3C=CC=CC=3)[C@@H:25]([O:35]CC3C=CC=CC=3)[C@H:24]([O:43]CC3C=CC=CC=3)[C:23]([CH2:51][O:52]CC3C=CC=CC=3)=[CH:22]2)=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:52][CH2:51][C:23]1[C@@H:24]([OH:43])[C@H:25]([OH:35])[C@@H:26]([OH:27])[C@H:21]([O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)[CH:22]=1
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cc2ccccc2O[C@@H]2C=C(CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
In a nitrogen stream, a boron trichloride 1.0 M methylene chloride solution (6.0 mL, 6.0 mmol) was added to a solution of 1-(4-methoxyphenyl)methyl-2-[(1R,4R,5S,6S)-4,5,6-trisbenzyloxy-3-(benzyloxymethyl)cyclohex-2-enyloxy]benzene (312 mg, 0.426 mmol) in methylene chloride (12 mL) at −78° C., and the mixture was stirred at the temperature for 1.5 hours. After addition of methanol, the temperature of the resulting solution was raised to room temperature and the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:8)] to obtain the title compound (37.9 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[C:6]2[CH2:7][CH2:8][O:9][C:5]2=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:12][C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([NH2:11])=[C:6]2[C:5]=1[O:9][CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(Cl)ccc2c1CCO2
Solvent: c1ccccc1
Product: Nc1c(Cl)cc(Br)c2c1CCO2
Yield: 87.9 %

Procedure:
A solution of 9.1 parts of 5-chloro-2,3-dihydro-4-benzofuranamine [described in J. Het. Chem., 17(6) 1333 (1980)], 9.6 parts of N-bromosuccinimide and 130.5 parts of benzene was stirred for 1 hour at reflux temperature. The solvent was evaporated and the residue was dissolved in 387.4 parts of trichloromethane. The solution was washed with water (2×200 parts). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; C6H14 /CH2Cl2 50:50). The eluent of the desired fraction was evaporated, yielding 11.8 parts (87.9%) of 7-bromo-5-chloro-2,3-dihydro-4-benzofuranamine (interm. 8).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH:16][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Temperature: 70 °C
Yield: 13.7 %

Procedure:
To a solution of 0.05 g (0.19 mMol) 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine in 2 ml THF were added 0.1 ml ethyl diisopropyl amine and 0.027 ml (0.23 mMol) 4-fluoro-benzoyl chloride. The reaction mixture was heated to 70° C. for 2 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:9, 1:4) to yield 0.01 g (14%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide as a light yellow solid; F.p.: 192-195° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 2-aminoethanol (2.3 mL, 39 mmol), and triethylamine (16 mL, 120 mmol) in anhydrous THF (100 mL) was added 4-bromobenzene-1-sulfonyl chloride (10 g, 39 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (5.5 g, 50%): 1H NMR (500 MHz, CDCl3) δ 7.74 (td, J=9.0, 2.1 Hz, 2H), 7.67 (td, J=9.0, 2.1 Hz, 2H), 5.08 (s, 1H), 3.72 (t, J=5.1 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 1.83 (s, 1H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of sodium hydride (0.84 g: 55% dispersion in mineral oil) and tetrahydrofuran (40 ml) was dropwise added a solution of ethyl diethylphosphonoacetate (4.33 g) in tetrahydrofuran (20 ml) with ice-cooling of 6° to 12° C. over a 12 minutes period. After stirring at room temperature for 30 minutes, to the mixture thus obtained was dropwise added a solution of 3,5-dichlorobenzaldehyde (3.07 g) in tetrahydrofuran (20 ml) with ice-cooling of 8° to 11° C. over a 10 minutes period. After stirring at room temperature for 4 hours, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried and concentrated. The residue was purified by flash column chromatography through silica gel (100 g). Fractions eluted with a 99:1 mixture of hexane and ethyl acetate were collected and worked up to afford the title compound (3.33 g), melting at 71°-73° C.