Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl.CCO>[F:15][C@H:3]1[CH:2]([NH:1][CH2:34][C:31]2[CH:32]=[CH:33][C:27]3[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=3[CH:30]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Product: O=C1CSc2ccc(CNC3CCNC[C@H]3F)cc2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (5a) (340 mg, 1.60 mmole) in ClCH2CH2Cl (8 mL) and EtOH (0.8 mL) was treated with anhydrous Na2SO4 (450 mg) and 3-oxo-3,4-dihydro-2-benzo[1,4]thiazine-6-carboxaldehyde (1n) (330 mg, 1.80 mmole). The resulting solution was stirred at room temperature for 6 hr, then sodium triacetoxy borohydride (500 mg, 2.40 mmole) was added. The resulting slurry was stirred at room temperature for a further 10 hr, then was quenched by the addition of water (2 mL) and the volatiles were removed in vacuo. The residue was partitioned between EtOAc (2×50 mL) and brine (20 mL). The organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate), the eluant was concentrated in vacuo and the residue was disolved in 10 mL of CH2Cl2 and treated with 1.25 mL of 4N HCl in dioxane for 2 h. The volitiles were removed in vacuo and the residue was dissolved in 10 mL of CH3OH. MP-carbonate resin (1.08 g) was added and stirred at rt for 1 h. The reaction was filtered to remove the resin and concentration under reduced pressure gave the desired compound as a white solid:
Reaction SMILES: I[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl[C:13]([F:19])([F:18])C(OC)=O.[F-:20].[K+].C(OCC)C>CN(C=O)C.[Cu](Cl)Cl>[F:18][C:13]([F:19])([F:20])[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1I
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Agent: Cl[Cu]Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1nccnc1C(F)(F)F
Temperature: 120 °C
Yield: 40.9 %

Procedure:
To methyl 3-iodopyrazine-2-carboxylate (7) (10 g, 37.88 mmol) in DMF (Volume: 300 mL) was added methyl chlorodifluoroacetate (27 g, 0.189 mol), potassium fluoride (13.2 g, 0.227 mol), and copper chloride (22.47 g., 0.227 mol). The reaction was heated at 120° C. for 12 h. The reaction mixture was poured into ethyl ether (1000 ml) and washed with brine (3×300 ml), dried over MgSO4 before the solvent was removed. The residue was loaded onto a silica column and was eluted using ethyl acetate/hexanes gradient to afford the title compound (3.19 g, 41%) as an amber oil: 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=5.4 Hz, 1H), 8.82 (d, J=5.4 Hz, 1H), 4.05 (s, 3H); EIMS m/z 206.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.O.[Pt](=O)=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccnc2)nn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: COc1ccc(C(O)C2CCCNC2)nn1
Yield: 92.5 %

Procedure:
(6-Methoxypyridazin-3-yl)pyrdin-3-ylmethanone (1.31 g, 6.1 mmol) were dissolved in ethanol (100 ml), platinum(IV) oxide hydrate (80% of Pt, 0.5 g, 2.2 mmol) was added, and the mixture was stirred with supply of hydrogen. Conventional work-up gave 1.26 g (93% yield) of (6-methoxypyridazin-3-yl)piperidin-3-ylmethanol as crude product, which was employed directly in the next step;
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=[O:10])=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:13][CH:14]1[CH2:15][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:9][O:10]1)[CH3:12]
Reactant: C=COCC
Reactant: O=C/C=C/c1ccccc1
Agent: Oc1ccc(O)cc1
Product: CCOC1CC(c2ccccc2)C=CO1
Yield: 87.2 %

Procedure:
313 g (2.37 Mole) of cinnamic aldehyde, 290 g (4.03 Mole) of ethyl vinyl ether and 45 g of hydroquinone were heated at 200° for 16 hours in a 1 l stainless steel autoclave (pressure about 20 atm.). After fractional distillation of the crude material thus obtained, there were isolated 422 g (87% yield) of 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyran, b.p. 89°/0.02 Torr;
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[C:7]([CH3:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=O>CO>[NH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([CH:12]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([NH2:9])=[C:7]([CH3:10])[CH:6]=2)[C:11]([OH:15])=[O:14])=[CH:6][C:7]=1[CH3:10]
Reactant: CCc1cccc(C)c1N
Reactant: O=CC(=O)O
Solvent: CO
Product: CCc1cc(C(C(=O)O)c2cc(C)c(N)c(CC)c2)cc(C)c1N
Temperature: 25 °C

Procedure:
A mixture of 6-ethyl-2-methylaniline (30.0 parts) and methanol (100 parts) was stirred at ambient temperature. Glyoxylic acid 50% w/v (16.5 parts) was added and the mixture was stirred for 24 hours at ambient temperature. The precipitated product was isolated by filtration, washed with methanol (20 parts) and dried to yield di(4-amino-5-ethyl-3-methylphenyl)acetic acid (31.0 parts).
Reaction SMILES: [C:1]([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12.CI>C1COCC1>[CH2:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12)[CH3:1]
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCCc1nc2nccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (0.978 mL, 1.7M/pentane) was added to a cooled (-78° C.) THF (5 mL) solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (97 mg, 0.554 mmol). After 2 hour the reaction was warmed to 0° C. for 1 minute then cooled back to -78° C. MeI (0.172 mL) was added, the mixture was stirred at -78° C. for 1 hour then warmed to 0° C. for 1 minute and then quenched (NH4OH). Extractive workup and purification (SiO2, 2% MeOH/EtOAc) gave 85 mg of 7-ethyl-2-propylimidazo[4,5-b]pyridine which was converted to the title compound as outlined in Example 7, Part B. 1H NMR (250 MHz, CD3OD) δ 8.28 (d, 1H, J=6 Hz), 7.72-7.65 (m, 2H), 7.62-7.54 (m, 2H), 7.22 (d, 1H, J=6 Hz), 7.17-7.08 (AB q, 4H), 5.61 (s, 2H), 3.12 (q, 2H, J=9 Hz), 2.89 (t, 2H, J=9 Hz), 1.80-1.63 (m, 2H), 1.41 (t, 3H, J=9 Hz), 0.99 (t, 3H, J=9 Hz).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4].Cl.[CH3:34][NH:35][O:36][CH3:37].C([Mg]Cl)(C)C>>[CH3:37][O:36][N:35]([CH3:34])[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COCOc1cc(C2CCCC2C(=O)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Product: COCOc1cc(C2CCCC2C(=O)N(C)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Yield: 96.9 %

Procedure:
Use conditions analogous to those described in Step D of Examples 1A and 1B to react (±)-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2,5-bis-methoxymethoxy-phenyl]-cyclopentanecarboxylic acid methyl ester (0.605 g, 1.29 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.189 g, 1.94 mmol) in the presence of isopropylmagnesium chloride (2.13 mL, 4.26 mmol) to afford the subtitled product (0.622 g, 97%) as an oil that may be used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[C:27](=[O:30])([O-:29])[O-].[Na+].[Na+].[C:33]1([CH:39](Br)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(C(C)=O)C(C)C>[C:20]([OH:22])(=[O:21])/[CH:19]=[CH:16]/[C:27]([OH:29])=[O:30].[C:33]1([CH:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([CH3:25])([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=3)=[O:12])[CH2:4][CH2:3]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(O)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Product: O=C(O)/C=C/C(=O)O
Yield: 34.8 %

Procedure:
To a mixture of ethyl 4-[4-(4-hydroxypiperid-1-yl)butyroyl]α,α-dimethylphenylacetate (18 g; 0.05 moles) and sodium carbonate (10.6 g; 0.1 mol) in methyl isobutyl ketone (100 ml), a solution of diphenylmethyl bromide (12 g; 0.05 moles) in methyl isobutyl ketone (50 ml) was slowly added and the resulting mixture boiled under reflux for 12 hours. Then another solution of diphenylmethyl bromide (6 g; 0.025 moles) in methyl isobutyl ketone (15 ml) was added and the mixture boiled under reflux again for 24 hours. The reaction mixture was cooled, washed with water, the solvent removed in vacuo and the residue treated with the stoichiometric amount of fumaric acid in ethanol. The obtained solid was recrystallized from methyl ethyl ketone and from ethanol to give ethyl 4-[4-(4-diphenylmethoxypiperid-1-yl)butyroyl]α,α-dimethylphenylacetate fumarate (5.6 g; yield 17.4%) which melts at 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[CH:27]=[C:26]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[CH:24][N:23]=2)=[C:19]([F:39])[CH:18]=1.CCCCCC>C(#N)C.C(OCC)C>[F:39][C:19]1[CH:18]=[C:17]([NH:16][C:13]([NH:14][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:12])[CH:38]=[CH:37][C:20]=1[O:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:28][C:29]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)=[O:30])[CH:27]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCOCC3)ncn2)c(F)c1
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCOCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
2-(4-Fluorophenyl)acetyl chloride (103 mg) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (116 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-amino-2-fluorophenoxy)-6-[(morpholin-4-yl)carbonylamino]pyrimidine (79.5 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 10 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (5 ml)-hexane (5 ml). The solid was filtered off and dried under aeration to provide the titled compound (71.9 mg, 56.9%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[H][H].[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:22]=[C:23](Br)[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:26]=[C:25]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1C(=O)N(c2cccc(C3OCCO3)c2)c2ccccc21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of isatin (5.0 g, 34.0 mmol) in anhydrous N. N-dimethyl formamide (150 ml) was treated with sodium hydride (60% dispersion, 1.632 g, 40.8 mmol) with stirring at room temperature for 20 minutes until the formation of hydrogen gas ceased. To the mixture was added cupric iodide (12.9 g, 68.0 g) followed by 3-(1,3-dioxolan-2-yl)bromobenzene (15.57 g, 68.0 mmol). After 8 hours of stirring at 150° C. under nitrogen, the brown mixture was cooled to room temperature, and then treated with chloroform (750 ml). The resulting mixture was filtered to remove the precipitate. The filtrate was evaporated under reduced pressure to dryness to afford a brown solid.
Reaction SMILES: CO[C:3]1[C:4](OC)=[CH:5][C:6]2S[C:9]([C:11]3[CH:19]=CC(C(O)=O)=CC=3)=[N:8][C:7]=2[CH:20]=1.ClC(OCC(C)C)=O.C([N:33](C(C)C)C(C)C)C.[NH2:40][CH2:41][CH2:42][CH2:43]CCCO>CN(C)C=O>[NH2:33][C:4]1[CH:3]=[C:20]2[C:7]([N:8]=[CH:9][CH:11]=[CH:19]2)=[C:6]2[C:5]=1[CH:43]=[CH:42][CH:41]=[N:40]2
Reactant: COc1cc2nc(-c3ccc(C(=O)O)cc3)sc2cc1OC
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCCCCO
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: Nc1cc2cccnc2c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml of dimethylformamide was dissolved 0.26 g (0.8 mmol) of Compound (1), which is 4-(5,6-dimethoxybenzothiazolyl)benzoic acid. Further, 0.12 ml (0.9 mmol) of isobutyl chloroformate and 0.16 ml (0.9 mmol) of ethyl diisopropylamine were added thereto, followed by stirring at room temperature for 1 hour. Then, 0.10 g (0.9 mmol) of 6-aminohexanol was added thereto, followed by stirring for 1 hour and a half. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.15 g of Compound (2).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][SH:3].Cl.[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:3][CH2:2][CH2:1][NH2:4])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 103.1 %

Procedure:
Dissolve 2-thioethylamine hydrochloride (5 g, 44.2 mmol), triphenylmethanol (11 g, 42.5 mmol) and triethylamine (7 mL, 49.9 mmol) in 100 mL chloroform. Heat and reflux until the solution temperature reaches a certain temperature, slowly drop a catalyst borontrifluoride ethyl ether complex (15 mL, 119.5 mmol) into the solution and continue heating and reflux for 4 hours. Then cool down, add sodium bicarbonate aqueous solution into the solution and stir the mixture. White solid product is precipitated out immediately. Get the solid by suction filtration, wash the solid with water, and dry the solid. Thus solid product 2-[(triphenylmethyl)thio]ethylamine (14.0 g, 99%) is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1C=CC=CC=1)[C:11]1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[OH:1][CH2:2][C:3]([CH2:8][O:9][Si:10]([CH3:17])([CH3:11])[C:23]([CH3:26])([CH3:25])[CH3:24])([CH2:6][OH:7])[CH2:4][OH:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(CO)(CO)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCC(CO)(CO)CO
Yield: 133.4 %

Procedure:
Pentaerythritol [2,2-bis(hydroxymethyl)propane-1,3-diol] (10.55 g, 77 mmol) was taken up in 100 mL of dry pyridine. Tert-butyldiphenylsilyl chloride (4.26 g, 15 mmol, 0.2 eq) was then added dropwise over 10 minutes to the pyridine solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours at which point TLC (EtOAc) indicated that the reaction was complete. The reaction was worked-up by diluting the reaction mixture with 250 mL of EtOAc and washing the organic layer with 10% HCl (3×200 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford a thick pale yellow oil. Column chromatography on 200 g of silica gel eluting with EtOAc followed by concentration of the appropriate fractions afforded 5.01 g of the product as a clear colorless oil which solidified very slowly upon standing (86%). 1H NMR (CDCl3, 300 MHz): δ1.08 (s, 9H), 3.66 (s, 2H), 3.74 (s, 6H), 7.42 (m, 6H), 7.65 (m, 4H); MS (70 eV, EI) 392 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)(=O)=O>C(O)(C)(C)C.CC(=O)CC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[CH:8]=2)[CH:3]=1
Reactant: CC(C)(C)[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.) was dissolved in a mixture of t-butanol/2-butanone (4 mL/2 mL). Then cesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was added to the mixture and the mixture was stirred at 110° C. for 10 min. Then trans-4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1 eq.) was added to the mixture. The suspension was stirred at 110° C. under a nitrogen atmosphere for 15 h. The reaction mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using petroleum ether as eluent to give 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene as a slight yellow solid (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H), 7.15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m, 2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34](Br)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2.[OH-].[Na+]>CN(C=O)C>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(-c3ccc(OC(F)(F)F)cc3)c2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A mixture of 40 mg (0.29 mmol) of 4-(trifluoromethoxy)phenylboronic acid, 70 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 ml (0.57 mmol) of 1N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally once more with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Silica gel 0.60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 52 mg (61% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:27]1[C:32]([F:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>>[F:33][C:32]1[C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:28][CH:29]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:31]=1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cc4F)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-3-fluoro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.75 min; Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Cl:14][CH2:15]I.C([Li])CCC.Cl.C(OCC)(=O)C.OC(C(O)(C)C)(C)C>CCCCCC.O1CCCC1>[Cl:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: ClCI
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OB(CCl)OC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To the mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol), and tetrahydrofuran (78 ml), n-butyllithium (a 1.6 M n-hexane solution, 41 ml, 65 mmol) was added dropwise at −78° C. (an outer temperature) for 20 min. and then the obtained mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0° C. (an outer temperature), and a 4 N hydrochloric acid-ethyl acetate solution was added dropwise thereto at the same temperature until the reaction mixture became neutral. At the same temperature, pinacol (7.7 g, 65 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 40 min. The solvents were evaporated under reduced pressure, and then the obtained residue was distilled under reduced pressure (63-70° C., 11 mmHg), thereby obtaining the entitled compound (9.2 g, 52 mmol, 81%).