Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][CH:13]=1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(#N)C>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Product: Clc1ccc2c(NCCCN3CCCCC3)ccnc2c1

Procedure:
2.73 g from 2.83 g of 3-(piperidin-1-yl)-propylamine and 3.94 g of 4,7-dichloroquinoline (reaction duration, 16 hours at 140° C.); the base (yellowish crystals from acetonitrile, m.p.: 113°-116° C.) was converted with isopropanolic hydrochloric acid into the dihydrochloride which when recrystallized from acetonitrile/ethanol, yielded colourless crystals, m.p.: 137°-141° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:16]#[N:17])=[C:11]2[N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1)C(=O)C.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1COCC1.CO>[Br:28][C:24]1[CH:23]=[C:22]([NH:18][C:11]2[C:10]3[C:15](=[C:6]([CH2:5][N:2]([CH3:3])[CH3:1])[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:16]#[N:17])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of dimethylamine in THF (2.0 M; 115 ml; 230 mmol) at 0° C. was added a solution of 8-bromomethyl 4-[(3-bromophenyl)-N-acetylamino]-6-nitro-quinoline-3-carbonitrile (11.6 g, 23 mmol) in 115 ml of THF during 15 m. After warming to 25° C. the mixture was stirred for 2 h. The THF was evaporated off, and the residue was refluxed in 230 ml of methanol with 12.7 g (92 mmol) of potassium carbonate for 1 h. The mixture was cooled, saturated with CO2, and concentrated. The residue was partitioned with methylene chloride and water. The organic layer was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give 6.0 g yellow solid, mp 223-226° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C(N(CC)CC)C.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: Cc1cc(C)nc(NCCN(C)C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)N(C(C)C)C(C)C)c1
Yield: 24.1 %

Procedure:
A solution of 5.80 g (30.0 mmoles) of 2-(2-dimethylaminoethylamino)-4,6-dimethylpyridine (from Example 1, B) and 2.20 ml (30.0 mmoles) of triethylamine in 50 ml of benzene is dried by azeotropic distillation. After adding 4.91 g (30.0 mmoles) of diisopropylcarbamoyl chloride, the reaction mixture is heated at reflux for 24 hours. The crude product, after removal of solvent, is chromatographed on silica gel using 5% methanol in chloroform as eluant. Appropriate fractions are combined, the solvent removed and product distilled through a short path still to give 2.32 g (24.1% yield) of N,N-diisopropyl-N'-(2-dimethylaminoethyl)-N'-(4,6-dimethyl-2-pyridyl)urea as a colorless oil boiling at 148°/0.35 mm.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][N:26]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1
Yield: 94.3 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (226 mg) and 1-(3,5-dichloropyridin-2-yl)piperazine (244 mg) and by the reaction and treatment in the same manner as in Example 87, N-{4-[4-(3,5-dichloropyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (425 mg) was obtained. Using the obtained N-{4-[4-(3,5-dichloropyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (425 mg) and methylboronic acid (504 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (91 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:3][CH2:2]1.Cl[CH:18]([CH:24]=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:16]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(OCCN2CCOCC2)ccn1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OCCN3CCOCC3)ccn12

Procedure:
4-(2-Morpholinoethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolved in ethanol (20 ml) and treated with ethyl 2-chloro-3-oxopropanoate (5% solution in benzene, 30 mL). The mixture was refluxed overnight. The reaction mixture was cooled and concentrated to afford a beige solid (1.31 g), which was purified by chromatography on silica, eluting with a gradient from 50% EtOAc/Hexanes to 100% EtOAc, followed by 10% MeOH/DCM to provide 1.0 g of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[OH-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1cn(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
The obtained 2-chloro-4,6-dimorpholino-1,3,5-triazine (1.44 g, 5.04 mol) was dissolved in DMF (40 ml), added with sodium hydroxide (430 mg, 10.2 mmol) and imidazole (694 mg, 10.2 mmol) and stirred at 110° C. -120° C. for 30 minutes. The reaction mixture was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was recrystallized from ethanol to obtain 1.37 g (yield: 85.1%) of the titled compound as colorless crystals.
Reaction SMILES: C(O[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-:33].[Na+]>C(O)C.O1CCCC1>[CH2:10]([C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][O:33]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(Cc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([Br:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[Br:20][C:16]1[N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:7]3[C:21]([Cl:24])=[CH:22][CH:23]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH3:29])[C:6]=3[Cl:25])[C:11]2=[N:18][C:17]=1[CH3:19]
Reactant: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 58.9 %

Procedure:
To a solution of 8-(3-acetylamino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (222 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (24 mg, 60% oil dispersion) in one portion at ambient temperature. The mixture was stirred for half an hour at the same temperature and iodomethane (142 mg) was added thereto. After stirring for half an hour, the mixture was poured into water. The separated oil was extracted with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 3-bromo-8-[2,6-dichloro-3-(N-acetyl-N-methylamino) benzyloxy]-2-methylimidazo[1,2-a]pyridine (135 mg) as a solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1([CH3:38])[C:28]([CH3:30])([CH3:29])[O:27][B:26]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[O:25]1.[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[C:49](=[O:59])[C:48]([C:60](O)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=2)[C:49](=[O:59])[C:48]([C:60]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([B:26]3[O:25][C:24]([CH3:38])([CH3:23])[C:28]([CH3:29])([CH3:30])[O:27]3)=[CH:32][CH:33]=2)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(O)c1cn(Cc2ccccc2)cc(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)c3cn(Cc4ccccc4)cc(-c4ccc(F)cc4)c3=O)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
EDC.HCl (152 mg), HOBt (73 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (128 mg) were added to a solution of 1-benzyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (171 mg) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 50° C. overnight. EDC.HCl (76 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64 mg) were added to the reaction mixture at 50° C. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was returned to room temperature and diluted by adding water. The precipitated solid was collected by filtration. The resulting solid was purified by silica gel column chromatography [hexane:ethyl acetate=5:1->4:1->3:1->1:1 (v/v)] to give 112 mg of the title compound as a solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([C:22]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
7.67 g (40.0 mmol) of EDCl was added to 106 ml of THF solution of 5.31 g (20.0 mmol) of Boc-Phe-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 1.82 ml (20.0 mmol) of aniline and 3.06 g (20.0 mmol) of HO-Bt, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (toluene/ethyl acetate=9/1 to 7/1 (volume ratio)), thereby obtaining 5.93 g of the product with a yield of 87.1%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16].O>CC#N>[CH:15]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.7 mmol) in CH3CN (100 mL) was added dropwise a solution of isopropylamine in water (7.6 g, 0.13 mol) at 0° C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure and the residue was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 99.6% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 4.31-4.22 (m, 3 H), 2.46 (s, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:36])[N:19]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:34]([O:33][C:31]([CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:16][CH:15]=3)[C:18]2=[O:36])[CH2:30][CH2:29]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)OCc4ccccc4)cc3)c2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)O)cc3)c2=O)CC1
Yield: 50 %

Procedure:
10% Pd—C (360 mg) was added to an ethanol (30 ml) solution of ethyl 1-{2-[3-{4-[(benzyloxy)carbonyl]phenyl}-2-oxopyridin-1(2H)-yl]ethyl}piperidin-4-carboxylate (1.647 g), followed by stirring in a hydrogen atmosphere under normal pressure at room temperature for 27 hours. The reaction mixture was filtered through Celite, washed with THF and ethanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 80:20) to obtain 4-(1-{2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzoic acid (671 mg) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 4-aminophenol (30.00 g, 275 mmol) in DMF (120 ml) at 0° C. under an atmosphere of nitrogen was added triethylamine (42.5 ml, 302 mmol, 1.2 eq). The reaction mixture was stirred for 10 minutes before dropwise addition of benzoyl chloride (31.9 ml, 275 mmol, 1.0 eq) over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was poured in ice cold water (800 ml) with vigorous stirring. A precipitate was collected by filtration and washed with water (2×500 ml). The precipitate was slurried in diethyl ether (1.5 L) and vigorously stirred for 30 minutes. The precipitate was collected by filtration and allowed to dry under reduced pressure to afford the title compound as an off-white solid (41.56 g, 71% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([Br:16])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>CCOCC>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([Br:16])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: CCOC(=O)c1cc2c(Br)c(Oc3ccc(OC)c(C(=O)c4ccc(F)cc4)c3)c(Br)cc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCS
Product: CCOC(=O)c1cc2c(Br)c(Oc3ccc(O)c(C(=O)c4ccc(F)cc4)c3)c(Br)cc2o1
Yield: 46.5 %

Procedure:
Ether cleavage of 108 mg of ethyl 4,6-dibromo-5-[3-(4-fluorobenzoyl)-4-methoxyphenoxy]-1-benzofuran-2-carboxylate with AlCl3/ethanethiol, in analogy with example . . . , yields 49 mg (47%) of ethyl 4,6-dibromo-5-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-1-benzofuran-2-carboxylate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16](O)[CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[CH2:25][CH:16]1[CH2:15][CH2:14][C:13]2[CH:19]=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=[CH:11][C:12]=2[O:17]1)[CH3:24]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCc2cc(OCc3ccccc3)ccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(OCc3ccccc3)ccc2O1
Yield: 74.2 %

Procedure:
A solution of 1.8 g of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-ol and 2.6 g of (carbethoxymethylene)triphenylphosphorane in 20 ml of toluene was stirred and refluxed for 22 hours. The solution was cooled and placed on a column of 50 g of silica gel packed in toluene. Elution with toluene and 19:1 toluene-ethyl acetate gave 1.7 g (74.2%) of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil. This material was dissolved in 25 ml of absolute ethanol and the solution was stirred in the presence of 0.2 g of 10% palladium on carbon, at room temperature, in an atmosphere of hydrogen. After 1.5 hours, hydrogen uptake ceased and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.2 g (97.6%) of racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)[CH2:13][C:12]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)[CH2:13][C:12]3=[N:31][C:30]#[N:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Reaction time: 1 h
Yield: 121.2 %

Procedure:
To a solution of 6-(phenylethynyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (86 mg, 0.27 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.54 mL, 0.54 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.16 mL, 0.427 mmol) dropwise. The resulting mixture was stirred 80 h. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 112 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI+ve m/z 343 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>>[CH:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:46]=[CH:47][C:38]=1[CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]3([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:22][CH2:21][CH2:20][O:19]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-bromomethyinaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy)-phenyl]-piperidine-1-carboxylate as white crystals; MS: 624 (M+H)+.