Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
A solution of 4-(2-methoxyethoxy)aniline (0.397 g, 2.37 mmol) and pyridine (1 mL, 12.4 mmol) in DCM (3 mL) in was treated with 4-nitrophenyl chloroformate (Aldrich) (0.505 g, 2.51 mmol) added in portions (exothermic!). The pale yellow solution was stirred at RT for 5 h. The reaction mixture was partitioned between 0.5N HCl (20 mL) and DCM (30 mL). The organic phase was washed with 0.5N HCl (30 mL), saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (50 g, eluent: EtOAc in hexanes 10%-50%) to give 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.57 g, 72% yield) as an off—white solid. 1H NMR (400 MHz, CDCl3) δ 8.25-8.32 (m, 2H); 7.32-7.43 (m, 4H); 6.87-6.97 (m, 3H); 4.09-4.15 (m, 2H); 3.72-3.79 (m, 2H); 3.46 (s, 3H). m/z (ESI, +ve ion) 333.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:17]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>CN(C)C=O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (20.5 g, 101 mmol) and cesium carbonate (50 g, 153 mmol) in N,N-dimethylformamide (200 mL) was added dropwise a solution of 3-nitrophenol (15.5 g, 111 mmol) in N,N-dimethylformamide (100 mL) for 1 hr, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water (300 mL) and extracted with ethyl acetate (600 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10→60/40), and fractions containing the object product was concentrated under reduced pressure to give the title compound (14.28 g, 54%) as colorless crystals.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][C:34]1[O:38][N:37]=[C:36]([CH3:39])[CH:35]=1.N(C(OC)=O)=NC(OC)=O>O1CCCC1>[CH3:39][C:36]1[CH:35]=[C:34]([CH2:33][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[O:38][N:37]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(CO)on1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CON2C(=O)c3ccccc3C2=O)on1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
8.17 g of N-hydroxyphthalimide and 23.9 g of triphenylphosphine were added to a solution of 5.15 g of 5-hydroxymethyl-3-methylisoxazole in 245 ml of tetrahydrofuran. A solution of 13.3 g of dimethyl azodicarboxylate in 20 ml of tetrahydrofuran was then added dropwise at room temperature under an atmosphere of nitrogen to the resulting solution. The mixture was then allowed to stand for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 7.21 g of N-(3-methylisoxazol-5-yl)methoxyphthalimide, melting at 129°-131° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8].C(OO)(C)(C)C.[O-]O>>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C1=CCCCC1
Agent: CC(C)(C)OO
Agent: [O-]O
Product: CC(=O)OC1C=CCCC1

Procedure:
In order to demonstrate that the 3,6-diacyloxycyclohexene can be prepared in a single step procedure, a mixture of 20.5 g. (0.25 moles) cyclohexene, 45 g. (0.75 moles) acetic acid and 45 g. of 90.5 weight percent purity tertiary butyl hydroperoxide (0.45 moles) and 0.4 g. cuprous chloride was heated at 80° - 85° C. for 10 hours at which time it was found that 97 weight percent of the hydroperoxide had been consumed. Analysis by glpc showed that 21 mole percent yield to 3-acetoxycyclohexene and a 25 mole percent yield to 3,6-diacetoxycyclohexene was obtained. The reaction mixture was treated as in Example I and the product distilled at 92° C. under 1 mm Hg pressure. Very little high boiling residue was found. It will be noted that although 0.5 moles of the hydroperoxide solution was used since it was not pure only 0.45 moles of the hydroperoxide itself was employed, i.e. slightly less than the desired 2:1 mole ratio of hydroperoxide to cyclohexene, a good yield of the diester was obtained.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16](Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C=O)C.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([S:3][C:1](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
2.2 g (19.3 mmol) Potassium thioacetate and 2.65 g (10 mmol) 4-Bromo-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml of DMF and stirred at 100° C. for 4 h. The mixture was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 20% ethyl acetate in heptane) gave 2.15 g of the expected compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH2:27][CH2:28][NH:29][C:30](=[O:31])[C:14]=4[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:33][C:34]1[N:35]=[CH:36][N:37](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:38]=1[CH3:39]>>[CH3:39][C:38]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:33][N:29]1[CH2:28][CH2:27][C:15]2[N:16]([CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]3[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:30]1=[O:31]
Reactant: O=C1NCCc2c1c1cccc(OCc3ccccc3)c1n2COCc1ccccc1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(OCc4ccccc4)c3n2COCc2ccccc2)C1=O
Yield: 55.4 %

Procedure:
2,3,4,5-Tetrahydro-6-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-1-one (500 mg) was reacted with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (671 mg) according to the method of Intermediate 35 to give the title compound (340 mg), m.p. 170°-172°. (The FCC Eluant was System A (100:8:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[N:8]2[CH2:20][CH2:19][C:18]#[N:21])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C12OCCCO2
Reactant: C=CC#N
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN1C(=O)C2(OCCCO2)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 65 h
Yield: 72.2 %

Procedure:
A mixture of 6′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (8.85 g, 36.9 mmol), and benzyltrimethylammonuim hydroxide (40% aqueous solution, 1.46 mL, 3.69 mmol, 0.1 mole % ) in anhydrous DMF was heated to 65° C. Acrylonitrile (4.86 mL, 73.9 mmol, 2 eq) was added drop-wise by syringe under a dry N2 atmosphere. After stirring 65 hr. the reaction was cooled to room temperature and poured into water (750 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of 100% CH2Cl2 followed by CH2Cl2/CH3OH/NH4OH (99.7/0.2/0.1) to give the title compound as a white solid (7.80 g, 73% yield). Anal: Calc'd for C14H13ClN2O3: C, 57.45; H, 4.48; N, 9.59. Found: C, 56.39; H, 4.35; N, 9.35. NMR (400 MHz, DMSO-d6): consistent. IR: consistent; MS: (EI+) m/z 292 [M+] 1 chlorine pattern observed. m.p.163-164° C.; HRMS: consistent.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([C:14]#[N:15])[CH:3]=1.Cl.[C:17]1([NH2:23])([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]#[N:15])=[CH:5][C:6]=1[C:11]([NH:23][C:17]1([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1)=[O:12]
Reactant: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1N

Procedure:
236 mg (1.16 mmol) 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile, 234 mg (1.75 mmol) bicyclopropyl-1-ylamine hydrochloride and 177 mg (1.75 mmol) triethylamine in 25 ml THF are heated 4 h at reflux. The mixture is cooled down and evaporated. The residue is dissolved in ethyl acetate and extracted with water. After purification on a short path of silicagel, 63 mg of the title compound are isolated as yellow crystals. F: 171-172° C.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.[CH2:25](Cl)Cl>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: ClCCl
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Reaction time: 2 h

Procedure:
In 300 ml of methylene chloride was dissolved 30.0 g of Compound b obtained in Reference Example 2. Under ice cooling, 10 ml of thionyl chloride was dropwise added to the solution. After stirring for further 2 hours under ice cooling, the reaction mixture was concentrated under reduced pressure. To the resulting residue, 500 ml of methanol and 20 ml of triethylamine were added and the mixture was stirred at room temperature for an hour. The solvent was distilled off under reduced pressure and the residue was extracted with 1 liter of ethyl acetate. The extract was washed in sequence with saturated aqueous sodium bicarbonate solution and then saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropyl ether to give 19.0 g of white crystalline methyl 11-methoxy6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([NH:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CC(=O)NCC1CNCCO1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 49.2 %

Procedure:
A mixture of 1 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.15 g of 2-acetylaminomethylmorpholine, 1 g of triethylamine and10 ml of pyridine was heated under reflux for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and ethyl acetate was added to the residue. The resulting crystals were collected byfiltration, and suspended in 20 ml of water. The suspension was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from ethanol gave 720 mg of 5-amino-7-(2-acetylaminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.[CH2:14]1CCN2C(=NCCC2)C[CH2:15]1.C1(Br)CC1>O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Oc1cnc(Cl)c2cccc(Cl)c12
Agent: BrC1CC1
Solvent: O
Product: CCOc1cnc(Cl)c2cccc(Cl)c12
Temperature: 120 °C
Yield: 1.8 %

Procedure:
To a solution of 1,5-dichloroisoquinolin-4-ol (0.5 g, 2.33 mmol) in DBU (1.7 ml, 11.68 mmol) was added cyclopropylbromide (0.93 ml, 11.68 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 120° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.01 g, 2.1%) as yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.27-8.24 (m, 2H), 7.76-7.74 (d, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 3.96-3.94 (m, 1H), 0.95-0.90 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[C:9]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3]=2[CH2:2][C:21]#[N:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 2′-bromomethyl-[1,1′:3′,1″]terphenyl (Tetrahedron Lett. 42; 5467-5472 (2001)) (1.65 g, 5.1 mmol) and sodium cyanide (0.27 g, 5.6 mmol) in 10 mL of DMF was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with diethyl ether and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (eluting with 0-4% ethyl acetate in hexane) to give [1,1′;3′,1″]terphenyl-2′-yl-acetonitrile as a white solid (0.78 g, 57%): MS (ESI) m/z 270.1 (M+H); HRMS calcd for C20H15N, 270.1277. Found (ESI+): 270.1274; 1H NMR (DMSO-d6): δ 3.57 (s, 2H), 7.20-7.50 (m, 13H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13](I)[CH2:12]1.Cl[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1>[Zn].O1CCCC1>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:19]2[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=2)[CH2:12]1
Reactant: CC1CCCC(I)C1
Reactant: CSc1nsc(Cl)n1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CSc1nsc(C2CCCC(C)C2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
1.31 g of zinc foil (99.998%) and 190 mg of 1,2-dibromoethane was added into 2 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was heated in an oil bath at 65° C. for 1 minute. After cooling to room temperature, 0.1 ml of trimethylsilyl chloride, 2.14 g of 3-methylcyclohexyl iodide and 10 ml of tetrahydrofuran were added to the mixture, and the mixture was exposed to ultrasonic wave in a water bath for 4 hours. Further, 1.31 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 390 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex and 10 ml of tetrahydrofuran were added in the mixture, and the reaction mixture was stirred for 3.5 days at room temperature. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 790 mg of 5-(3-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[C:5]=2[CH:6]=1
Reactant: COC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: OCCc1ccsc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCCc2ccsc2)c2cc(C)oc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 2-methyl-4-hydroxy-6-methoxycarbonylbenzofuran (Method 12; 1.24 g, 6.0 mmol) and 2-(3-thienyl) ethanol (768 mg, 0.67 ml, 6.0 mmol) in DCM (DCM, 50 ml) was added polymer-supported triphenyl phosphine (2.5 g, ca 3 mmol/g, 1.5 eq), and the suspension cooled to 5° C. under an argon atmosphere. To this was added di t-butyl azodicarboxylate (1.725 g, 7.5 mmol, 1.5 eq), and the reaction mixture stirred overnight, allowing to warm to ambient temperature. It was then filtered through diatomaceous earth, washed through with DCM, and the filtrate and washings evaporated in vacuo to ˜50 ml total volume. To this was added trifluoroacetic acid (2 ml), and the solution evaporated in vacuo to give a red oil. This was chromatographed (70 g Bondelut, eluting with hexane containing ethyl acetate, 0-50%) to give a red solid; this was re-chromatographed (as previous) to give the title compound as a colourless crystalline solid (150 mg, 8% yield). NMR: 2.46 (s, 3H), 3.10 (t, 2H), 3.83 (s, 3H), 4.33 (t, 2H), 6.64 (s, 1H), 7.12 (dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.46 (dd, 1H), 7.66 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccc(F)c4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 3-fluorobenzene-boronic acid (173 mg, 1.24 mmol) were reacted as described in Example 61. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 gave 3-[2-(3-fluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 464 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[O:12][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCc1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(Oc2ccc(OC)cc2)c(OC)c1

Procedure:
A mixture containing 2-methoxy-4-propylphenol (0.625 mmol; 100 μl), copper(II) acetate (0.625 mmol; 114 mg), 4-methoxyphenylboronic acid (1.25 mmol; 190 mg), triethylamine (3.12 mmol; 0.43 ml), some crushed molecular sieves 4 Å in dichloromethane (3 ml) was stirred at rt under air for 24 h. The residue is filtered with chloroform on Celite. The organic phase is washed with saturated NH4Cl, saturated NaHCO3 and brine. After drying (MgSO4), concentration and purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80), the title compound is collected as a colorless oil (70 mg; 0.26 mmol; 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:31][C:32](=[O:33])[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)[CH:39]=1)[CH3:30]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4, 150 mg) in CH2Cl2 (3 ml) were added 3-ethoxycarbonylphenylboronic acid (210 mg), copper-(II)-acetate (197 mg), molecular sieve and pyridine (143 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give the title compound (195 mg) as a colorless foam. MS (m/e)=564.2 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27]C(B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46](C)=C(C)[C:44](C)=[C:43](C)[C:42]=1[CH3:51]>>[CH3:27][C:28]1[C:43]([CH3:44])=[C:42]([CH3:51])[C:41]([CH3:46])=[C:24]([CH3:25])[C:23]=1[O:22][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])=[O:38])=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Cc1c(C)c(C)c(Br)c(C)c1C
Product: Cc1c(C)c(C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C)c1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 1-bromo-2,3,4,5,6-pentamethyl-benzene. MS: 554.2 [M−H]−.