Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:12][C:11]1[CH:18]=[CH:17][C:15]([O:16][CH:2]([CH3:10])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][O:6]2)=[O:4])=[CH:14][CH:13]=1
Reactant: CC(Cl)C(=O)N1CCCO1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, hydroquinone (13.2 g), anhydrous potassium carbonate (29.0 g) and dimethylformamide (100 ml) was stirred at 120° C. for 2 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of chloroform and 1 N hydrochloric acid and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (21.6 g) as a pale yellow oil which was purified by silica gel column chromatography to yield a colorless oil. nD20 =1.5412.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[O:25])[CH3:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(CC)CC>ClCCl>[C:23]([N:22]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:14][CH:15]=1)(=[O:20])=[O:21])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:25])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reaction time: 168 h
Yield: 31.9 %

Procedure:
To a stirred solution of N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide (Example 39) (0.612 g, 1.72 mmol) in dichloromethane was treated with ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol). After 7 days the reaction was still incomplete by TLC. Additional ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol) were added and the reaction was stirred for an additional 6 days. The reaction was diluted with dichloromethane and washed with KHSO4 solution, NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear oil. This oil was purified by flash chromatography yielding N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (0.243 g, 32%) as a clear colorless oil of suitable purity for use in the next step: 1H NMR (CDCl3/300 MHz) 8.03 (d, 2H, J=8.7 Hz), 7.47-7.27 (m, 9H), 4.61 (s, 2H), 4.21 (q, 2H, J=7.1 Hz), 2.51 (s, 3H), 2.33 (s, 3H), 1.28 (t, 3H, J=7.1 Hz). FABLRMS m/z 443 (M+H). FABHRMS m/z 442.1201 (M+, C22H22N2O6S Calc'd 442.1199).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][C:13]=1[OH:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.O1CCCC1>[CH2:4]([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[OH:28])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccccc2)c(O)c1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of lithium hydroxide hydrate (300 mg, 7.15 mmol) in water (15 cm3) was added dropwise to a stirred solution of benzyl 4-benzyloxy-3-hydroxybenzoate (1.177 g, 3.52 mmol) in tetrahydrofuran (35 cm3). The resulting emulsion was stirred overnight, by which time a clear, pale yellow solution had formed. More lithium hydroxide hydrate (300 mg, 7.15 mmol), water (25 cm3) and tetrahydrofuran (25 cm3) were added, and stirring was continued for 24 h. The tetrahydrofuran was removed under reduced pressure. Water (100 cm3) was added to the residual mixture, which was washed with diethyl ether (2×50 cm3), acidified to pH 1 with 5% HCl and extracted with dichloromethane (3×100 cm3). The combined extracts were washed with brine (50 cm3), dried (NaSO4) and evaporated to give 4-benzyloxy-3-hydroxybenzoic acid as a white solid (638 mg, 74%). The diethyl ether washings were extracted with 1 M potassium hydroxide (2×25 cm3). The combined extracts were acidified to pH 1 with 5% HCl and extracted with dichloromethane (3×100 cm3). The combined extracts were dried over MgSO4 and evaporated to give a further 119 mg of product (total yield 757 mg, 88%), m.p. 163-165° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](#[N:12])[CH2:10]O>CCOCC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:9]#[N:12])[CH2:5][CH2:4]1
Reactant: COC1CCNCC1
Reactant: N#CCO
Solvent: CCOCC
Product: COC1CCN(CC#N)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4-Methoxypiperidine (286) (10.1 g, 87.6 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 10.0 g, 96.4 mmol) at 5° C. and the solution was stirred at 70° C. for 1 h. The solution was cooled, diluted with Et2O (50 mL) and washed with water (2×20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give nitrile 287 (10.25 g, 76%) as a colourless oil: 1H NMR δ 3.51 (s, 2H, CH2CN), 3.35 (s, 3H, OCH3), 3.21-3.28 (m, 1H, CHO), 2.72-2.78 (m, 2H, CH2N), 2.40-2.46 (m, 2H, CH2N), 1.90-1.98 (m, 2H, CH2N), 1.60-1.69 (m, 2H, CH2).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH3:36])=[C:28]([C@H:11]2[CH2:10][CH:9]([OH:8])[CH2:13][N:12]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:33]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CC(O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3OC)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3OC)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of the cis and trans isomers) (0.0487 g, 0.0946 mmol) in THF (1 mL) at 0° C. was added 1 M TBAF in THF (0.104 mL, 0.104 mmol). The reaction mixture was warmed to ambient temperature and stirred for 2.5 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers; 37.9 mg, 100% yield). LC/MS (ES+APCI) m/z=401.1 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH2:31]Br>>[Br:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH2:31][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:8]2[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: COc1ccc(Br)c(CBr)c1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(OC)ccc3Br)cc1)n2C1CCCCC1

Procedure:
Ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate obtained in Example 3 and 2-bromo-5-methoxybenzyl bromide were treated in the same manner as in Example 4 to give the title compound (59 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]([CH3:16])([CH2:14]C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1.[Na]>C(O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:27]=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]([CH3:14])([CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:18]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(CC)Oc1ccc(C=O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=CC(=O)c2ccc(Br)cc2)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of ethyl 2-(4-formylphenoxy)-2-methyl-2-ethylacetate and 4.9 parts of p-bromoacetophenone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides ethyl 2-[4-(2-p-bromobenzoylethenyl)phenoxy]-2,2-dimethylacetate. This compound has the following structural formula. ##SPC7##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][OH:16])[CH2:9]2)[CH:5]=[C:4]([Cl:17])[N:3]=1.CCN(C(C)C)C(C)C.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([NH:33][C:34](=[O:35])[O:16][CH2:15][C@H:10]2[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]3[CH:5]=[C:4]([Cl:17])[N:3]=[C:2]([NH2:1])[N:7]=3)[CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CO[C@H](COC(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 20-mL screw-cap vial was added [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methanol (100 mg, 0.387 mmol), Hunig's base (0.135 mL, 0.773 mmol) and CHCl3 (10 mL). The reaction was cooled to 0° C., then phenyl isocyanate (0.046 mL, 0.425 mmol) in CHCl3 (2 mL) was added dropwise via syringe. The solution was allowed to warm to room temperature and then stirred overnight. An additional portion of Hunig's base (0.135 mL, 0.773 mmol) and phenyl isocyanate (0.046 mL, 0.425 mmol) was added, and the reaction stirred at 60° C. overnight. The solvents were removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (123 mg). LC-MS (ES) m/z=378 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]([C:20]3[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=3)=O)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:29][N:28]=3)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: O=S(=O)(NCCN1CCOCC1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (100 mg) and hydrazine hydrate (excess) in ethanol (5 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 2 with 1N HCl and extracted with DCM. The aqueous layer was adjusted to pH 7 with NaHCO3, the precipitate was collected by vacuum filtration, washed with water to give the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: COC(=O)C(C)Oc1cccc(CCl)c1
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)c1
Yield: 89.8 %

Procedure:
By the method of Example 1, Step I, 1.0 g (0.0038 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step F) and 1.72 g (0.0076 mole) of methyl 2-(3-chloromethylphenoxy)propionate were reacted in the presence of 0.79 g (0.0057 mole) of anhydrous potassium carbonate in 25 mL of N,N-dimethylformamide, yielding 1.54 g of methyl 2-[3-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH =8.0 Hz); 5.04 (s, 2H); 6.76-7.38 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH2:22])[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: O=C(O)C=Cc1ccccn1
Reactant: Nc1cc(-c2ccco2)on1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccn1)Nc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of 6 mg of 3-pyridin-2-yl-acrylic acid and 6 mg of 5-furan-2-yl-isoxazol-3-ylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.014 mL of TEA. The reaction solution was stirred for 18 hrs at room temperature, followed by concentration under reduced pressure. The concentrate was purified by preparative HPLC to provide 4 mg of N-(5-furan-2-yl-isoxazol-3-yl)-3-pyridin-2-yl-acrylamide. (Yield: 36%).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:27]=[C:24]([CH:25]=[O:26])[C:23]([OH:28])=[CH:22][CH:21]=1.[Cl:29][CH2:30]/[CH:31]=[CH:32]/[CH2:33]Cl.[OH-].[Na+]>O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:28][CH2:33]/[CH:32]=[CH:31]/[CH2:30][Cl:29])=[C:24]([CH:27]=1)[CH:25]=[O:26]
Reactant: ClC/C=C/CCl
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc(Cl)ccc1OC/C=C/CCl

Procedure:
To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammonium hydroxide, 160 g of 5-chloro-salicylaldehyde and 140 ml of trans-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 42 g of sodium hydroxide in 200 ml of water at such a rate that the pH of the mixture is kept between 7 and 8. Thereafter the mixture is refluxed until the pH is about 7, cooled and extracted with methylene chloride. The extract is washed with 5% aqueous sodium hydroxide, dried, evaporated and the residue heated to 30°/0.1 mmHg in order to remove the excess of 1,4-dichloro-2-butene. The residue is taken up in 1 lt of diethyl ether, the solution filtered, the filtrate evaporated and the residue recyrstallized from ethyl acetate, to yield the 5-chloro-2-(4-chloro-trans-2-butenyloxy)-benzaldehyde melting at 62°-63°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH2:21]O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH:20]=1)[CH2:21][O:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(O)cccc2c1
Reactant: OCc1cc(Br)ccc1I
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3cc(Br)ccc3I)cccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To a solution of 6-methoxynaphthalen-1-ol (4.45 g, 25.6 mmol), (5-bromo-2-iodophenyl)methanol (8.0 g, 25.6 mmol) and triphenylphosphine (7.4 g, 28.2 mmol) in tetrahydrofuran (128 mL) at 0° C. was added diisopropyl azodicarboxylate (5.54 mL, 28.2 mmol). The reaction was allowed to warm to room temperature overnight. After 15 hours, more triphenylphosphine (1.3 g, 5 mmol) and diisopropyl azodicarboxylate (0.99 mL, 5 mmol) were added and the reaction was stirred at room temperature. After 24 hours, the reaction was concentrated and recrystallized from CH2Cl2 and hexanes to yield 1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene (7.82 g, 65%). The mother liquor was purified by flash column chromatography to yield more product (790 mg, 6.5%).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1>O1CCCC1>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)C(F)(F)COc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
2,2,3,3-Tetrafluoropropan-1-ol (5.54 g, 41.31 mmol) was added to a suspension of sodium hydride (2.20 g, 55.08 mmol, 60% in mineral oil) in tetrahydrofuran (50 mL) and reaction mixture was stirred for 30 minutes at room temperature. Then a solution of 2-chloro-3-(trifluoromethyl)pyridine (5.00 g, 27.54 mmol) in tetrahydrofuran (50 mL) was added and mixture was heated at 40° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and then quenched slowly with water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in heptane to give the title compound as a oil (3.10 g, 41%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[C:6]([CH3:13])[N:5]=1)[CH3:2].[CH3:14][C:15]1([CH3:34])[O:19][CH:18]([CH2:20][O:21][C:22]2[C:31]([CH3:32])=[CH:30][C:25]([C:26]([NH:28]O)=[NH:27])=[CH:24][C:23]=2[CH3:33])[CH2:17][O:16]1>>[CH3:14][C:15]1([CH3:34])[O:19][CH:18]([CH2:20][O:21][C:22]2[C:23]([CH3:33])=[CH:24][C:25]([C:26]3[N:28]=[C:10]([C:8]4[CH:7]=[C:6]([CH3:13])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=4)[O:12][N:27]=3)=[CH:30][C:31]=2[CH3:32])[CH2:17][O:16]1
Reactant: CCNc1nc(C)cc(C(=O)O)n1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)no2)n1

Procedure:
2-Ethylamino-6-methyl-pyrimidine-4-carboxylic acid and 4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine are coupled followed by cyclisation in analogy to Example 1 to give (4-{3-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-phenyl]-[1,2,4]-oxadiazol-5-yl}-6-methyl-pyrimidin-2-yl)-ethyl-amine; LC-MS: tR=1.12 min; [M+H]+=440.21.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)N=C2C=CC(c3cccc(Cl)c3)=CN21
Yield: 63.1 %

Procedure:
To a round-bottom flask was added 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69 mg, 0.25 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), dioxane (5 mL) and water (1 mL). The mixture was heated at reflux until the starting material was consumed monitored by HPLC-MS. The solution was cooled and water was added. The reaction mixture was extracted twice with ethyl acetate and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to provide the desired product as an off-white solid (43 mg, 63%). 1H NMR (CDCl3) δ 7.84 (dd, J=1.8 and 9.1 Hz, 1H), 7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH+); HRMS: calc'd MH+ for C15H13ClN2O 273.0794; found 273.0800.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.[O-]CC.[Na+]>C(O)C>[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1/[CH:33]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1
Reactant: COCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 46.7 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-(2-methoxyethoxy)-3-methoxybenzaldehyde (218 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 178 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.37 (s, 3H), 3.50 (br s, 2H), 3.78 (s, 3H), 4.04 (br s, 2H), 6.82 (d, J=15.6 Hz, 1H), 6.94-6.95 (m, 1H), 7.00-7.02 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 7.84-7.86 (m, 2H), 8.05-8.07 (m, 1H), 8.27 (d, J=15.6 Hz, 1H), 8.85-8.87 (m, 1H); ESI-MS (m/z) 553.81 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]([O:14]C(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(#N)C.C(O)(=O)C.Cl>[O:9]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][NH:1][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCC1(O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1NCC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.65 g (5.0 mmol) of 1-(aminomethyl)-cyclohexanol, 1.2 g (5.5 mmol) di-tert.-butyldicarbonate ((Boc)2O) and 0.611 g 4-dimethylaminopyridine were dissolved in 50 ml acetonitrile and agitated overnight at room temperature. The mixture was then fully turned over, the residue was dissolved in 20 ml acetic acid and again turned over. The residue was taken up in 25 ml 1 M hydrochloric acid and extracted with 50 ml toluene.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].S(=O)(=O)(O)O.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]([CH3:1])([CH2:9][CH3:10])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CO
Reactant: CCC(C)=CCCC(C)=O
Agent: O=S(=O)(O)O
Product: CCC(C)(CCCC(C)=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2 kg 6-methyl-oct-5-en-2-one in 4 l methanol was added 800 ml concentrated sulphuric acid at 3° C. over a period of 40 minutes. After further stirring for 5 h at room temperature, the solution was poured onto 8 kg of ice water and extracted with tert.-butyl methyl ether. The combined organic phases were washed with 20% Na2CO3 (200 ml) and concentrated NaCl solution (3×150 ml). After removal of the solvent, the residue was distilled over a 70 cm Sulzer column to give 840 g recovered starting material (boiling point: 72°-75° C./10 mm Hg) and 970 g 6-methoxy-6-methyl-2-octanone (bp.: 95°-98° C./10 Torr=13.3 mbar).