Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[CH:2].C1C(=O)N([Br:20])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:20][C:2]#[C:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C#CBr)cc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-ethynylbenzoate (50 g, 0.31 mol) in acetone (750 mL) was added AgNO3 (5 g, 29.7 mmol) and the reaction mixture was stirred for 1 hr. NBS (61.2 g, 0.34 mol) was added and the reaction mixture was stirred at room temperature for 20 hr, filtered and concentrated under reduced pressure. The residue was diluted in EA, and washed with iced 20% H2SO4. The organic layer was washed with water and brine, dried (Na2SO4), filtered, concentrated under reduced pressure to give a residue, which was recrystallized from MeOH (1 mL/4 g) to yield methyl 4-(bromoethynyl)benzoate (INT-1.4) as an off-yellow solid (67 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][OH:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([O:19][CH2:18][C:17]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: OCc1cc2ncccc2nc1-c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)ncnc1OCc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methanol (65 mg, 0.256 mmol) in DMF (1.5 mL) was added sodium hydride (12.3 mg, 0.31 mmol, 60% suspension in oil) and the reaction was stirred at rt for 10 min. After this time 4-amino-6-chloropyrimidine-5-carbonitrile (39.5 mg, 0.256 mmol) was added and the reaction was stirred at rt for 30 min. After this time an additional portion of NaH (12.3 mg, 0.31 mmol, 60% dispersion in oil) was added and the reaction was heated at 50° C. for 2 h and at rt overnight. After this time the reaction was cooled to rt and partitioned between EtOAc (50 mL) and LiCl (20 mL, 1M aq. solution). The separated organic layer was washed with LiCl (20 mL, 1M aq. solution) and then it was dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by reversed-phase HPLC (10 to 60% acetonitrile in water) to give 4-amino-6-((2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methoxy)-5-pyrimidinecarbonitrile as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.04 (1H, dd, J=4.2, 1.7 Hz), 8.61-8.66 (1H, m), 8.44-8.51 (1H, m), 8.28 (1H, s), 7.71 (1H, dd, J=8.6, 4.1 Hz), 7.36-7.56 (3H, m), 7.21 (1H, tdd, J=8.3, 8.3, 2.7, 1.2 Hz), 5.67 (2H, s), 5.62 (2H, br. s.): LC-MS (ESI) m/z 373.1 [M+H]+.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:16][CH:2]([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])(=[O:15])[CH:13]=[CH2:14]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)O
Product: C=CC(=O)OC(OC12CC3CC(CC(C3)C1)C2)C(C)C
Yield: 74 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanol instead of 2-adamantanol and acrylic acid instead of methacrylic acid, 1-(1-adamantyloxy)-2-methylpropyl acrylate was produced (four step yield 74%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a stirred solution of 2-aminothiazole (5.0 g, 49.930 mmol) in acetic acid (40 ml) was added ethyl acetoacetate (9.746 g, 74.90 mmol) at room temperature. The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was allowed to cool to room temperature. The residue obtained after concentration of the reaction mixture was basified with saturated solution of sodium bicarbonate and diluted with ethyl acetate (500 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 4.20 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22](=[O:23])[O:21]1>CN(C)C=O>[C:7]1([N:13]2[C:17]([S:18][C:20]3([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22](=[O:23])[O:21]3)=[N:16][N:15]=[N:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2Cl)c2ccccc21
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC(Sc2nnnn2-c2ccccc2)(c2ccc(Cl)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 300 ml of dried dimethylformamide, was added 5.6 g (0.05 mol.) of potassium tert-butoxide and 8.9 g (0.05 mol.) of 1-phenyl-5-mercaptotetrazole. The mixture was stirred for 20 minutes at room temperature. Thereafter, to the mixture which was cooled to 5° C. and kept there, was added gradually dropwise a solution prepared by adding 13 g (0.04 mol.) of 3-chloro-3-(2,4-dichlorophenyl)phthalide in 75 ml of dried dimethylformamide. After dropwise addition, the cooling bath was removed, and the mixture was stirred for 5 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 23.5 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 800 g, eluate: hexane-ethyl acetate (3:1 by volume) mixture). Thus, the intended compound, 3-(1-phenyl-tetrazole-5-ylthio)-3-(2,4-dichlorophenyl)phthalide (3), was obtained in a form of white crystals. Yield 7.8 g, Melting Point 148° to 149° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.O.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd]Cl>[F:18][C:19]1[C:24]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A solution of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1) (6.00 g, 25.1 mmol) in dioxane (54 mL) was sequentially treated with water (7.2 mL), 2-fluoropyridin-3-ylboronic acid (Asymchem Laboratories, Inc., Morrisville, N.C.) (5.31 g, 37.7 mmol), sodium carbonate monohydrate (9.35 g, 75.4 mmol) and PdCl2 (dppf) (Strem Chemicals, Inc., Newburyport, Mass.) (0.616 g, 0.754 mmol). The stirred mixture was degassed (alternating vacuum/nitrogen) and heated under nitrogen at 100° C. for 10 h. The mixture was cooled and extracted into EtOAc (500 mL) from water (400 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic extracts were dried (MgSO4), filtered through Celite® (diatomaceous earth), and concentrated. The crude product was dissolved in a small volume of DCM and purified by flash chromatography (50% to 75% to 100% EtOAc/hexane) to give 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.96 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 8.91 (s, 1H), 8.58 (m, 1H), 8.49 (s, 1H), 7.62 (m, 1H), 5.85 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.79 (m, 1H), 1.61 (m, 2H).
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.C([C:15]1([CH2:25][O:26][C:27]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:30]([C:31]([OH:33])=O)=[C:29]([F:39])[CH:28]=2)[CH:22]2[CH2:23][CH:18]3CC(C[CH:16]1[CH2:17]3)[CH2:21]2)#N.C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC1CCCC2>>[C:15]12([CH2:25][O:26][C:27]3[C:35]([CH:36]4[CH2:37][CH2:38]4)=[CH:34][C:30]([C:31]([NH:12][S:9]([CH:6]4[CH2:8][CH2:7]4)(=[O:11])=[O:10])=[O:33])=[C:29]([F:39])[CH:28]=3)[CH2:21][CH:22]1[CH2:23][CH2:18][CH2:17][CH2:16]2
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.87 (d, J=13.1 Hz, 1H), 3.92-3.73 (m, 2H), 3.13-3.01 (m, 1H), 2.10-1.96 (m, 1H), 1.95-1.49 (m, 4H), 1.40-1.03 (m, 8H), 1.03-0.93 (m, 1H), 0.94-0.82 (m, 2H), 0.77-0.59 (m, 3H), 0.41-0.32 (m, 1H); MS (ES+) m/z 408.1 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O.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:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
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: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME, (100 mL) under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol %). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59–1.93 (m, 1OH), 6.18 (m, 1H), 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:10][C@H:2]1[C@H:3]2[O:8][CH2:7][C@@H:6]([OH:9])[C@H:4]2[O:5][CH2:1]1)[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:18]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C=CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4:3,6-dianhydro-D-mannitol (4.00 g, 27.4 mmol) and Cs2CO3 (20.0 g, 60.2 mmol) in DMF (60 ml), 6-bromo-1-hexene (5.5 ml, 41.1 mmol), was added; the mixture was stirred at room temperature for 18 hrs. Then it was diluted with EtOAc and washed with a 5% solution of sodium dihydrogen phosphate (2×40 ml) and water (2×40 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 85.5 %

Procedure:
A solution of methyl 3-amino-2-thiophenecarboxylate (400 mg, 2.54 mmol) and pyridine (0.226 mL, 2.80 mmol) in methylene chloride (12 mL) was treated with 4-tert-butylbenzoyl chloride (0.500 mL, 2.54 mmol). After consumption of the starting material, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and water. The organic layer was washed once with water, once with saturated sodium chloride solution, dried (magnesium sulfate), and filtered. Concentration and purification of the residue by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 689 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:40])[NH:1][C@@H:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH:5]=2)[CH3:3])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(C#C[Si](C)(C)C)c1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#C[Si](C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38.5 %

Procedure:
(R)—N-[4-(1-Amino-ethyl)-2-trimethylsilanylethynylphenyl]methanesulfonamide (75.0 mg, 0.242 mmol, 1 eq.) and Triethylamine (67.5 μl, 0.484 mmol, 2 eq.) were dissolved in methylene chloride. The mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (47.2 μl, 0.266 mmol, 1.1 eq.) was added into the reaction mixture. The reaction mixture was stirred for 40 min. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (45.3 mg, 39%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].Cl.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>O1CCCC1>[OH:11][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:10])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccccc1C(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccccc1OC
Reaction time: 4 h
Yield: 96 %

Procedure:
Under argon atmosphere, 20 mL (10.7 mmol, 2 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.74 mL (5.35 mmol) of o-methoxyacetophenone in 2.75 mL of THF at 7˜10° C. The mixture was stirred at to 4˜6° C. for 4 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.43 g of the desired product (NMR yield 96%; internal standard dioxane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.[OH-].[K+]>C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)=[CH:8][CH:7]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Oc1ccc(-c2ccco2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(-c3ccco3)cc2)on1

Procedure:
5-{5-[4-(2-Furanyl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =H, Het=2-furanyl] was prepared from 3.6 g 4-(2-furanyl)phenol (m.p. 128-129° C., King and Walton, Synthesis 1976, p. 40), 5.4 g 5-(5-bromopentyl)-3-methylisoxazole and 1.5 g potassium hydroxide in acetonitrile according to the procedure of Example 1, part (c), and was obtained (4.2 g) as a light-tan solid, m.p. 86-88° C. when recrystallized from isopropyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)C.[OH-].[Na+].O>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:5]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: OC[C@H](O)CCl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (47 mg, 0.125 mmol) in ethanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (90 μL) and the mixture is stirred at 60° C. for 20 h. Another portion of (S)-3-chloro-propane-1,2-diol (60 μL) is added and stirring is continued at 60° C. for 5 days. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-propan-1-one (6 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.25; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.30-7.21 (m, 4H), 6.88 (s, 2H), 4.11-4.05 (m, 1H), 3.87-3.80 (m, 4H), 3.18-3.11 (m, 2H), 2.98-2.85 (m, 4H), 2.39 (s, 3H), 2.25 (s, 6H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:35][CH2:36][CH2:37]Br>CN(C=O)C>[Br:35][CH2:36][CH2:37][O:21][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:4]=1)=[O:22]
Reactant: BrCCBr
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Temperature: 50 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (1.00 g, 2.40 mmol) was dissolved in DMF (20 ml). Cesium carbonate (1.56 g, 4.8 mmol) and 1,2-dibromoethane (0.83 ml, 9.6 mmol) were added, and the reaction was stirred at 50° C. for 18 hours. The reaction was quenched with water, basified with 10% aqueous NaOH, and extracted with ethyl acetate twice. The ethyl extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil which was purified by chromatography (25% hexanes in ethyl acetate) to yield 490 mg of 3-(2-bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a yellow solid. 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (100 mg, 0.19 mmol) was dissolved in DMF (2.0 ml), and potassium carbonate (32 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (38 mg, 0.21 mmol) were added. The reaction was stirred for 18 hours at room temperature, quenched in water, and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil. The oil was dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction was evaporated to dryness, and the crude solid was purified on reverse phase HPLC to yield 63 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide as a white solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide (30 mg, 0.047 mmol) was dissolved in dichloromethane (1.5 ml) and THF (1.0 ml). N-ethyl-N-isopropylpropan-2-amine (18 μl, 0.10 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added, and the reaction stirred at room temperature for 72 hours. Additional N-ethyl-N-isopropylpropan-2-amine (9 μl, 0.051 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added and the reaction stirred for 2 hours. After a further addition of methanesulfonyl chloride (4 μl, 0.051 mmol), the reaction was stirred for 2 hours and evaporated to a crude solid which was purified on reverse phase HPLC to yield 8 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 607 (M)+.