Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1S(Cl)(=O)=O.CN1C=CN=C1.[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:45])[C@H:25]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:26]([OH:36])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:45])[C@H:25]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:26]([O:36][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CON=C[C@@H](F)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Agent: Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON=C[C@@H](F)[C@H](OCc1ccccc1)[C@@H](COCc1ccccc1)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 92 %

Procedure:
1.26 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.430 mL of 1-methylimidazole were added to a solution of 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime in 10.4 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 14.5 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. A solid was removed by filtration, and the organic layer was then fractionated. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[C:28]([C:34]([NH:36][CH3:37])=[O:35])=[N:29][C:30](Br)=[CH:31][N:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:36][CH3:37])=[O:35])=[N:29][C:30]([C:15]2[CH:14]=[N:13][CH:12]=[C:11]([C:9]([NH:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:10])[CH:16]=2)=[CH:31][N:32]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: CC1(C)OB(c2cncc(C(=O)NCc3ccccc3)c2)OC1(C)C
Product: CNC(=O)c1nc(-c2cncc(C(=O)NCc3ccccc3)c2)cnc1N
Yield: 38 %

Procedure:
3-amino-N-methyl-6-(5-{[(phenylmethyl)amino]carbonyl}pyridin-3-yl)pyrazine-2-carboxamide was synthesized according to the procedure described above from N-(phenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxamide and 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide. Yield 38%. 1H NMR (400 MHz, d6-DMSO): 9.58 (d, 1H), 9.36 (t, 1H), 9.02 (m, 3H), 8.86 (t, 1H), 7.34 (m, 4H), 7.24 (m, 1H), 4.50 (d, 2H), 2.83 (d, 3H); MS (EI) for C19H18N6O2: 363 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(CBr)c1
Reaction time: 48 h

Procedure:
a solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14](Cl)[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO.O>[CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14]([O:20][CH3:19])[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1ccn2nc(SCc3ccccc3)nc2n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccn2nc(SCc3ccccc3)nc2n1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of 6.0 g (22 mmol) of 2-benzylthio-5-chloro-1,2,4-triazolo[1,5-a]pyrimidine in 25 ml of methanol was treated with 5.0 g (23.8 mmol) of a 25% solution of sodium methoxide in methanol. After stirring for 1.5 hours the reaction mixture was diluted with 100 ml of water and neutralized with 3N HCL (aq). The solid which separated was collected by filtration, washed with water and dried to afford 5.0 g (84%) of the desired product as a white solid, m.p. 126°-128° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added 2,4-thiazolidinedione (22 mg, 0.184 mmol) and piperidine (18 μL, 0.184 mmol). The mixture was heated in microwave for 20 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=372)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16](=[O:18])[NH2:17])[NH:8][CH2:7][CH2:6]2.[O-:19][CH2:20]C.[Na+].C(=O)(OCC)OCC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:18])[NH:17][C:20](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: CC[O-]
Reactant: COc1cc2c(cc1OC)C(=CC(N)=O)NCC2
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2

Procedure:
A solution of 6,7-dimethoxy-1-carbamoylmethylene-1,2,3,4-tetrahydroisoquinoline (5.0 g) and an excess of sodium ethoxide (prepared from 12.0 g of sodium metal and 600 ml of ethanol) in ethanol is heated. 150.0 ml of diethyl carbonate is added to the solution. The reaction mixture is refluxed for an additional 2.5 hr. The solvent is removed under vacuum and the residue is acidified to give a white precipitate, yield 4.80 g. The product crystallizes from dimethylformamide, mp. 323°-325° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (57.5 mg), 5-chloro-2-hydroxybenzophenone (309 mg), and 4-dimethylaminopyridine (173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 5 hr. The mixture was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 114 mg of the title compound.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH:9](Br)Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13]1(=[O:20])[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1.[I-].[Na+]>CN(C=O)C>[CH:5]1[C:4]2[C:3](=[CH:2][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:9]=2)=[CH:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=4)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: BrC(Br)c1ccccc1C(Br)Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a clear solution of α,α,α′,α′-tetrabromo-o-xylene (30.5 g, 0.073 mol) in DMF (100 mL) was added benzoquinone (3.125 g, 0.03 mol) and sodium iodide (27.25 g, 0.18 mol). The resulting brown suspension was heated and stirred at 120° C. overnight. After cooling to RT, the yellow solids were filtered via vacuum filtration. The yellow solids were washed with water, saturated sodium bisulfite solution and dried to yield the product (8.1 g, 91%). 1H NMR (500 MHz, CDCl3): δ 8.96 (s, 4H), 8.14 (m, 4H), 7.72 (m, 4H). 13C NMR (125.68 MHz, CDCl3): δ 183.2, 135.47, 130.80, 130.30, 129.98, 129.66. m/z: 308 [M+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH:27]1[CH2:29][CH2:28]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(F)nc2c1nc(Cc1cc3c(cc1I)OCO3)n2CCCNS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (100 mg, 0.21 mmol) in DMF (3 mL) was added cyclopropanesulfonyl chloride (89 mg, 0.32 mmol) and triethylamine (90 uL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS72 as a white solid (82 mg, 67%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.32 (s, 1H), 6.79 (s, 1H), 6.02 (s, 2H), 4.27 (s, 2H), 4.22 (t, J=7.3 Hz, 2H), 3.18 (t, J=6.4 Hz, 2H), 2.45-2.50 (m, 1H), 2.00-2.06 (m, 2H), 1.12-1.17 (m, 2H), 0.99-1.04 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 159.0 (d, J=209.8 Hz), 156.9 (d, J=19.7 Hz), 152.4 (d, J=18.5 Hz), 151.2 (d, J=2.3 Hz), 149.3, 148.4, 131.4, 119.0, 116.3 (d, J=3.6 Hz), 110.4, 102.4, 88.7, 40.7, 40.1, 39.3, 30.2, 29.9, 5.3; HRMS (ESI) m/z [M+H]+ calcd, for C19H21FIN6O4S, 575.0374. found 575.0390.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1>CCOC(C)=O>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([O:15][CH3:5])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)cc(I)c1O
Reactant: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(I)c1O

Procedure:
Thionyl chloride (30 mL, 411 mmol) is added dropwise to methanol (100 mL) in an ice bath. The addition is controlled to hold the temperature at 25° C. Upon completion of the addition 6 (25 g, 84 mmol) is added and the reaction heated to reflux for 4 hours. The solids dissolve at first then after 2 hours solids start to come out of solution. After 4 hours TLC (hex:EtOAc; 9:1) shows no starting material. The reaction is cooled in the refrigerator for 12h. The solids formed are filtered washed with water (30 mL), and dried under vacuum at 27° C. to yield methyl 5-chloro-3-iodosalicylate as an off white solid. (mp 143°-145° C.)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[CH:14]([S:16]([NH2:19])(=[O:18])=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:14]1([S:16]([NH2:19])(=[O:17])=[O:18])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:26]
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccccc21
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a stirred, 15° C. suspension of sodium hydride (60% in mineral oil, 500 mg, 12.2 mmoL, 1 eq) in 50 mL of dry dimethylformamide (from molecular sieves) under nitrogen was added dropwise over 15 minutes a solution of (8) (3 g, 12.2 mmoL) in 100 mL of dimethylformamide. A solution of ethyl bromoacetate (2.0 g, 12.2 mmoL, 1 eq) in 20 mL of dimethylformamide was then added dropwise over 10 minutes. After 3 h at room temperature, the reaction was diluted with water (100 mL), acidified (pH 5) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (5×100 mL), dried (MgSO4), filtered and evaporated. The crude oil was purified by chromatography on silica gel using a gradient of 10%-30% ethyl acetate in hexane to provide 1 g (25%) of product: mp 167°-170° C., 1H NMR (CDCl3) 7.8-7.2 (m, 8H, aromatic protons), 3.9 (broad single, 2H), 3.6 (s, 2H), 3.5 (q, 2H), 1.7 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:27].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[N:12][C:11]=2[C:22]([NH2:27])=[O:24])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1 g) in methylene chloride (10 ml) was added ammonia-methanol solution (60 ml) which was prepared by bubbling an ammonia gas (14 g) into methanol (120 ml), and the mixture was stirred for 24 hours at ambient temperature. After evaporating the solvent, the residue was recrystallized from methanol to give 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxamide (0.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH2:27][OH:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([CH:27]=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step C (1.2 g, 2.4 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.03 g, 4.8 mmol) in portion at room temperature. After stirring for 0.5 h, the mixture was diluted with water (15 mL), extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/PE=1:8) to afford the title compound. LC/MS m/z=499.2[M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.C1(=O)O[CH2:25][CH2:24][O:23]1>CN(C)C=O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][OH:23])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
83 g (0.6 mole) of potassium carbonate were added to a solution of 262 g (1.2 moles) of 7-chlorodibenzofuran-3-ol in 600 ml of dry dimethylformamide, and a solution of 212 g (2.55 moles) of ethylene carbonate in 300 ml of dimethylformamide was then added dropwise in the course of 90 minutes at 100° C. The mixture was stirred for 8 hours at 120° C. and was then filtered under suction at 100° C., and the filtrate was evaporated down. The residue was dissolved in 2.5 liters of ethyl acetate, the solution was washed with three times 300 ml of water, the organic layer was dried, decolorized with 10 g of animal charcoal and evaporated down to 500 ml, and the residue was cooled to 10° C. The precipitate was filtered off under suction, washed with 60 ml of methanol, 50 ml of ether and 200 ml of petroleum ether in succession at +5° C., and dried. 225 g (71.4% of theory) of 2-(7-chlorodibenzofuran-3-yloxy)-ethanol of melting point 118°-120° C. were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8]O)=[CH:6][N:5]=[CH:4]1)[CH3:2].BrP(Br)Br.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([N:3]1[C:7]([CH2:8][S:21][C:19]2[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cncc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 12 %

Procedure:
To a solution of (1-ethyl-1H-imidazol-5-yl)methanol (631 mg, 5.0 mmol) in dichloromethane (20 mL) was added dropwise tribromophosphane (0.94 mL, 10.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. After evaporation, the crude 5-(bromomethyl)-1-ethyl-1H-imidazole was dissolved in cold ethanol (30 mL), and 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 5 mmol) and triethylamine (2.8 mL, 20 mmol) were added. After 2 hours, the solvent was evaporated, and the residue was purified by chromatography (4% methanol in dichloromethane) to provide a white solid (150 mg, 12% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 2.22 (s, 3H), 4.02 (q, 2H), 4.46 (s, 2H), 6.03 (br, 1H), 6.88 (s, 1H), 7.64 (s, 1H); M+ 251.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (260 mg, 0.77 mmol) in chloroform (7 ml) was added triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride (158 mg, 0.92 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) of the product as a solid. HR-MS: m/z Calculated for C25H27NO7S 486.1581; Found 486.1576.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33][CH2:32]1
Reactant: OB(O)C1CCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CCC2)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:61]([O:68][CH2:69][CH2:70][CH2:71][CH2:72]O)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:72][CH2:71][CH2:70][CH2:69][O:68][Si:61]([C:64]([CH3:65])([CH3:67])[CH3:66])([CH3:62])[CH3:63])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.6 g, 1.01 mmol), triphenyl phosphine (0.4 g, 1.52 mmol), and 4-{[tert-butyl(dimethyl)silyl]oxy}-1-butanol (0.31 g, 1.52 mmol, J. Org. Chemn. 1986, 51, 3388-3390) in anhydrous dichloromethane (9 mL) at 0° C. under nitrogen atmosphere was slowly added a solution of diisopropyl azodicarboxylate (0.29 mL, 0.3 g, 1.52 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature for 2 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 1:1) to provide the title compound as a solid foam (0.39 g). 1H NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 0.80 (3H, d), 0.82 (9H, s), 1.22 (1H, dd), 1.4 (1H, quintuplet), 1.55 (2H, quintuplet), 1.7 (2H, quintuplet), 1.8-1.9 (1H, m), 2.35 (1H, t), 2.65-2.80 (3H, m), 2.9 (1H, d), 3.0 (1H, dd), 3.2-3.3 (2H, m), 3.4-3.5 (1H, m), 3.52-3.62 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.18 (2H, s), 6.77 (2H, d), 7.0-7.1 (3H, m), 7.19 (1H, d), 7.21 (1H, s), 7.3 (1H, d); MS: 801 (M+23); C38H58N2O11SSi.