Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][O:12][C:11](=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.N1C=CC=CC=1.[CH3:37][C:38](OC(C)=O)=[O:39].[NH4+].[Cl-]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[C:38]([O:14][CH:11]1[CH2:10][CH:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:12]1)(=[O:39])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC(OCc2ccccc2)CO1
Agent: CC(C)C[AlH]CC(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CC(OCc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a stirred solution of 4-(benzyloxy)dihydrofuran-2(3H)-one (3.15 g, 16.39 mmol) in CH2Cl2 (100 mL) was added, dropwise, 1M DIBAL-H/toluene (2.56 g, 18.03 mmol) over 10 min at −78° C. After 2 h, pyridine (3.98 mL, 49.2 mmol), solid 4-(dimethylamino)pyridine (DMAP) (2.202 g, 18.03 mmol) and Ac2O (6.19 mL, 65.6 mmol) were added and the solution was stirred for 6 h at −78° C. and slowly warmed to room temperature overnight (15 h). The resulting orange reaction mixture was stirred with sat. NH4Cl (50 mL) for 30 min. The organic layer was separated and washed with 1N aq. NaHSO4 (3×50 mL). The combined aq. layers were extracted with CH2Cl2 (2×50 mL) and the combined CH2Cl2 layers washed with 1N aq. NaHSO4 (50 mL), sat. NaHCO3 (50 mL) followed by brine (50 mL), then dried (Na2SO4), filtered and concentrated to afford a yellow oil. Flash column chromatography on a silica gel column using 15-30% ethyl acetate/hexane provided 4-(benzyloxy)tetrahydrofuran-2-yl acetate (3.5769 g, 15.14 mmol, 92% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ: 7.26-7.39 (5 H, m), 6.41 (0.3 H, dd, J=5.7, 2.0 Hz), 6.24-6.30 (0.7 H, dd, J=4.9, 1.8 Hz), 4.46-4.58 (2 H, m), 4.32-4.37 (0.3 H, m), 4.22-4.28 (0.7 H, m), 4.00-4.10 (2 H, m), 2.15-2.38 (2 H, m), 2.07 (3 H, s). LCMS (M-C2H30) calcd for C13H16O4: 177.09; found: 177.0.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to at a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. And the above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and then pyrrolidine (7.8 ml) is added thereto within 15 min at the temperature, the above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.3 g). The yield is about 75.6%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCN2CCCCC2)cc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, piperidine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a graded solvent mixture of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=329.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([Cl:19])[CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.N.C(#[N:23])C>O>[NH2:23][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([Cl:19])[CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: CC#N
Agent: N
Solvent: O
Product: Nc1nc(-c2ccccc2)c2cc(Cl)cc(Cl)c2n1

Procedure:
A mixture of 300 mg of 2,6,8-trichloro-4-phenylquinazoline (compound No. II-5), 30 g of an aqueous 28% ammonia solution and 6 ml of acetonitrile was reacted in a pressure-resistant reaction vessel at 105° C. for 1.5 hours. The resulting reaction solution was cooled and then poured into 100 ml of water. The mixture was extracted with 60 ml of ethyl acetate and the resultant extract was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform) to obtain 230 mg of the titled compound. Mp. 212.7° C. 1H NMR (CDCl3): 5.56 (2H, br. s), 7.54-7.60 (3H, m), 7.63-7.68 (2H, m), 7.74 (1H, d, J=2.3 Hz), 7.79 (1H, d, J=2.3 Hz).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH2:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH:19][S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)(=[O:39])=[O:38])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)quinolin-8-amine (0.10 g, 0.347 mmol) in CH2Cl2 (10 mL) was added DIPEA (0.120 mL, 0.695 mmol) followed by pyridine-2-sulfonyl chloride (0.065 g, 0.366 mmol). The mixture was stirred at room temperature for 18 hours. An aqueous solution of saturated NaHCO3 was added (30 mL), the resulting precipitate was collected by filtration and washed with methanol to obtain N-(2-(3-(trifluoromethyl)phenyl)quinolin-8-yl)pyridine-2-sulfonamide (0.025 g, 17% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=[N:24]O)[CH2:18][C@@:17]2([CH3:26])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].O>C(O)CC>[NH2:24][C@@H:19]1[CH2:18][C@@:17]2([CH3:26])[C@@H:11]([CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[C@H:10]2[C@H:20]1[C@:21]1([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[CH2:6][C@H:5]([OH:27])[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:22]1
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Solvent: CCCO
Solvent: O
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
A refluxing solution (under nitrogen) of (Z)-2β-ethoxy-3α-hydroxy-5α-pregn-17(20)-en-11-one 11-oxime (450 mg) in propan-1-ol (15 ml) was treated with pieces of Na (450 mg). When there was no trace of Na left the mixture was added to chilled water to give a fine precipitate which was collected by filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCN1
Reactant: Brc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1cccc(Br)c1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
To a stirring solution of 1,3-dibromobenzene (3 g, 12.72 mmol) in 1,4-dioxane (100 mL) was added 2-pyrrolidinone (0.975 mL, 12.72 mmol), palladium(II) acetate (0.143 g, 0.636 mmol), xantphos (0.736 g, 1.272 mmol) and cesium carbonate (8.29 g, 25.4 mmol). The mixture was then heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL). The organic phase was collected, and the aqueous phase further extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over MgSO4, filtered and removed solvent under vacuo. The residue was purified on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to give the title compound (2.06 g). LCMS (A): m/z (M+H)+ 240/242, C10H10BrNO requires 239/241 (acidic).
Reaction SMILES: C([NH2:5])(C)(C)C.C(O)C.[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10].[OH2:16]>>[OH:16][NH-:5].[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10]
Reactant: O
Reactant: CC(C)(C)N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: [NH-]O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of compound 25.4 (0.027 g), ethanol (1.5 mL), TFA (0.6 mL) and water (0.5 mL) was stirred at 60° C. for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC to afford compound 25.6 as a TFA salt (0.014 g, 51%). 1H NMR (CD3OD): δ 1.4 (t, J=8 Hz, 6H), 2.9 (M, 4H), 3.2 (m, 2H), 3.58 (brs, 2H), 3.65 (m, 2H), 4.25 (m, 4H), 4.42 (d, J=10 Hz, 2H), 4.85 (m, 2H), 6.75 (d, J=9 Hz, 2H), 6.9 (m, 4H), 7.0 (d, J=9 Hz, 2H), 7.4-7.6 (m, 6H), 8.1 (brs, 2H). 31P NMR (CD3OD): δ 20.8. MS: 769 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH:11]([C:14]1([CH3:24])[CH2:23][CH2:22][C:17]2(OCC[O:18]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH2:1]([O:8][C:9](=[O:25])[NH:10][CH:11]([C:14]1([CH3:24])[CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]1)[CH2:12][CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(C)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.50 g of [1-(8-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-propyl]-carbamic acid benzyl ester (77) were dissolved in 15 mL of a 2:1 mixture of acetone and 6N aqueous hydrochloric acid. The reaction mixture was stirred for 16 h at room temperature, then dropped into 150 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane (100 mL each), the combined organic phases were dried over magnesium sulphate, filtered and concentrated to give the ketone 78, which was used directly in the next step. Rt=0.59 min (Method P). Detected mass: 304.2 (M+H+).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:4][CH:3]=[CH:2][C:1]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C(=O)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C=CCBr)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of benzyl crotonate (4.0 g, 22.73 mmol) in anhydrous carbon tetrachloride (20 ml) was added N-bromosuccinimide (4.045 g, 22.7 mmol). The resulting suspension was refluxed at 100° C. under nitrogen for 20 minutes. After cooling to room temperature, the solid was removed by filtration. The filtrate was evaporated under reduced pressure to dryness. The oily residue was separated on a flash column (silica, F 4×40 cm), packed with hexane. The column was eluted with 4 liters of 4% ethyl acetate. The desired product was obtained as an oil (510 mg, 9% yield). Rf: 0.4 (10% ether/hexane) 1H NMR (CDCl3): δppm 3.99 (2H, dd, J1=7.4 Hz, J2=1.3 Hz), 5.19 (2H, s), 6.07 (1H, dt, J1=15.3 Hz, J2=1.1 Hz), 7.04 (1H, m), 7.36 (5H, m). 13C NMR (CDCl3): δppm 29.0 (t), 66.5 (t), 124.2 (d), 128.2 (d), 128.3 (d), 128.5 (d), 135.8 (s), 142.2 (d), 165.2 (s).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[C:20]([O:14][CH:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:10]([F:12])([F:13])[F:11])[N:21]=[C:16]([NH2:15])[N:17]=1
Reactant: OC(C1CCCCC1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(C2CCCCC2)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65.2 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to the solution of 1-cyclohexyl-2,2,2-trifluoro-ethanol (182 mg, 1 mmol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 202 mg of 4-chloro-6-[1-cyclohexyl-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 65%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:13]([OH:15])=[O:14].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1=C(F)c2ccc(O)cc2CC1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1=C(F)c2ccc(OCc3ccccc3)cc2CC1

Procedure:
That is, for example, 3,4-dihydro-1-fluoro-6-hydroxy-2-naphthalenecarboxylic acid (i) is reacted with benzyl bromide in the presence of a base such as potassium hydroxide, to obtain 3,4-dihydro-1-fluoro-6-benzyloxy-2-naphthalenecarboxylic acid (ii).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[S:6].[CH3:7]OS(=O)(=O)OC.[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[Na+]>>[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[CH3:7][S:6][C:2]1[S:3][CH:4]=[CH:5][S+:1]=1
Reactant: S=c1sccs1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CSc1scc[s+]1
Reaction time: 0.5 h

Procedure:
A mixture comprising 26.8g (0.2 mole) of 1,3-dithiol-2-thion and 25.2g (0.2 mole) of dimethylsulfuric acid was reacted at 60° C for 30 minutes and then at 90° C for 30 minutes. After cooling, the reaction product was poured into 150 ml of a saturated aqueous sodium perchlorate solution to deposit crystals. The crystals were recovered by filtration, washed with ether, dried and then recrystallized from methanol to obtain 42.5g of yellow crystals, m.p. 42°-46° C, yield 85.8%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]4[CH3:18])[C:5]4[CH2:11][S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CSCC2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CSCC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (100 mg, 0.35 mmol) in DME/H2O (4:1, 10 mL) was added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (116 mg, 0.38 mmol) and Na2CO3 (111 mg, 1.05 mmol) followed by PdCl2(dppf) (15 mg, 0.02 mmol). The resulting mixture was stirred overnight at 70° C. under nitrogen. The solvent was removed under vacuum to give a residue which was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 filtered and evaporated to give the crude product which was purified by preparative TLC (DCM/MeOH=20/1) to give the desired product as a yellow solid (40 mg, 27%).
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][O:7][C:8](=[O:24])[C:9]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:14])[C:10]([O:12]C)=[O:11]>C(O)(C)C>[CH3:6][O:7][C:8](=[O:24])[C:9]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(COc1ccc(Cl)cc1)C(=O)OC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Product: COC(=O)C(C)(COc1ccc(Cl)cc1)C(=O)O
Reaction time: 17 h

Procedure:
300 ml Phosphate buffer are heated to 30° C. and 124 mg of pig liver esterase are added and left for 15 minutes 3 g of 2-(4-chlor-phenoxy-methyl)-2-methyl-malonic acid dimethyl ester in 10 ml of isopropanol the mixture is stirred at +30° C. for 17 hours. The reaction mixture is extracted with ethylacetate to remove neutral organic matter, the remaining solution acidified to pH 2 with 2N hydrogenchlorid and extracted again with ethylacetate. The organic extract is dried over sodium sulfate, the solvent evaporated and the residue chromatographed (RP-18 column, eluant: acetonitril/water 1:1). Yield 1.73 g, M.p. 93° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]=[CH:5][C:4]1=[O:65])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:52]([CH3:54])[CH3:53])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH2:6][CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone in toluene containing a catalytic amount of acetic acid is treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0). After 5 minutes, 1.1 equivalents of tri-n-butyltin hydride is added and the reaction is stirred at RT until the proton NMR of an aliquot indicates that the reaction is complete. After quenching the reaction mixture with water and extraction with ether, the ether extracts are washed with brine and dried over magnesium sulfate. Chromatography of the residue over SiO2 yields 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. Alternatively, the enone can be reduced by dissolving this material (350 mg) and 15 mg of 5% Rh/C in 10 ml of ethanol or ethyl acetate and stirring under a hydrogen atmosphere. When the reaction is complete (tlc and/or 1H NMR), the mixture is filtered through diatomaceous earth, concentrated and the residue subjected to flash chromatography (75% CH2Cl2 : 5% MeOH: 20% n-hexane) to give 294 mg of the titled compound.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:8][CH:9]=3)[N:17]=2)=[CH:33][CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N/C(=N\O)c1ccc(Oc2ccccn2)cc1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccccn5)cc4)no3)cc2)cc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
(Z)-N′-Hydroxy-4-(pyridin-2-yloxy)benzamidine (339 mg, 137 μmol) and 4-benzyloxybenzoyl chloride (24 mg, 106 μmol) were suspended in pyridine (2.0 mL) the solution was refluxed for 21 hours. The reaction mixture was then cooled to room temperature and solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (Hex/EtOAc 2:1) to give the product as a white solid (20 mg, 46%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.16 (2H, s), 6.99 (1H, d, J=8.2 Hz), 7.05 (1H, ddd, J=7.2, 5.0, 0.80 Hz), 7.11 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.34-7.38 (1H, m), 7.40-7.46 (4H, m), 7.73 (1H, ddd, J=8.8, 8.2, 2.0 Hz), 8.16 (2H, d, J=9.0 Hz), 8.20 (2H, d, J=8.6 Hz), 8.24 (1H, dd, J=5.0, 2.0Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 70.4 (CH2), 112.3 (CH), 115.5 (CH), 117.3, 119.3 (CH), 121.4 (CH), 123.5, 127.7 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 130.3 (CH), 136.2, 139.9 (CH), 148.0 (CH), 156.8, 162.5, 163.3, 168.5, 175.7. MS (FAB+): 422 (MH+). HRMS for C26H19N3O3 (MH+): calculated: 422.1505; found 422.1505.