Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CN=C1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([CH3:12])([O:14][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH3:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(O)c1cccc2c(I)n[nH]c12
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(O[Si](C)(C)C)c1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
In a round-bottomed flask, 2-(3-iodo-1H-indazol-7-yl)-propan-2-ol (crude from Step 2, 479 mg, 1.11 mmol) was dissolved in DMF (3.2 ml) and imidazole (189 mg, 2.77 mmol) and trimethylsilyl chloride (0.17 ml, 1.33 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 383 mg (88%) of 3-iodo-7-(1-methyl-1-trimethylsilanyloxy-ethyl)-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.86 (br. s., 1H), 7.40 (dd, J=6.8, 2.3 Hz, 1H), 7.12-7.21 (m, 2H), 1.73 (s, 6H), 0.11 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Mg].[CH2:13]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[C:25](=O)[CH2:26][CH2:27][CH2:28][CH:29]=2)[CH2:20][CH2:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].Cl.C([O:34]CC)C>>[CH2:13]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH2:25][CH2:26][C:27]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][CH:5]=3)([OH:34])[CH2:28][CH:29]=2)[CH2:20][CH2:19]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
A solution of 6.9 g of 4-trifluoromethylbromobenzene in 30 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-(4-trifluoromethylphenyl)-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: [OH-].[Na+].O.C[O:5][C:6](=[O:40])[CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[S:11][CH:12]=1.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[N:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)OC)cs2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)O)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.5 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.02 mL) with water (0.06 mL) was added to a solution of [2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (Example 63-(2); 15.9 mg, 0.0297 mmol) in methanol (0.4 mL) at room temperature, and the mixture was stirred at room temperature for 5.5 hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (15 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][Cl:21])[CH:15]=1>C1COCC1.CN(C=O)C>[ClH:21].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:7]2[C:2](=[O:1])[C:3]3=[N+:10]([O-:11])[O:9][N:8]=[C:4]3[N:5]=[CH:6]2)[CH:15]=1
Reactant: ClCc1cccnc1
Reactant: [O-][n+]1onc2ncnc(O)c21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: O=c1c2c(ncn1Cc1cccnc1)no[n+]2[O-]
Temperature: 60 °C
Yield: 10.8 %

Procedure:
5.0 g (33 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide and 0.3 g (38 mmol) of lithium hydride are heated at 50° C. for 30 min in 70 ml of THF. After addition of a solution of 5.9 g (46 mmol) of 3-picolyl chloride in 30 ml of DMF, the mixture is heated at 60° C. for 2 h. The solvents are stripped off completely in a rotary evaporator, and the residue is digested several times with THF. The product is precipitated from the combined THF extracts by addition of ethereal hydrochloric acid and recrystallised from methanol. 1 g of 6-(3-picolyl)-[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide hydrochloride is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1SC.C([O-])(O)=O.[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[O-:25][S:26]([O-:29])(=S)=O.[Na+].[Na+].[C:32]([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:26]([CH3:32])(=[O:29])=[O:25]
Reactant: CSc1nncn1C
Reactant: O=S([O-])([O-])=S
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cnnc1S(C)(=O)=O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 4-methyl-3-(methylsulfanyl)-4H-1,2,4-triazole (31 g, 239.96 mmol, 1 eq.) in 1000 ml of DCM cooled to 0° C. was added NaHCO3 (42.33 g, 503.92 mmol, 2.1 eq.) followed by m-CPBA (70%, 118.31 g, 479.92 mmol, 2.0 eq.) portion wise. The reaction was warmed to r.t. and stirred. A sat. aqueous 1/1 Na2S2O3/Na2CO3 solution was added slowly and the mixture stirred 15 min. The layers were separated and the organics were washed with H2O, dried over MgSO4 and concentrated. The crude was triturated in IPE and filtered to give 4-methyl-3-(methylsulfonyI)-4H-1,2,4-triazole (9.35 g, 59% yield) as yellow solid.
Reaction SMILES: [H-].[Li+].[CH3:3][C:4]([CH3:19])([CH3:18])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:20][C:21]([CH3:34])([CH3:33])[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[CH3:3][C:4]([CH3:19])([CH3:18])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([N:13]([O:14][CH3:15])[C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22](=[O:23])[C:21]([CH3:20])([CH3:33])[CH3:34])=[CH:32][CH:31]=2)=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CONC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CON(C(=O)c1ccc(C(=O)C(C)(C)C)cc1)C(=O)c1ccc(C(=O)C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.64 grams(80 mmol) of lithium hydride in 150 ml of toluene, 9.4 grams (40 mmol) of solid 4- (2,2-dimethyl-1-oxopropyl)-N-methoxybenzamide is added portion-wise at room temperature and stirred for 1 1/2 hours. To this suspension, 9.93 grams (44.2 mmol) of 4- (2,2-dimethyl-1-oxopropyl)-benzoyl chloride dissolved in 50 ml of toluene is added at room temperature. The reaction mixture is stirred for 60 hours and then heated at 65°-70° C. for 22 hours. The mixture is poured into 250 ml. of cold pH7 phosphate buffer under nitrogen and the aqueous phase is then separated and extracted twice with t-butyl methyl ether. The organic layers are washed with dilute sodium bicarbonate solution and after drying over magnesium sulfate, the organic phase is evaporated to dryness. The crude product is crystallized from t-butyl methyl ether/heptane and then recrystallized 3 times from toluene/heptane. After each recrystallization, the nugget-like crystals, enriched in the desired product, are physically separated from the powdery crystals to yield the title compound (m.p. 103°-105 ° C. ).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.[C:39](OC)(=[O:43])[C:40]([CH3:42])=[CH2:41].C1(C=CC(O)=CC=1)O>>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:39](=[O:43])[C@H:40]([CH3:42])[CH2:41][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:39](=[O:43])[C@@H:40]([CH3:42])[CH2:41][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(C)C(=O)OC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Agent: Oc1ccc(O)cc1
Product: C[C@@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Product: C[C@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Temperature: 90 °C
Yield: 149.3 %

Procedure:
A mixture of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.85 g, 3.09 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, and methyl methacrylate (3.72 g, 37.15 mmol) stabilized with hydroquinone was heated at 90° C. for 14 hrs. The reaction mixture was concentrated and loaded onto a silica gel column, eluted with 2-6% isopropanol/methylene chloride to afford (2S,6R)-2-(4-cyclohexyl-phenoxymethyl)-6-methyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one and (2S,6S)-2-(4-cyclohexyl-phenoxymethyl)-6-methyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one (total 0.79 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]([F:16])([F:15])[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.Cl>ClCCl.O>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:14][NH:13][C:11](=[O:12])[C:10]([F:15])([F:16])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:23])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[O:37])=[CH:34][CH:33]=1
Reactant: NNC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NNC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F)c1ccc(F)cc1
Yield: 55.4 %

Procedure:
In 7 ml of dichloromethane was suspended 0.33 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide. To the suspension was added 0.12 g of triethylamine. Thereto was dropwise added 0.19 g of 4-fluorobenzoyl chloride at 5°-10° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of dichloromethane and 10 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.25 g of N'-(4-fluorobenzoyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrohydrazide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C@H:23]1[C@@H:27]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[CH2:26][NH:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][C@H:27]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[C@H:23]([NH2:22])[CH2:24]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: N[C@@H]1CNC[C@@H]1n1ccnn1
Product: Nc1c(F)c(N2C[C@@H](N)[C@@H](n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 65 %

Procedure:
Prepared by following the same procedure as described for Example 17 by using 5-amino-1-cyclopropyl -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and cis-3-amino-4-(1,2,3-triazol-1-yl)pyrrolidine. Yield: 65%, m.p. 275°-277° C. 1H NMR (TFA) δ: 1.33-1.50 (m, 4H), 4.32-5.12 (m, 6H), 6.34 (m, 1H), 8.64 (s, 1H), 8.89 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CCN(CC)CC.Br[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:21][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (10.0 g, 61.30 mmol) in DMF (40 mL) at RT was added NEt3 (9.40 mL, 67.43 mmol) and, in a dropwise fashion, (bromomethyl)cyclohexane (9.41 mL, 67.43 mmol). The reaction was then stirred for 15 hours at 50° C., after which it was allowed to cool to RT and then concentrated under vacuum. The residue was dissolved in Et2O (100 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1 to 3:1) to afford N-(cyclohexylmethoxy)phthalimide (8.40 g, 53%), as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[C-:32]#[N:33].C([Al+]CC)C>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2([C:32]#[N:33])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:10][C@@H:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CNCCN1Cc1ccccc1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.9 %

Procedure:
In a 5 L flask, (2S)-1-benzyl-2-methylpiperazine (260.0 g, 1.366 mol), dichloromethane (1000 mL), t-butyl 4-oxo-1-piperidinecarboxylate (272 g, 1.37 mol) and titanium tetraisopropoxide (480.0 mL, 1.626 mol) were mixed and the mixture was stirred at room temperature for 20 h. The mixture was cooled down to 0° C. and diethylaluminum cyanide in toluene (1.0 M, 1600 mL) was added dropwise. The resulting mixture was stirred at room temperature for 20 h. The reaction content was then split into two 5 L flasks, To each flask, 1 L of ethyl acetate, 500 g of sodium bicarbonate, 150 g of celite were added before they were cooled down to −40° C. using dry ice/acetonitrile. To each flask, 200 mL of saturated aqueous sodium sulfate was then slowly added with vigorous stirring. After the reaction mixture was slowly warmed up to room temperature and stirred for 4 hours, 1 L of methanol was added to each flask. After being stirred overnight, the reaction mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with 3 L of methanol for 5 hours, and insoluble solid was filtered off. The combined filtrates were concentrated to dryness, and 3 L of methylene chloride was added. Insoluble solid was filtered off. The filtrate was dried with magnesium sulfate, the solvent was removed to give 484 g (88.9%) of product as a slight yellow solid. The crude product was essentially pure and used directly for next step. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.32 (m, 5H), 4.04 (d, 1H), 3.95 (brs, 2H), 3.15 (d, 1H), 3.15 (brs, 2H), 2.82 (m, 1H), 2.73 (m, 2H), 2.44 (m, 2H), 2.25 (t, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.66 (m, 1H), 1.46 (s, 9H), 1.17 (d, 3H); MS (EI) 399.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:16]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:85]1(B(O)O)[CH2:87][CH2:86]1>C1(C)C=CC=CC=1.O>[CH:85]1([C:2]2[CH:18]=[CH:17][C:16]([CH:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[O:20]3)=[CH:15][C:3]=2[CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[O:11][CH2:10][CH2:9][CH2:8]3)[CH2:87][CH2:86]1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCCO2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COC[C@H]2OC(c3ccc(C4CC4)c(Cc4ccc5c(c4)CCCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
To a stirred solution of 6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (300 mg, 0.363 mmol) in toluene (1.6 mL) was added tricyclohexylphosphine (10 mg), potassium phosphate (346 mg, 1.63 mmol), water (81 μl), cyclopropylboronic acid (93 mg, 1.09 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (4 mg) was added. After heating overnight at 100° C., the reaction mixture was cooled to room temperature and was filtered through celite. The celite was washed with an additional ethyl acetate (30 mL) and the organic layer of the filtrate was separated and washed with water (20 mL) followed by brine (20 mL), then dried over sodium sulfate and concentrated to give crude product which was further purified by column chromatography to furnish 6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (250 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:10]([CH2:17][OH:18])[CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(F)c(F)cc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1CO
Reaction time: 0.5 h

Procedure:
Trimethylacetyl chloride (4.01 mL, 32.55 mmol) was added to the solution of the crude (2-amino-4,5-difluorophenyl)methanol in CH2Cl2/THF (50 mL/10 mL) at 0° C., followed by the addition of DIEA (10.8 mL, 62 mmol). The resulting mixture was stirred for 30 min, and then partitioned between saturated NaHCO3(100 mL) and CH2Cl2 (150 mL). After separation, the organic phase was washed with brine (40 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected product, which was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 1.28 (s, 9H), 4.62 (s, 2H), 6.94 (dd, J=10.20, 8.44 Hz, 1H), 8.08 (dd, J=12.72, 7.68 Hz, 1H), 9.04 (s, 1H); Mass spec. 244.11 (MH+), Calc. for C12H15F2NO2 243.11.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=1.ClC1C=CC2SC3C(=CC=CC=3)N([Li])C=2C=1.C(Br)C#C>CCOCC>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:3][C:2]#[CH:1])[C:9]=2[CH:8]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: C#CCBr
Agent: [Li]N1c2ccccc2Sc2ccc(Cl)cc21
Solvent: CCOCC
Product: C#CCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To a solution containing 0.2 mole of butyllithium in 350 ml. of absolute ether (prepared in situ under nitrogen) were added 46.5 g. (0.2 mole) of 2-chlorophenothiazine while the mixture was maintained at -10° C. The reaction mixture was then allowed to stir for forty-five minutes at 0° C. To the resulting solution of 2-chloro-10-phenothiazinyllithium were added 30 g. (0.25 mole) of propargyl bromide in 30 ml. of absolute ether. This reaction mixture was allowed to stir at room temperature overnight. After quenching with dilute hydrochloric acid, the ethereal phase of the reaction mixture was washed with water and dried over anhydrous calcium sulfate. Upon removal of the solvent a semi-solid mass of crude 2-chloro-10-propargylphenothiazine remained. Recrystallized from methanol and from ether-hexane, pure 2-chloro-10-propargylphenothiazine melted at 112.0°-115.0° C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[C:25](Cl)=[N:24][S:23][N:22]=1>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>[Cl:20][C:21]1[C:25]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:24][S:23][N:22]=1
Reactant: Clc1nsnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccccc1
Reaction time: 8 h
Yield: 48 %

Procedure:
1.9 g (0.00517 mol) of tributylphenyl stannane and 0.29 g (0.00025 mol) of tetrakis (triphenylphosphine)palladium(0) were added to a solution of 0.775 g (0.005 mol) of 3,4-dichloro-1,2,5-thiadiazole in 10 mL of toluene under nitrogen and heated at reflux. After 8 h, 0.145 g (1.25×10−4 mol) of tetrakis(triphenylphosphine)palladium(0) were added. After 24 h of reflux, 48% of product formed by quantitative HPLC (versus a reference prepared as reported by L. Weinstock et al., J. Org. Chem., vol. 32, p 2823 (1967)).