Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](F)[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.Cl>CO>[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:2][CH3:1])[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
To a solution of sodium methoxide in methanol (28%, 4 ml) was added 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (350 mg), and the mixture was heated under reflux for 6 hrs. To the reaction mixture were added water and 10% hydrochloric acid to acidify the aqueous layer of the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (260 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][C@@H:25]3[CH2:27][C@H:22]2[CH2:23][N:24]3C(OC(C)(C)C)=O)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1.C(O)(C(F)(F)F)=O.[Cl:45]CCl>>[ClH:45].[C@H:22]12[CH2:27][C@H:25]([NH:24][CH2:23]1)[CH2:26][N:21]2[C:12]1[CH:13]=[C:14]2[N:19]([CH3:20])[CH:18]=[CH:17][C:15]2=[N:16][C:11]=1[C@@H:9]([NH:8][C:6]1[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:10]
Reactant: ClCCl
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2C[C@@H]3C[C@H]2CN3)c1C#N
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 100 mL pear flask was added tert-butyl (1S,4S)-5-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 0.44 mmol) in dichloromethane (4.5 mL) to give a solution. To this solution was added TFA (1.5 mL). The mixture was stirred at room temperature for 30 minutes. All the volatiles were removed in vacuo, and the residue was re-suspended in toluene and concentrated to remove residual TFA. The residue was then diluted in ACN and water (total of about 90 mL), followed by the addition of 2 N HCl (4 mL). The mixture was lyophilized to give an HCl salt of the title compound as a yellow-green solid (160 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (d, J=7.07 Hz, 3H), 2.00 (d, J=10.61 Hz, 1H), 2.33 (br s, 1H), 2.43 (s, 3H), 3.09-3.25 (m, 1H), 3.45 (d, J=10.11 Hz, 2H), 3.96-4.06 (m, 4H), 4.10-4.18 (m, 1H), 4.49 (br s, 1H), 5.95 (quin, J=6.88 Hz, 1H), 6.78 (d, J=2.27 Hz, 1H), 7.76 (br s, 1H), 8.03 (br s, 1H), 8.25 (br s, 1H), 8.63 (br s, 1H), 9.08 (br s, 1H), 9.78 (br s, 1H), 10.19 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C21H25N9, 404. found 404.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30]C(OCC1C=CC=CC=1)=O)=[N:19]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:41].[H][H]>[Pd].CO>[ClH:41].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:30])=[NH:19])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1S(C)(=O)=O
Yield: 30 %

Procedure:
A methanol solution of compound 11 (0.29 g, 0.5 mmol) and 1N HCl (0.5 mL), containing 10% palladium on carbon, was stirred under 35 psi of hydrogen atmosphere for 2 h. The suspension was filtered through a pad of Celite and the filtrate was concentrated to afford 52 mg (30%) of the title product.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:35])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.6 g, 3.92 mmol) in THF (15 mL) were sequentially added NMO (50% in water, 1.219 mL, 5.88 mmol) and osmium tetroxide (4% in water, 0.958 mL, 0.157 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. A cloudy solution of sodium periodate (1.425 g, 6.66 mmol) in water (14 mL) was added. The mixture was stirred at room temperature under nitrogen for 0.5 hr. Water (20 mL) was then added and the mixture was stirred at room temperature for 30 min. The solid was filtered, washed with water (2×2 mL) and methanol (2 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (1.6 g, 3.90 mmol, 100% yield) as a white solid. The compound had an HPLC retention time=4.02 min. (condition C); LC/MS M+1=410.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, 3,6-dibromocarbazole (9.75 g, 30 mmol) was slowly added to a suspension of sodium hydride (45 mmol) in dried THF (100 mL), and then stirred for 30 minutes at room temperature. Benzylbromide (6.72 g, 40 mmol) was dropped into the reaction mixture to be stirred for 20 hours. After addition of water (about 100 mL), a precipitated solid was filtrated, and the filtrate (residuum of the filtration) was washed with an aqueous sodium hydrogencarbonate solution, and then was dissolved in ethanol. The solution was dried by magnesium sulfate, filtrated and concentrated. The residuum was recrystallized with ethanol to give N-benzyl-3,6-dibromocarbazole as a white solid. The yield was 61%.
Reaction SMILES: [Zn:1].[CH:2]([OH:5])([CH3:4])[CH3:3]>>[CH3:3][CH:2]([CH3:4])[O-:5].[Zn+2:1].[CH3:3][CH:2]([CH3:4])[O-:5]
Reactant: [Zn]
Reactant: CC(C)O
Product: CC(C)[O-]
Product: [Zn+2]

Procedure:
On Day 1, one kilogram of fine zinc chips with a catalyst is added to a magnetically stirred, 6.5-gallon flint glass carboy containing 15 liters of ultra-dry Isopropanol prepared in Example 2, and reacted at 110° F. to form zinc isopropoxide. Carbon dioxide is added as described in Example 4 to form isopropoxy zinc isopropyl carbonate (PZPC). On completion of the reactions, magnets are inserted to provide magnetic filtering, and the concentrates are maintained at 110° F. as described in Example 4.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]([CH3:25])[CH3:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>C(O)(C(F)(F)F)=O>[Br:26][C:21]1[C:22]([N:23]([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:27]
Reactant: CN(C)c1c(Br)cc2c3c(cccc13)C(=O)N(OCc1ccccc1)C2=O
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1c(Br)cc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 91.8 %

Procedure:
Following the procedure of Example 52, 2-benzyloxy-5-bromo-6-dimethylamino-benzo[de]isoquinoline-1,3-dione (0.17 g, 0.39 mmol, from Example X1) and a 1.0 M solution of boron tris(trifluoroacetate) in TFA (2 mL) were reacted to give 0.12 g of the title compound, mp 185-187° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29][CH3:30])=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>ClCCl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH3:30][O:29][C:18]1[N:19]=[N:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:22][C:17]=1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1

Procedure:
A solution of 5.5 g 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 5 ml TFA in 10 in 10 ml dichloromethane stirred for 18 h at room temperature. The solvent is evaporated and the crude product purified by suspended on water and collecting the precipitate.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C@H:9]2[C@@H:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:25]([Cl:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[ClH:32].[CH2:25]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([C:15]([OH:17])=[O:16])[C@@H:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C[C@@H]2NCCC[C@@H]2C(=O)O)cc1
Reactant: ClCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H]2[C@@H](C(=O)O)CCCN2Cc2ccccc2)cc1
Product: Cl

Procedure:
A mixture of 9.9 g. of cis-2-(p-methoxybenzyl)-3-piperidinecarboxylic acid hydrobromide, 7.6 g. of sodium bicarbonate, 3.8 g. of benzyl chloride, and 100 ml. of dimethylformamide is stirred and refluxed for two hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is taken up in 100 ml. of water. By acidification with 30 ml. of N hydrochloric acid, there is produced cis-1-benzyl-2-(p-methoxybenzyl)-3-piperidinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[OH:11])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Yield: 86.4 %

Procedure:
To a solution of 17 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 11.8 g of ethyl bromoacetate in 50 ml 2-butanone and the mixture is heated at 95°. To the mixture is added 12 g of potassium carbonate and 5.3 ml of dimethylformamide and the reaction mixture is refluxed at 100° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The aqueous phase is extracted two times with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from acetone and hexane gives 19.5 g of ethyl[ (6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate, mp 101°-103°.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:33]([CH:36]1[CH2:38][CH:37]1[C:39]#[N:40])(O)[CH3:34]>ClCCl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:33]([CH:36]1[CH2:38][CH:37]1[C:39]#[N:40])([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH3:34]
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cc(F)cc2c(C(C)(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
273 mg (1.23 mmol) of indium(III) chloride and 0.1 ml (1.34 mmol) of trifluoroacetic acid were added to 250 mg (1.12 mmol) of the compound from Example 11A and 437 mg (2.24 mmol) of the compound from Example 133A were introduced into 44 ml of dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 313 mg (69% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:25]([C:24]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:23]=2[Cl:22])=[O:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(Br)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a mixture of 4-amino-N-[(1,1-dimethylethoxy)carbonyl)-L-phenylalanine methyl ester (20 mmol, 5.88 g), 2-chloro-5-bromobenzoic acid (22 mmol, 5.18 g) and HBTU (22 mmol, 8.34 g) in DMF (70 mL) was added diisopropylethylamine (50 mmol, 8.7 mL) at room temperature. The suspension was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the mixture was diluted with water (100 mL) and the solids were collected by filtration and washed with water (150 mL). After air drying, the crude product was purified by silica gel column chromatography to obtain 1.02 g (10%) of a white solid: mp 158-161° C. HR MS (C22H24BrClN2O5): Ob, 533.0442. Calcd mass, 533.0455 (M+Na).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.[B:17](OC)([O:20]C)[O:18]C.Cl>CCOCC.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[C:9]1[CH:8]=[C:7]([B:17]([OH:20])[OH:18])[CH:12]=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: C[Si](C)(C)c1cccc(Br)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
t-Butyllithium (28 cm3, 1.7 M in pentane) was added to a solution of (21) (9.65 g, 42 mmol) in ether (200 cm3) cooled in a dry ice/acetone bath, and the reaction was stirred for 30 minutes. Trimethyl borate (20 cm3, 170 mmol) was added, and the reaction was stirred for 16 hours, gradually warming to room temperature. Aqueous hydrochloric acid (3 M, 20 cm3) was added, and the reaction was stirred for a further 2 hours. Water (200 cm3) was added, and the layers were separated. The aqueous layer was extracted with ether (3×30 cm3). The combined organic extracts were washed with brine (300 cm3) and dried over magnesium sulfate, and the solvent was removed to leave a white solid. The crude product was passed through a plug of silica using light petroleum then ether as the eluent. The ether band was collected, and the solvent was removed to leave (22) as a brown solid (7.04 g, 86%).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7]2)=[CH:9][CH:10]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccc(-n2cccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (5 mL) was added 4-Pyrrol-1-yl-phenol (160 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooled to rt, the mixture was poured into 150 mL ice-water solution and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (30 mL), dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel eluting with ethyl ethyl acetate:hexane (1:10-1:4) to yield the title compound (270 mg, 80%); LCMS; m/z (ESI+ 243.3, M+1); 99%;
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH2:32]([OH:35])[CH2:33][OH:34]>C1COCC1.[Cl-].[Na+].O>[OH:34][CH2:33][CH2:32][O:35][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 37 h

Procedure:
4-Chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole (5.57 g) was suspended in 100 ml of THF and 30 ml of ethylene glycol, 1.5 g of sodium hydride was added to the suspension, and the mixture was stirred at 50° C. for 37 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4.87 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)#[CH:2].Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:24]=2)[N:19]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:2]#[C:1][C:3]2[CH:16]=[CH:15][CH:14]=[C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH:4]=2)[CH:27]=[CH:26]3)=[CH:33][CH:32]=1
Reactant: C#Cc1cccc(OCCN2CCCC2)c1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Product: Clc1ccc(-c2ccc3nc(C#Cc4cccc(OCCN5CCCC5)c4)ccc3c2)cc1

Procedure:
Prepared analogously to Example 18d from 1-[2-(3-ethynyl-phenoxy)-ethyl]-pyrrolidine and 2-bromo-6-(4-chloro-phenyl)-quinoline.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>O1CCCC1>[CH3:35][S:36]([O:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:20])=[N:5][CH2:4]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(CO)S3)[nH]c12)S(=O)(=O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of N-{2-[5-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (2.0 g) and triethylamine (1.4 mL) in tetrahydrofuran (50 mL) was added methanesulfonyl chloride (860 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.85 g, yield 77%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 481 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClCCl.N1C=CC=CC=1.C(OCC)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:1][CH2:2][C:3]([C:4]#[N:5])([CH3:7])[CH3:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C#N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (0.5 g) in dichloromethane (8 mL) and pyridine (1.5 mL) is added at 0° C. p-toluene-sulfonylchloride (1.0 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with diethylether and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (petrole ether/ethyl acetate 90:10→50:50) to give the title compound. Yield: 770 mg; Mass spectrum (ESI+): m/z=254 [M+H]+.