Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][S:28]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:30])=[O:29]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 7.1 %

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was suspended in dichloromethane (15 ml), 4-dimethylaminopyridine (305 mg, 2.5 mM) added, and the mixture stirred vigorously for 15 minutes. After cooling to 0° C. under nitrogen, methanesulfonyl chloride (229 mg, 2 mM) was added dropwise, and the mixture stirred 18 hours at ambient temperature. Precipitated solid was removed, and the organic solution concentrated, then purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (30 mg). MS (ESP): 422 (MH+) for C18H20FN5O4S
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[Cu][C:22]#[N:23]>CN(C=O)C>[CH3:20][O:19][C:3]1[C:2]([C:22]#[N:23])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3c(Br)c(OC)ccc3o2)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C#N)c(OC)ccc3o2)cc1
Yield: 61.8 %

Procedure:
4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran 133 (0.258 g, 0.77 mmol) was taken into 20 mL of DMF along with copper (I) cyanide (0.173 g. 1.94 mmol) and heated at reflux for three hours. Additional copper (I) cyanide was added several times to complete the reaction. The reaction was filtered through a cotton plug that was then washed several times with ethyl acetate. The filtrate was diluted with additional ethyl acetate and then washed with water (2×), brine (1×), dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes as the eluent to yield the desired compound (0.133 g, 61.8%) as a white solid: Mp. 120–122° C.; 1H NMR (DMSO-d6) δ 7.96 (d, 2 H, J=8.8 Hz), 7.92 (d, 1 H, J=9.1 Hz), 7.91 (s, 1 H), 7.14 (d, 1 H, J=9.1 Hz), 7.09 (d, 2 H, J=8.9 Hz), 3.95 (s, 3 H), 3.83 (s, 3 H); MS 280 (M +H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:7]=2)=[O:4])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
103.1.B (905 mg, 2.65 mmole), 5 ml of DMF and 0.69 ml of DIEA. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (0.49 g, 2.92 mmole) was added to the mixture. The reaction was stirred at room temperature overnight. After then, the solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 103.1.C (552 mg, 49% yield) as orange syrup.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](Cl)[N:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:19]([SH:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:22][CH:19]([CH3:21])[CH3:20])[N:4]([CH3:12])[N:3]=1
Reactant: CC(C)S
Reactant: COC(=O)c1c(Cl)nn(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1c(Cl)nn(C)c1SC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 g of methyl 3,5-dichloro-1-methylpyrazol-4-ylcarboxylate and 25.5 g of potassium carbonate are suspended in 150 ml of DMSO and to this suspension are slowly added 16.1 ml of isopropylmercaptan at a temperature of 25° to 35° C. After stirring for 3 hours at room temperature, the reaction mixture is poured into 200 ml of ice-water and then 300 ml of ethyl acetate are added. After phase separation, the organic phase is washed with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated to dryness under vacuum. Distillation of the residue (113°-114° C., 2×10-3 bar) gives 31.5 g of 3-chloro-4-(methoxycarbonyl)-1-methyl-5-isopropylthiopyrazole in the form of a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][O:23][CH2:24]Cl.C(N(C(C)C)CC)(C)C>ClCCl.C(Cl)(Cl)Cl>[CH3:22][O:23][CH2:24][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COCCl
Reactant: CCOC(=O)CCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCCCCCCCCCCOCOC
Reaction time: 8 h

Procedure:
To a solution of 5.44 g of ethyl 16-hydroxyhexadecanoate in 80 ml of dichloromethane was added under ice-cooling 1.63 ml of methoxymethyl chloride, 4.1 ml of diisopropylethylamine was added dropwise and then the mixture was stirred overnight. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:13]([O:15][CH3:16])=[O:14])[C:11](=O)[C:5]=2[CH:4]=1.[BH4-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl.CO.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH2:8][CH2:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:5]=2[CH:4]=1
Reactant: COC(=O)C1CCCc2ccc(OC)cc2C1=O
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=Cc2cc(OC)ccc2CCC1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
To methyl 3-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (1079 mg, 4.35 mmol) dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (2.5 ml) was added at −40° C. (inner temperature) sodium borohydride (300 mg, 7.93 mmol), and the resulting mixture was stirred at −15° C. to −10° C. for 1.5 hours. The reaction mixture was cooled to −40° C., was mixed with water (10 ml) and extracted with dichloromethane (×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure. To the residue dissolved in dichloromethane (15 ml) were added at 0° C. triethylamine (3.03 ml, 21.7 mmol) and methanesulfonyl chloride (0.505 ml, 6.52 mmol), and the resulting mixture was stirred at room temperature for 18 hours. In order to complete the reaction, DBU (1.95 ml, 13.0 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, was mixed with water and was extracted with ethyl acetate (×3). The combined organic layers were washed with 1 N hydrochloric acid (×3) and an aqueous saturated solution of sodium chloride, were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate/hexane=1/9). The objective fractions were concentrated under reduced pressure to obtain methyl 2-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (730 mg, 3.14 mmol, 72%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:32]Br)=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=1>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:32][C:26]3[C:25]([Br:24])=[CH:30][CH:29]=[C:28]([Cl:31])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (4.94 g, 15.77 mmol) in THF (75 mL) was added NaH (60% dispersion in mineral oil) (0.526 g, 13.14 mmol). After stirring the reaction at room temperature for 10 minutes, 3-bromo-2-(bromomethyl)-6-chloropyridine (3.0 g, 10.51 mmol) was added as a solution in THF (20 mL). The reaction was stirred at room temperature for 16 hours and then quenched with saturated NH4Cl (40 mL). The mixture was diluted with EtOAc (100 mL) and hexanes (50 mL). The organic layer was washed with water (2×100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=518.8 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.81-7.83 (m, 3H), 7.18 (d, J=8.5 Hz, 1H), 5.87 (d, J=8.5 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H), 4.42 (m, 1H), 4.32 (d, J=17.1 Hz, 1H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH3:11])[N:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])=[CH:2]1.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH3:11])[N:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:2]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1-c1ccoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccoc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of ethyl (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylate (800 mg), tetrahydrofuran (10 ml) and ethanol (10 ml) was added 2N aqueous sodium hydroxide solution (6.5 ml) and the mixture was stirred at 60° C. for 1 hr. 1N Hydrochloric acid was poured into the reaction mixture, and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[5-(3-furyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (703 mg, 99%) as crystals. Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 218-219° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)=[CH:5][NH:6]2.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)[CH2:15][CH:16]=1)=[CH:5][NH:6]2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1cccc2[nH]cc(C3=CCNCC3)c12
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cccc(F)c23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.3 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.44 g, 2.3 mmol). The resulting free base was obtained as a yellow foam. Yield 0.14 g (15%). mp 90-95° C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: [N:1]1([C:10]([O-])=[O:11])C2C(=CC=CC=2)CC1.CCCCCCCCCCS[C:24]1[C:29](=O)[CH2:28][C:27](C)(C)[C@@:26]([OH:41])(/C=C/C(/C)=C\C(O)=O)[C:25]=1C>>[C:10](=[O:11])([O:41][C:26]1[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=1)[NH2:1]
Reactant: CCCCCCCCCCSC1=C(C)[C@](O)(/C=C/C(C)=C\C(=O)O)C(C)(C)CC1=O
Reactant: O=C([O-])N1CCc2ccccc21
Product: NC(=O)Oc1ccccc1
Yield: 88 %

Procedure:
tert-Butyl-2-(1-(4-dimethylamino)phenyl)-1H-imidazole-2-carbonyl)indoline-1-carboxylate (white solid) represented by the following formula (as10) was obtained in the same manner as in Example 1-15, except that tert-butyl-2-(3-oxo-3-(1-(4-dimethylamino)phenyl)-1H-imidazol-2-yl)propyl)phenyl carbamate (an10) obtained in Synthesis Example 14 was used as a substrate in an amount of 21.7 mg (0.05 mmol), the compound represented by the general formula (25) wherein R5 is the functional group F was used as a quaternary ammonium salt in an amount of 6.4 mg (0.005 mmol), and the reaction time was changed to 5 hours. The yield was 88%, and the enantioselectivity determined by HPLC measurement (chiral column: “DAICEL CHIRALPAK IA”, eluant: hexane/ethanol (=10/1), flow rate: 1 mL/min, t1=16 min, t2=24 min) was 78% ee (see Table 1-5). The analysis data for the resulting compound (as10) is shown below.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[O:34][C:33]([CH:35]([CH:37]2[CH2:41][CH2:40][CH2:39][S:38]2)O)=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[N:15]([CH:35]([CH:37]1[CH2:41][CH2:40][CH2:39][S:38]1)[C:33]1[O:34][C:30]([CH3:29])=[CH:31][CH:32]=1)=[N+:16]=[N-:17]
Reactant: Cc1ccc(C(O)C2CCCS2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(N=[N+]=[N-])C2CCCS2)o1
Temperature: 0 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
39.3 ml (0.18 mol; 1.2 eq) of diphenylphosphoryl azide and then 27.3 ml (0.18 mol; 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise to a solution of 30.21 g (0.15 mol; 1.0 eq) of (5-methylfuran-2-yl)-(tetrahydrothiophen-2-yl)methanol in 350 ml of toluene cooled to 0° C. The mixture was allowed to return to ambient temperature gently and was then stirred for 2 days. The reaction medium was treated with water and extracted with ethyl acetate. The organic phases were combined, washed with a 1 M sodium hydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/800G, puriFlash) eluted with heptane/ethyl acetate (95/5). 26.95 g of 2-[azido-(tetrahydrothiophen-2-yl)methyl]-5-methylfuran were obtained (mixture of the 2 diastereoisomers). Yield=79%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([I:11])[C:8]([OH:12])=[C:7]([Br:13])[CH:6]=1)[CH3:2].[CH2:15](O)[CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([I:11])[C:8]([O:12][CH2:15][CH2:16][OH:17])=[C:7]([Br:13])[CH:6]=1)[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)c1cc(Br)c(O)c(I)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCCO)c(I)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
To a mixture of 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 255 mmol) in 1 L of dry THF was added ethylene glycol (63.2 mL, 1.02 mol) and triphenylphosphine (87 g, 322 mmol). The solution was cooled to 0° C. and diisopropyl azodicarboxylate (60.2 mL, 306 mmol) was added dropwise with stirring. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete after 3 h. Worked up by removing ˜½ of the THF via concentration in vacuo, adding water, and extracting with ethyl acetate several times. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, decanted, and concentrated in vacuo to give a viscous oil which solidified on standing. The major portion of the solid byproducts were removed by stirring with 50% ethyl acetate/hexane. The solid byproduct was filtered off and the liquid was concentrated in vacuo to give a solid which was further purified. Flash chromatography eluting with 5–15% ethyl acetate hexane gave pure 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (65 g, 62%). 1H NMR (300 MHz, CDCl3) δ 1.37 (t, J=6.5 Hz, 3H, —CO2CH2CH3), 3.95 (t, J=5 Hz, 2H, —OCH2CH2OH), 4.19 (t, J=5 Hz, 2H, —OCH2CH2OH), 4.32 (t, J=6.5 Hz, 2H, —CO2CH2CH3), 8.18 (d, 1H, arom), 8.37 (d, 1H, arom).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].CN(C)C=O.[H-].[Na+].[CH3:30][O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34]>O>[CH3:30][O:31][C:32](=[O:37])[C:33]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2)([CH3:35])[CH3:34]
Reactant: Cc1c(Cc2ccc(Cl)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: COC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one (0.14 g), N,N-dimethylformamide (10 mL), sodium hydride (60% in oil, 0.020 g) and 2-bromo-2-methylpropionic acid methyl ester (0.11 g) was stirred at 100° C. for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 0.056 g.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1(C(O)=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(C1C=CC(C#N)=C(Cl)N=1)(C)(C)C>>[Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: O=C(O)C1CCCC1
Agent: CC(C)(C)c1ccc(C#N)c(Cl)n1
Product: N#Cc1ccc(C2CCCC2)nc1Cl
Yield: 41 %

Procedure:
This compound was synthesized in 41% yield from 2-chloronicotinonitrile and cyclopentanecarboxylic acid using the same procedure as for 6-tert-butyl-2-chloronicotinonitrile.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH2:36][CH2:37][O:38][CH3:39])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:42](O)C>O1CCCC1.ClCCl>[CH:22]1([CH:21]=[C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)[C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH2:36][CH2:37][O:38][CH2:39][CH3:42])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCO
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 96 %

Procedure:
A mixture of 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.7 mmol) in ethanol (4 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 5 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (300 mg, 96%) which was used in the next step without further purification: LC/MS m/e calcd for C24H27FN2O3S [M+H]+ 443.56, observed 443.3.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Si:11]([O:28][CH2:29][CH:30]([CH2:43]O)/[CH:31]=[CH:32]/[P:33](=[O:42])([O:38][CH:39]([CH3:41])[CH3:40])[O:34][CH:35]([CH3:37])[CH3:36])([C:24]([CH3:27])([CH3:26])[CH3:25])([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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Si:11]([O:28][CH2:29][CH:30](/[CH:31]=[CH:32]/[P:33]([O:38][CH:39]([CH3:41])[CH3:40])([O:34][CH:35]([CH3:36])[CH3:37])=[O:42])[CH2:43][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)OP(=O)(/C=C/C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)C
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(Cl)ncnc21)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
To a solution of 6-chloropurine (213 mg, 1.37 mmol), diisopropyl (E)-3-(t-butyldiphenylsilyloxy)methyl-4-hydroxybut-1-enylphosphonate (694 mg, 1.37 mmol) and triphenyl phosphine (540 mg, 2.06 mmol) in N,N-dimethylformamide (22 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (358 mg, 2.06 mmol). The solution was stirred at room temperature for 16 h. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:4, 1:2) then ethyl acetate-methanol (99:1, 9:1) to give (E)-9-[2-(t-butyldiphenylsilyloxy) methyl-4-(diisopropoxyphosphoryl)but-3-enyl]-6-chloropurine as a colourless gum (244 mg, 28%); λmax (EtOH) 265 (9,215nm; υmax (film) 2980, 2930, 1590, 1560, 1425, 1385, 1335 and 1245 cm-1 ; δH (CDCl3) 1.10 (9H, s, CH3), 1.20 (12H, m, CH (CH3)2), 3.07 (1H, m, CH), 3.69 (2H, d, J 6 Hz, CH2O ), 4.50 (4H, m, CH2N and CH(CH3)2), 5.57 (1H, pseudo-t, J 17 Hz, PCH=CH), 6.66 (1H, ddd, J 8 Hz, 17 Hz and 26 Hz, PCH=CH), 7.30-7.70 (10H, m, Ph), 8.00 (1H, s, H-2/H-8), 8.73 (1H, s, H-2/H-8) (Found: M+ 641.2459. C32H42N4ClO4PSi requires M+ 641.2479).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[CH:19]=[CH:18][N+:17]=2[O-:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C)C.C(O)(C)C.CC(C)=O>C(O)C.[Pd]>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][N+:17]=2[O-:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1ccc(OCc2ccccc2)cc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: [O-][n+]1ccc(O)cc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 78.6 %

Procedure:
2-[3-[3-(Piperidinomethyl)phenoxy]propylamino]-4-benzyloxypyridine-N-oxide (0.94 g) in ethanol (100 ml) was hydrogenated at 344 KPa (50 p.s.i), for 5 hours in the presence of 10% palladium on charcoal (0.1 g). The reaction mixture was filtered and the filtrate evaporated under reduced pressure to give an oil. Trituration under diethyl ether containing a little isopropanol gave as a buff solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-hydroxypyridine-N-oxide (0.59 g), m.p. 140°-142.5° C. (recrystallised from isopropanol-acetone).