Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C(Cl)(=O)C(Cl)=O.[NH3:30]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([NH2:30])=[O:8]
Reactant: COC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with methyl 5-iodosalicylate to give methyl 5-iodo-2-(naphth-2-ylmethoxy)benzoate (68%). Using conventional procedures the ester was hydrolysed with base to give the corresponding acid; the acid chloride was prepared by reaction with oxalyl chloride; and the acid chloride was reacted with ethanolic ammonia to give 5-iodo-2-(naphth-2-ylmethoxy)benzamide (84% from the ester), m.p. 163° C. The benzamide so obtained was reacted with trifluoroacetic anhydride in the presence of pyridine and dimethoxyethane as reaction solvent. There was thus obtained 3-cyano-4-(naphth-2-ylmethoxy)phenyl iodide (72%), m.p. 108°-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:14])[CH3:13].O1CCCC1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:14][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC1=C(C(=O)OCC)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with a 2.0 M solution of ethylamine in tetrahydrofuran (9.6 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-ethylamino-cyclopent-1-enecarboxylic acid ethyl ester (1.52 g, 8.30 mmol, 43.2%), as a light yellow oil. LC-MS (ESI) calcd for C10H17NO2 183.13, found 184.1 [M+H+].
Reaction SMILES: [ClH:1].CO[C:4](=[NH:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.N([C:24]1[C:37]([NH:38]C2C=CC=CC=2)=[CH:36][CH:35]=[CH:34][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])C1C=CC=CC=1>CO.C(OCC)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH2:5][C:4]1[NH:16][C:36]2[CH:35]=[CH:34][C:25]([C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:24][C:37]=2[N:38]=1.[ClH:1]
Reactant: COC(=N)Cc1ccc(OC)c(OC)c1
Reactant: O=C(c1ccccc1)c1cccc(Nc2ccccc2)c1Nc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(Cc2nc3cc(C(=O)c4ccccc4)ccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl-(3,4dimethoxyphenyl)-acetimidate hydrochloride (2.5 g; 10 mmol) and 2,3-diamiinobenzophenone (2.1 g; 10 mmol) in methanol (70 mL) was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated to dryness, and H2O was added. The solid (2.3 g) was subjected to flash chromatography on silica gel (CH2Cl2/MeOH; 9:1) to afford a gummy material. This was dissolved in diethyl ether, and Ether-HCl was added to obtain the title compound as a buff solid, hydrochloride, penta-hydrate (250 mg), m.p. 172-175° C. Anal. Calcd. for C23H20N2O3HCl.5H2O: C, 66.97; H, 5.23; N, 6.79. Found: C, 67.11, H, 4.84; N, 6.77. Mass Spectrum: (EI; M+) m/z 372. 1H-NMR (D)MSO-d6; 400 MHz) δ8.0 (s, 1H) 7.84-7.9 (m, 2H), 7.68-7.77 (m, 3H), 7.55-7.61 (m, 2H), 7.2 (s, 1H), 6.93-7.01 (m, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.77 ppm (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])C.[OH-].[K+].Cl>O.C(O)C>[C:11]([CH:7]1[C:8]([CH3:10])([CH3:9])[CH:6]1[C:4]([OH:5])=[O:3])#[N:12]
Reactant: CCOC(=O)C1C(C#N)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(C#N)C1C(=O)O
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A suspension of 33.4 g (0.2 mol) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid ethyl ester and 16.8 g (0.3 mol) of potassium hydroxide in 200 ml of water and 100 ml of ethanol was stirred at 20°-25° C. for 15 hours. The alcohol was then stripped off and the aqueous solution was acidified with dilute hydrochloric acid and extracted twice with 100 ml of ether (or methylene chloride) each time. The combined organic extracts were dried over Na2SO4 and concentrated and the residue was distilled. 21.2 g (76% of theory) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid were obtained in the form of an oil of boiling point 110°-120° C., which crystallized on cooling (melting point: 101°-106° C.). ##STR44##
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH4+:14].[OH-]>CCO>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-3,5-dinitropyridine (2.035 g, 10 mmol) in EtOH (15 mL) was added aq. NH4OH (6 mL) dropwise at room temperature with stirring over 20 min. The resulting mixture was stirred at room temperature for 15 min, then cooled to 0° C. The precipitate was filtered, washed with water (3×5 mL) and dried to give 1.64 g (89%) of 61 as a yellow powder, mp 190°-1° C. (lit. 190°-2° C., Chemical Abstracts 63:14876 (1965)). 1H NMR (DMSO-d6): 8.697 (bs, 1H, D2O exchange), 8.947 (d, 1H, J=2.5), 9.164 (d, 1H, J=2.5), 9.224 (bs, 1H, D2O exchange).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[N:6][CH:7]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12.O>CN(C=O)C>[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([N:9]3[C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)[CH2:12][O:11][C:10]3=[O:13])=[N:22][C:21]=12
Reactant: O=C1N[C@@H](c2ccc(F)cn2)CO1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of (S)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (4.3 g, 24 mmol) in DMF (75 mL) was added sodium hydride (0.94 g, 24 mmol) in portions and the reaction stirred for 15 minutes at room temperature, followed by the addition of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (5.5 g, 24 mmol) in a solution of DMF (50 mL) and the reaction was stirred for an additional 1 hour. The reaction was poured into water (400 mL) and extracted into ether (400 mL). The water layer was separated and washed with ether (200 mL). The combined organic layers were washed with water (100 mL) and brine (200 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 15% EtOAc/DCM as eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (6.7 g, 18 mmol, 75% yield).
Reaction SMILES: [CH2:1]([N:9]1[C:17]([CH2:18]O)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH2:1]([N:9]1[C:17]([CH2:18][Br:22])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Nc1ncnc2c1nc(CO)n2CCc1ccccc1
Solvent: ClCCl
Product: Nc1ncnc2c1nc(CBr)n2CCc1ccccc1

Procedure:
A solution of N9-phenethyl-8-hydroxymethyladenine (1 mmol) in methylene chloride was treated with phosphorus tribromide (1 mmol) at 25° C. for 1 h. Extraction and chromatography gave N9phenethyl-8-bromomethyl-adenine as a white solid. TLC: Rf=0.31, 10% MeOH—CH2Cl2.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10]N1C(=O)CCC1=O>ClCCl>[Cl:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cc2[nH]ccc2cn1
Solvent: ClCCl
Product: Clc1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.9 %

Procedure:
A solution of 1H-pyrrolo[3,2-c]pyridine (200 mg, 1.69 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (332 mg, 2.5 mmol) and stirred at room temperature for about 5 hours. The reaction mixture was diluted with dichloromethane and washed with aq. sodium hydrogen carbonate solution, brine, dried over anhydrous sodium sulphate and concentrated. Purification by silica gel (100-200) column chromatography using methanol and dichloromethane gradient as eluent afforded 3-chloro-1H-pyrrolo[3,2-c]pyridine (103 mg, 40%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.C(=O)C1C=CC=CC=1>>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Solvent: O=Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCl

Procedure:
Analogously to the building block synthesis of 4-chloromethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and benzaldehyde gave 4-chloromethyl-5-methyl-2-phenyloxazole.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[O:8])=[O:5])#[N:2].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:2][C:1]1[N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[N:6]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:4](=[O:5])[CH:3]=1
Reactant: CCCNC(=O)N(CC1CCCCC1)C(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCn1c(N)cc(=O)n(CC2CCCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 1-(2-cyanoacetyl)-1-cyclohexylmethyl-3-propylurea from above (7.10 g, 26.8 mmol) in water (45 mL)-ethanol (15 mL) was heated to 100° C. (oil bath), with adjustment of the pH to 10 by the addition of solid sodium carbonate. The resulting yellow solution was stirred for 1 h, during which time white crystalline solids formed. After 1 h 40 min, the mixture was cooled to 0° C. (icebath), and the white crystals were filtered off, washed with water (3×15 mL), and air-dried to provide 6-amino-3-(cyclohexylmethyl)-1-propyluracil as a slightly moist crystalline solid (8.85 g, quantitative yield). A small portion of this material was dried at 0.1 Torr to provide an analytically pure sample, m.p. 121°-122° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C[OH:42]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([C:26](=[O:42])[NH:27][C:30]4[CH:31]=[C:32]([CH3:33])[CH:35]=[CH:36][CH:29]=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:4]([O-:5])=[O:3]
Reactant: CO
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(CN)cccc23)CC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)Nc4cccc(C)c4)cccc23)CC1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of 4-(5-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 55 (62 mg, 0.159 mmol) in MeOH (4 mL) was added 4-chloro-benzaldehyde (45 mg, 0.318 mmol) and sodium cyanoborohydride (50 mg, 0.795 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo and the resultant crude material was purified by reverse phase HPLC to provide the title compound (H-45) as its formate salt. 1H NMR (300 MHz, MeOD) δ 8.78 (d, 1H), 8.38 (s, 1H), 8.33 (m, 2H), 7.70 (m, 3H), 7.45 (m, 4H), 4.57 (s, 2H), 4.20 (s, 2H), 4.05 (q, 2H), 3.75 (d, 2H), 3.20 (m, 1H), 2.75 (m, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 1.17 (t, 3H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (2.71 g) was dissolved in tetrahydrofuran (60 ml) under a nitrogen atmosphere, and then triethylamine (2.27 ml) and phenyl chloroformate (2.05 ml) were added dropwise thereto while cooling in an ice water bath, followed by stirring at room temperature for 25 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to provide a crude product of 4-(2-fluoro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (5.00 g). The crude product was dissolved in tetrahydrofuran (50 ml), and then pyrrolidine (3.64 ml) was added at room temperature, followed by stirring for 1 hr. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and an brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:4, then ethyl acetate) to provide the titled compound (2.927 g, 78%) as pale brown crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](O)=[O:21])[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](=[O:21])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: C1CCNCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)N3CCCCC3)CN2C(=O)OC(C)(C)C)OC1(C)C

Procedure:
Add piperidine (0.013 g, 0.151 mmol) to a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of isomers) (0.05 g, 0.101 mmol), bromo tris-pyrrolidinophosphonium hexafluorophosphate (0.094 g, 0.201 mmol), dimethylamino-pyridine (0.001 g, 0.01 mmol) and triethylamine (0.021 mL, 0.151 mmol) in 2.2 mL of dichloromethane. Stir the reaction overnight. Concentrate under reduced pressure and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate (70% gradient to 100%) to provide both isomers of the desired compound. The 4(R) isomer is the slower eluting (0.033 g, 60%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[F:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[K+].C(O)C>O>[F:17][C:18]1[C:23]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (239 mg, 1 mmol) prepared at Step 6, 2-fluoropyridin-3-yl boronic acid (189 mg, 1.3 mmol), potassium acetate (216 mg, 2.2 mmol), and bis(di-tert-butyl-(4-dimethyl amino phenyl) phosphine)dichloropalladium (14 mg, 0.02 mmol) were added into a mixed solvent of ethanol and water (5/1). The reactant was refluxed and stirred under nitrogen pressure at 80° C. for 2 hours. After the reaction, the solution was concentrated and washed with water and salt water, and then extracted with ethylacetate. After drying the organic layer with sulfuric anhydride magnesium and vacuum concentrating, the residuals were refined by means of column chromatography, so that 279 mg of the target compound, 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 93%), was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7](OC)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22]C(=O)C)[C:15]=2O.C[O:29]C1C=C(OC)C=CC=1C1C(C)=C2C(=CC(OC(=O)C)(O)C=C2)OC1=O>>[OH:2][C:3]1[C:8]([OH:29])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2
Reactant: COc1ccc(C2C(=O)OC3=CC(O)(OC(C)=O)C=CC3=C2C)c(OC)c1
Reactant: COc1ccc(-c2c(C)c3ccc(OC(C)=O)c(O)c3oc2=O)c(OC)c1
Product: Cc1c(-c2cccc(O)c2O)c(=O)oc2cc(O)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 5 with substitution of acetic acid 3-(2,4-dimethoxyphenyl)-8-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl ester, prepared in Example 2, for acetic acid 3-(2,4-dimethoxyphenyl)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl ester.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[N:10]([O-])=O.[Na+].[CH3:14][C:15]1([CH3:24])[CH2:20][CH:19]([OH:21])[CH2:18][C:17]([CH3:23])([CH3:22])[NH:16]1>O.C(#N)C>[CH3:14][C:15]1([CH3:24])[CH2:20][CH:19]([OH:21])[CH2:18][C:17]([CH3:23])([CH3:22])[N:16]1[N:10]=[N:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(N=NN2C(C)(C)CC(O)CC2(C)C)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A mixture of concentrated HCl (30 ml, 32%) and water (30 ml) is charged into 100 ml three necked round bottomed flask followed by addition of p-Toluidine (10 g, 0.0.093 mol). The mixture is cooled to 0 to 5° C. and solution of sodium nitrite (11.2 g, 0.16 mol) in water (15 ml) is added into it while maintaining the temperature at 0 to 5° C. This reaction mixture is then slowly added into a solution of 2,2,6,6-tetramethyl-4-hydroxypiperidine (69 g, 0.44 mol) in acetonitrile (2000 ml) and the mixture is stirred at 0 to −5° C. for 1 h. The reaction mass is filtered and the mother liquor evaporated to dryness at 40° C. The solid residue is extracted with cyclohexane (500 ml) and diethyl ether (800 ml). The extracts are decolorized with charcoal (25 g) filtered through bed of celite and concentrated at 25 C to afford 6.0 g of 2,2,6,6-Tetramethyl-1-(p-tolyl-diazenyl)-piperidine-4-ol as a yellow solid, m.p. 85-86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.S(Cl)(Cl)=O.C(Cl)(Cl)Cl.[NH3:22]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:22])=[O:13])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc2[nH]c(C(N)=O)cc2c1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g of 5-methylindole-2-carboxylic acid, 0.25 mL of thionyl chloride, 5 mL of chloroform and small drop of DMF was refluxed for 2 hs. The reaction mixture was cooled to RT, poured into a mixture of 5 g of ice and 5 mL of 25% ammonia solution, and then stirred for 2 hs. The precipitated product was filtered off, washed with water and dried to yield 350 mg of 5-methylindole-2-carboxamide. 1H NMR (600 MHz, DMSO-d6): δ 11.37 (s, 1H), 7.89 (br, 1H), 7.36 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.28 (br, 1H), 7.02 (s, 1H), 6.99, (d, 1H, J=8.4 Hz), 2.36 (s, 3H). 13C NMR (150 MHz, CDCl3): δC 160.95, 132.95, 129.77, 126.15, 125.44, 123.10, 118.77, 110.02, 100.65, 19.20.
Reaction SMILES: [CH3:1][Mg]Br.COC(=O)[CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].C([O:16][CH2:17][CH3:18])C>>[OH:12][CH2:11][CH2:10][S:9][CH2:8][CH2:7][C:17]([CH3:18])([OH:16])[CH3:1]
Reactant: COC(=O)CCSCCO
Reactant: C[Mg]Br
Reactant: CCOCC
Product: CC(C)(O)CCSCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
100 ml of a 1N solution of methylmagnesium bromide in diethyl ether are placed under argon gasification and treated dropwise with a solution of 5.0 g of 3-[(2-hydroxyethyl)thio]propionic acid methyl ester (prepared according to Example 5) in 25 ml of diethyl ether so that a slight reflux results. After completion of the addition, the resulting mixture is stirred at room temperature for a further 16 hours. Subsequently, the excess Grignard reagent is destroyed by the cautious addition of saturated ammonium chloride solution to the mixture and the mixture is extracted three times with 100 ml of methylene chloride each time. The organic phases are dried over magnesium sulfate and concentrated. Low-pressure chromatography (0.4 bar) of the residue on silica gel with ethyl acetate and subsequent bulb-tube distillation (150° C./0.23-0.18 mm Hg) gives 2.25 g (46 percent) of 4-[(2-hydroxyethyl)thio]-2-methyl-2-butanol as a viscous, colorless oil; nD23 =1.5027.