Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH:24]=[C:25]([CH3:27])[CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
The mixture 2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (134) (283 mg, 0.75 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (135) as white solid (250 mg, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>CO>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[Cl:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 389 mg (1.79 mmol) tert-butylindole-5-carboxylate in 12 ml methanol is mixed with 335 mg (2.50 mmol) N-chlorosuccinimide and stirred at room temperature overnight. The methanol is removed by rotation and the resulting residue is taken up in 15 ml ethyl acetate. The organic phase is washed twice with 1M sodium hydrogen carbonate solution, dried on sodium sulfate and concentrated by rotation. Column chromatographic processing of the residue on silica gel (flow agent: hexane/ethyl acetate 9:1) yields a solid.
Reaction SMILES: C=O.[CH2:3](NCC)C.[CH2:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>CO>[CH2:22]([O:21][P:17]([C:8]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH2:3])(=[O:24])[O:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC

Procedure:
Paraformaldehyde (104.2 g) and diethylamine (50.8 g) are combined in methanol (2 1), warmed until clear, then treated with methylene bisphosphonic acid, tetraethyl ester (190.09 g) and refluxed for 18 hrs. The sample is then concentrated, methanol added, the methanol removed by heat and reduced pressure, toluene is added and removed by heat and reduced pressure. The residue is dissolved in toluene (1 1), treated with p-TSA (0.5 g) and refluxed through a Dean Stark trap for 18 hrs. The sample is concentrated under reduced pressure with heat, dissolved in methylene chloride washed twice with water, dried with magnesium sulfate, and concentrated under reduced pressure with heat. The sample is purified by distillation at reduced pressure to give the title compound, bp=140° (0.6 torr); MS (m/e) 300, 285, 273, 255, 245, 227, 217, 199, 192, 181, 163, 153 and 135; IR (neat) 2984, 2934, 2909, 1651, 1580, 1479, 1444, 1392, 1254, 1166, 1098, 1042, 1025, 974, 855, 813 and 800 cm-1 ; NMR (CDCl3) 7.1, 6.7, 4.1 and 1.3 δ.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:10]1
Reactant: O=Cc1ccsc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccsc2)=CC1=O
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.5 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 12 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). The reaction solution was heated to 60° C. for 4 hours. After the reaction solution cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow crystalline solid. The residue was purified by chromatography (silica gel, hexane/ethyl acetate) to yield yellow crystals (2.1 g, 72% yield), m.p. 79°-80° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:10][CH2:8][CH3:9]
Reactant: CCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OC(C)Cl
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of 1-chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74%) of the intermediate ethyl chloroethyl carbonate as a crude product.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26]([O:28]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Yield: 40 %

Procedure:
A solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (210 mg, 0.55 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 20 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 80 mg (40%) of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.55 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 8.35 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=8 Hz), 7.8 (d, 1H, J=8 Hz), 7.65 (m, 4H), 7.45 (m, 2H), 7.25 (t, 1H, J=8 Hz), 7.15 (t, 1H, J=8 Hz), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 6.2 (s, 2H). MS (ES) m/e 365, 367.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])=[O:5].[OH-].[K+].CI.[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([N:6]([CH2:26][O:27][CH3:28])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:8])=[O:5]
Reactant: COCCl
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: COCN(C(=O)Nc1ccc(Cl)cc1)C(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.3 g of N-(2,6-dichlorobenzoyl)-N'-(4-chlorophenyl)-urea and 1.88 g of powdered potassium hydroxide (90%) are dissolved 40 ml of dimethyl formamide, after which 4.7 g of methyl iodide are added drop by drop to the clear solution. The resulting reaction is exothermic. After stirring for two hours the solution is diluted with ice water and the solid substance is isolated. Yield 10.3 g. Melting point 124°-126° C. In a completely similar manner but using methoxymethylchloride instead of methyliodide, N-(2,6-dichlorobenzoyl)-N-(methoxymethyl)-N'-(4-chlorophenyl)-urea is produced. Melting point 121.5°-122.5° C.
Reaction SMILES: [O-2].[Ba+2].[N+:3]([O-:6])([O-:5])=[O:4].[Ba+2].[N+:8]([O-])([O-])=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19]>O>[N+:3]([O-:6])([O-:5])=[O:4].[NH2:8][N+:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([Br:12])[CH:14]=1
Reactant: Cc1ccncc1Br
Agent: O=[N+]([O-])[O-]
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Product: Cc1cc[n+](N)cc1Br
Temperature: 25 °C
Yield: 113.3 %

Procedure:
Barium oxide (950 mg, 90%, 5.56 mmol) were carefully added into 6 ml water in small portions followed by addition of barium nitrate (983 g, 3.76 mmol) and 3-bromo-4-methylpyridine (1.72 g, 10 mmol). The resulting suspension was stirred at r.t. and a solution of hydroxylamine O-sulfonic acid (995 mg, 8.36 mmol) in 2 ml water was added drop-wise. The white suspension was stirred at 90° C. for 15 h before cooling down to r.t. The white precipitate was filtered off and washed with water. The aqueous phase was evaporated to dryness to give 1.065 g of 205 as off-white solid (yield: 45.7%) which were directly used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>C1COCC1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 4-aminobenzoic acid (10 g, 73 mmol) in 100 mL of anhydrous THF was added pyridine (1.15 g, 146 mmol), and quinoline-8-sulfonyl chloride (20 g, 88 mmol) at 0° C. The resulting mixture was stirred at 70° C. overnight. After filtration, the residue was washed with EtOH and 14 g of title compound was obtained as pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Br:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:29][CH3:30])[C:25]([CH2:27]Cl)=[N:26][C:22]=2[CH:21]=1>C1COCC1>[Br:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:29][CH3:30])[C:25]([CH2:27][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:10])=[N:26][C:22]=2[CH:21]=1
Reactant: CCn1c(CCl)nc2cc(Br)ccc21
Reactant: CC(=O)c1cccc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-ethanone (0.55 g, 4.0 mmol) in THF (30 mL) at −78° C. under N2 is added LDA (2M in hexanes, 2.0 mL, 4.0 mmol). After 10 minutes, 5-bromo-2-chloromethyl-1-ethyl-1H-benzoimidazole (1 g, 3.65 mmol) in THF (5 mL) is added. The mixture is stirred at this temperature for an additional 1 hour and is gradually warmed to room temperature. The reaction is then quenched with saturated NH4Cl. The mixture is extracted with ethyl acetate (3×50 mL). Upon drying, the organic solvent is removed to give 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20].C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)(=[O:25])=[O:24])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (100 mg, 0.48 mmol) and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (171 mg, 0.63 mmol) were dissolved in anhydrous dichloromethane (5 mL) and were flushed with argon. Anhydrous triethylamine (0.155 mL, 1.11 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under vacuum to give 194 mg (91% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Temperature: 85 °C
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80-90° C. overnight. The reaction mixture was poured into water (200 ml)/NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191-192° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([CH2:30][NH:31][C@H:32]1[C@H:36]([O:37][CH3:38])[CH2:35][NH:34][CH2:33]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][C@@H:36]([O:37][CH3:38])[C@H:32]([NH:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CO[C@@H]1CNC[C@H]1NCC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NCC(=O)OC(C)(C)C)[C@H](OC)C3)ccc2c1=O

Procedure:
With use of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Example A-1 (4) and (+)-trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxypyrrolidine obtained in Example B-2, there was produced (-)-7-[trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxy-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (amorphous) in the same manner as in Example C-1 (1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1>C(OC)(C)(C)C>[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
Benzyl alcohol (37.5 g, 0.347 mol) and sodium hydroxide (2.96 g, 0.074 mol) were mixed and heated, and sodium hydroxide was dissolved. After cooling, 2-amino-6-chloropurine (6.00 g, 0.035 mol) was added, and the reaction was completed by heating and stirring at 80-90° C. for 5 hr. Methyl tert-butyl ether (120 ml) was added to the reaction mixture, and the mixture was extracted twice with 1% aqueous sodium hydroxide solution (70 ml). The obtained aqueous alkali layers were combined, washed with toluene, and after removing toluene, neutralized with 35% hydrochloric acid to pH 6-8. The precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2-amino-6-benzyloxypurine (7.60 g, 0.032 mol, yield 92%) as crude crystals.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.O>[N:15]([CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])=[N+:16]=[N-:17]
Reactant: CC(OS(C)(=O)=O)c1cc(Br)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethyl methanesulfonate (4.68 g, 16.71 mmol) in anhydrous DMF (45 mL) DMF was added sodium azide (2.17 g, 33.41 mmol) and stirred at room temperature for 2 hours. The reaction was then diluted with 80 mL of water, then extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give the crude product which was used directly without further purification. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.2 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 4.65 (q, J=6.8 Hz, 1H), 1.60 (dd, J=6.8, 0.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[CH2:42]([N:44]([CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])[CH3:43]>C(Cl)Cl>[ClH:41].[CH2:42]([N:44]([CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][C:48]([O:24][C:11]1[C:5]2[C:6]3[CH2:10][CH2:9][S:8][C:7]=3[C:2]([CH3:1])([CH3:25])[O:3][C:4]=2[CH:14]=[C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])[CH:12]=1)=[O:49])[CH3:43]
Reactant: CCN(CC)CCCC(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN(CC)CC)c2c(c1)OC(C)(C)C1=C2CCS1
Yield: 53 %

Procedure:
0.5 g. (1.39 mmole) of 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran, 0.31 g. (1.50 mmole; Aldrich Chemical Co.) of dicyclohexylcarbodiimide and 0.272 g. (1.39 mmole) of 4-diethylaminobutyric acid hydrochloride (F. F. Blicke, W. B. Wright, Jr., and M. R. Zienty, J. Amer. Chem. Soc., 63 2488 (1941)) were combined in 30 ml. of methylene chloride and stirred at room temperature for 4 hours. The insoluble by-product of dicyclohexylurea was separated by filtration and the methylene chloride was removed on a rotary evaporator. Attempts to crystallize the material were unsuccessful and 400 mg. (53%) of dark brown residue was obtained. The structure was confirmed by the IR and NMR spectra; and TLC gave Rf 0.5 in 5% MeOH/CHCl3. The acid addition salt may be converted to the free base form by methods well known in the art, and the resulting free base form may then be reacted with another suitable acid to form a different acid addition salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.P(Br)(Br)([Br:17])=O>CC#N>[Br:17][C:9]1[CH2:10][CH2:11][C:12](=[O:13])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=C1CCC(=O)C1c1ccc(F)cc1
Solvent: CC#N
Product: O=C1CCC(Br)=C1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a 1-Liter 3-neck flask was charged 50 g (0.26 mol) of 2-(4-fluorophenyl)-1,3-cyclopentanedione as a solid to 260 mL of dry MeCN (KF<100 ug/mL). To the resulting suspension was added 18.5 g (0.13 mol) of Na2HPO4 and the sides of the reaction flask were washed with an additional 100 ml of dry MeCN. In a separate flask containing 150 mL of MeCN was added 56 g (0.195 mol) of POBr3. The resulting POBr3 solution was then added drop-wise to the slurry, and the mixture was heated to 65° C. for 1.5 h and cooled to rt. The reaction mixture was quenched with 1N KOH to a final pH of <8.0 and aged for 30 min. During the quench the precipitation of insolubles occurs at pH<4 which turns to an oily mass around pH 7–7.5. The bottom oily layer and aqueous layer were separated. The top MeCN layer containing the product was filtered over a small plug of solka floc, which was then rinsed with one bed volume of MeCN. The combined MeCN layers were then concentrated to a final volume of 500 mL. To the concentrated solution was added 600 mL of water at rt and the mixture seeded with 500 mg of 3-bromo-2-(4-fluorophenyl)-2-cyclopenten-1-one. After aging for 30 min, the remaining 700 mL of water were added drop-wise. After 45 min, the slurry was filtered, washed with 100 mL of water and dried under vacuum at 25° C. giving 3-bromo-2-(4-fluorophenyl)-2-cyclopenten-1-one as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:12]=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of 2-choro-4-cyanobenzyl bromide (6.9 g, 30.0 mmol) in DMF (150 ml), was added sodium azide (2.0 g, 30 mmol) The reaction was stirred overnight at room temperature, and then filtered. The DMF was removed from filtrate in vacuo. The residue was dissolved in EtOAc (300 ml), washed with water (200 ml×3), brine (200 ml×1), dried over sodium sulfate. Removed solvent in vacuo to give 5.8 g of raw 2-choro-4-cyanobenzyl azide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC1(C)CCc2cc(O)ccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)CCC2(C)C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a stirred suspension of 60% sodium hydride (240 mg, 5.87 mmol) in anhydrous tetrahydrofuran (5 ml) was added a solution of crude 1,1-dimethylindan-5-ol (878 mg) in anhydrous tetrahydrofuran (10 ml) dropwise at 0° C. After 15 minutes at 0° C., to this was added ethyl bromoacetate (1.16 g, 6.94 mmol) via a syringe at 0° C. After 2 hours at ambient temperature, the mixtute was quenched with water (15 ml) and extracted with ethyl acetate. The combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with hexane/ethyl acetate=8/1–6/1 to furnish 890 mg (67% yield in 2 steps) of the title compound as a pale yellow oil.