Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[CH2:20][C:21](=O)[C:22]([CH3:33])([C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=1)[CH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][CH:20]=[C:21]([C:22]([CH3:33])([C:24]3[CH:25]=[C:26]([F:32])[C:27]([F:31])=[C:28]([F:30])[CH:29]=3)[CH3:23])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(C)(C(=O)CCl)c1cc(F)c(F)c(F)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C(C)(C)c3cc(F)c(F)c(F)c3)cs2)ccc1-n1cnc(C)c1
Yield: 69.1 %

Procedure:
A suspension of 78.7 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and of 90.2 mg (0.36 mmol) 1-chloro-3-methyl-3-(3,4,5-trifluoro-phenyl)-butan-2-one in ethanol (3 ml) was heated to reflux over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol 19/1 to 9/1 as eluent to yield 95 mg (69%) of the title compound as a light yellow solid. MS ISP (m/e): 459.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.38 (s, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.23-7.18 (m, 3H), 7.01 (s, 1H), 6.88 (d, 1H), 6.69 (s, 1H), 3.68 (s, 3H), 2.13 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CS(C)=O>[N:11]1([C:8]2[N:7]=[C:6]([C:17]3[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=3)[N:5]=[C:4]3[C:9]=2[N:10]=[C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:3]3[CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), morpholine (61 μl, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 3 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (56 mg, 50%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:59]=[CH:58][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]OS(C)(=O)=O)[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:60]=[N+:61]=[N-:62].[Na+].C1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:60]=[N+:61]=[N-:62])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:59][CH:58]=2)=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCOS(C)(=O)=O)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCN=[N+]=[N-])O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.5 %

Procedure:
5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-methanesulfonyloxy-1-hepten-1-yl)-thymidine (219 mg, 0.25 mmole), sodium azide (100 mg, 1.5 mmole) and tetrabutyl ammonium iodide (10 mg, 0.025 mmole) were placed in a dry flask under nitrogen and benzene (5 mL) was added. The mixture was heated under reflux for 14 hours, poured onto ice (15 mL) and extracted four times with dichloromethane (30 mL each). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure to provide a white solid. Chromatography on a silica gel column with ethyl acetate/hexane mixtures gave 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-azido-1-hepten-1-yl)-thymidine (5) (192 mg, 94%), m.p. 72°-74° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1.C(O)(=O)C>ClCCCl.CO>[NH:21]1[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:3]2[C:2]([N:1]3[CH:34]=[CH:38][CH:37]=[CH:36]3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3cccc3)cn2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (121 mg, 0.285 mmol) was dissolved in DCE (6 mL) and 2,5-dimethoxytetrahydrofuran (75.3 mg, 0.57 mmol) and acetic acid (2 mL) were added. The solution was heated for 1 h at 80° C. then a further aliquot of acetic acid (2 mL) was added. The solution was heated at 80° C. for a further 30 min then cooled to room temperature and partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane and the combined organic phases were evaporated to give an orange oil. The residue was dissolved in methanol and absorbed onto a TsOH solid phase extraction cartridge, washed once with methanol and allowed to stand for 1 h. The cartridge was then eluted with a solution of 7M ammonia in methanol and the solution was evaporated to dryness. The residue was purified by HPLC to give 5-(4-(piperidin-3-ylmethylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile (4.3 mg, 4%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].F[C:16]1C([N+]([O-])=O)=C(O)C=CC=1.CI.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:16][O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(O)cccc1F
Reactant: O=[N+]([O-])c1c(F)cccc1OCCO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCOc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
In analogous manner to that described in Preparation Example 1 Variant A a), 3g of 2-[3-fluoro-2-nitrophenoxy]ethanol were prepared from 5g of 3-fluoro-2-nitrophenol. 1.4g of the alcohol were then reacted with 7ml methyliodide with the addition of 14ml of 50% sodium hydroxide and 0.1g of the phase transfer catalyst, triethylbenzylammonium chloride. The mixture was stirred at room temperature for 2 hours. 20ml of water was then added and the product extracted into 50ml diethyl ether and the ether layer dried using magnesium sulphate. 0.8g (yield of 53%) of 3-fluoro-2-nitrophenyl (2-methoxyethyl) ether were obtained, after the solvent had been removed by evaporation, as an oil which solidified on standing. 0.8g (54% yield) of 5,7-dimethyl-2-(N-[2-fluoro-6-(2-methoxyethoxy)phenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (Compound No. 11) were prepared from the ether via the 2-amino derivative in an analogous procedure to that described in Preparation Example 1, Variant A.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:13])[C:7]2([CH2:11][CH2:10][NH:9][CH2:8]2)[O:6][C:5](=[O:12])[CH2:4]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([C:36](O)=[O:37])[CH2:35][CH2:34]3)=[C:29]([F:39])[CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[CH3:2][C:3]1([CH3:13])[C:7]2([CH2:11][CH2:10][N:9]([C:36]([C:33]3([C:30]4[CH:31]=[CH:32][C:27]([N:24]5[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:26][CH2:25]5)=[CH:28][C:29]=4[F:39])[CH2:34][CH2:35]3)=[O:37])[CH2:8]2)[O:6][C:5](=[O:12])[CH2:4]1
Reactant: CC1(C)CC(=O)OC12CCNC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)O)CC3)c(F)c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2-one hydrochloride (20.3 mg, 0.0000988 mol) and 1-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2-fluorophenyl}cyclopropanecarboxylic acid (36.0 mg, 0.0000988 mol) in N,N-dimethylformamide (0.30 mL, 0.0039 mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (48.1 mg, 0.000109 mol) followed by N,N-diisopropylethylamine (0.0206 mL, 0.000118 mol). After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried. The crude residue was used directly in the next step without further purification. LCMS (M+H) 516.3. (M+Na) 538.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])=O)[CH:2]=1.C[O-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:14][C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[CH:2]=1
Reactant: NC(=O)c1ccccc1NC(=O)c1cccnc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2cccnc2)nc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of the benzamide compound (11.5 g, prepared in Reference example 6) in 100 mL of toluene was added 95% sodium methoxide (5.7 g). The solution was heated at 60°-80° C. for three hours under nitrogen atmosphere. After cooling to room temperature, the solution was diluted with ammonium chloride solution. After stirring for one-half hour, the mixture was filtered. An NMR of the filtered material indicated the reaction was incomplete. The material was taken up in toluene and ethanol and 95% sodium methoxide (5.7 g) was added. The resulting solution was heated to reflux and stirred via a mechanical stirrer, under nitrogen atmosphere, overnight. The solvent had evaporated and the concentrate in the flask was collected and washed with ammonium chloride solution and methylene chloride. The solid material was collected by filtration and allowed to dry to give the title compound as a gray powder having the following physical data.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=[O:18])C1C=CC=CC=1>>[O:18]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:11]1
Reactant: O=Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Product: O=C1CCOc2ccccc21

Procedure:
2-Hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII under suitable conditions to provide chroman-4-one compounds of structure XXXXIII. In some embodiments, 2-hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII, pyrrolidine, and methanol, with heating to about 50° C. for about 2 days to provide chroman-4-one compounds of structure XXXXIII. Chroman-4-one compounds of structure XXXXIII are then reacted tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate, potassium bicarbonate, a suitable arylbromide, and 1,4-dioxane/water (4:1,) at about 110° C. to provide chroman-4-one compounds of structure XXXXIV. Chroman-4-one compounds of structure XXXXIV are then treated with methyl magnesium chloride in tetrahydrofuran at about 0° C., followed by 80% AcOH/H2O with warming to about 90° C. to provide compounds of structure XXXXV.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:11]=1[C:12]#[N:13]>O>[OH:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=1[C:12]#[N:13]
Reactant: COc1cccc(OC)c1C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(O)cccc1O
Temperature: 210 °C
Yield: 59.9 %

Procedure:
Another potential method utilizes pyridine hydrochloride in place of the boron tribromide. Into a 500 mL 3-neck round bottom flask equipped with stir bar, nitrogen inlet and condenser was charged 2,6-dimethoxybenzonitrile (15.0 g, 91.9 mmol), followed by pyridine hydrochloride (150 g). The mixture was heated to 210° C. for 2 hours and allowed to cool to room temperature. Water was then added to the flask to dissolve the solidified mixture. The aqueous layer was then extracted with ethyl acetate (150 mL) 3 times. The combined organic layer was dried under anhydrous sodium sulfate, and the solvent was removed to yield 7.44 g (60.0%) of a light pink solid, m.p.: 202.8-204.8° C. 1H-NMR (DMSO-d6): 6.39-6.41 (d, 2H, Ar—H), 7.20-7.24 (t, 1H), 10.78 (s, 2H, Ar—O—H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:7]1[C:2]([CH3:1])=[CH:3][C:4](=[O:9])[NH:5][C:6]1=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Product: Cc1cc(=O)[nH]c(=O)n1Cc1ccccc1

Procedure:
substituting 6-methyl-2,4(1H,3H)-pyrimidinedione and benzyl bromide gave 1-benzyl-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 228°-230° C.;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=1.C(Cl)CCl>C(Cl)Cl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To 3-(trifluoromethyl)benzoic acid (380 mg, 2.00 mmol), 4-amino-2-methylphenol (271 mg, 2.20 mmol) and EDC (767 mg, 4.00 mmol) was added CH2Cl2 (80 mL). The resulting mixture was stirred for 66 hours at RT, concentrated, dissolved in EtOAc and washed with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc/hexanes) to yield N-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)benzamide as a white solid. MS m/z=296 [M+1]+. Calc'd for C15H12F3NO2: 295.26.
Reaction SMILES: [C:1]([NH:4][O:5][CH2:6][C:7]([NH2:9])=[S:8])(=[O:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([N:4]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:7](=[S:8])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NOCC(N)=S
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1OCC(=S)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
1.48 g (10 millimoles) of alpha-(acetylaminooxy)-thioacetamide are dissolved in a mixture of 10 ml of acetic acid and 1.3 ml of acetic anhydride, thereafter 1.3 ml (13 millimoles) of freshly distilled benzaldehyde and then 0.5 ml of concentrated sulfuric acid are added. The mixture is stirred for 3 hours at room temperature, then 2.8 g of crystalline sodium acetate are added, stirred for 10 minutes, thereafter the solvent is evaporated under vacuum. The residue is dissolved in 30 ml of ethyl acetate, the solution is extracted with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate then evaporated to dryness. The residue is crystallized from ethanol at a temperature of +5° C. 1.25 g (52.9%) of crystalline title product are obtained. M.p.: 172°-174° C. Rf (A)=0.43.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:27])([F:26])[C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](O)=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:5][C:6]([F:27])([F:26])[C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18]([Cl:3])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl

Procedure:
Thionyl chloride (4.4 parts by volume) was added to 3.26 parts of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid, and the mixture was refluxed for 3 hours. After the reaction, the excess of thionyl chloride was removed under reduced pressure to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride. A solution of the resulting propionyl chloride in 10 parts by volume of ether was added dropwise under ice cooling to a solution of 3.34 parts of diethyl aminophosphonate in 20 parts by volume of ether. Ten minutes later, 1 part by volume of triethylamine was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, a saturated aqueous solution of sodium bicarbonate and water in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.6 parts of a crude product. The crude product was recrystallized from ethyl acetate/ether to give 1.1 parts of the captioned compound. This compound had a melting point of 134.5° to 135° C., and its IR and NMR spectral data are shown in Table 1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with ethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.21 (t, 3H, J=7.1 Hz), 1.98-2.06 (m, 6H), 3.04-3.16 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.05-4.14 (m, 4H), 5.02-5.08 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=446.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.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>O1CCCC1.FC(F)(F)C(O)=O>[CH2:24]([N:18]1[C:19](=[O:20])[C:15]2[C:16](=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[C:17]1=[O:21])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 12.8 %

Procedure:
A solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (150 mg, 0.48 mmol), phenethylalcohol (70 μl, 0.58 mmol) and triphenylphosphine (191 mg, 0.73 mmol) in anhydrous tetrahydrofuran (6 ml) was treated with diisopropyl azodicarboxylate (141 μl, 0.73 mmol) at room temperature and stirred for 6 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a brown oil. The oil was dissolved in trifluoroacetic acid (7 ml) and heated to 65° C. for 24 hours. The mixture was concentrated under reduced pressure and the product was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid which was purified by flash column chromatography (12 g SiO2, 30% ethyl acetate in hexanes). Fractions containing the product were concentrated under reduced pressure. The solid was triturated in ethyl acetate, cooled to 0° C. and filtered to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione as a white solid (18 mg, 13%). M.p.=237-239° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.51 (s, 1H), 7.23 (m, 6H), 3.85 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H); LCMS: 293 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10](O)=[O:11])=[C:4]([N+:13]([O-])=O)[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:8][CH2:9][C:10](=[O:11])[NH:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CNc2ccc(F)cc2N1
Temperature: 90 °C
Yield: 103.1 %

Procedure:
Iron powder (6.52 g, 116.8 mmol, 5.0 eq) is added at room temperature to a stirred solution of (4-fluoro-2-nitro-phenylamino)-acetic acid (6.85 g, 23.4 mmol, 1.0 eq) in glacial acetic acid (40 mL). The resulting suspension is heated at 90° C. for 3 hours, then cooled to room temperature, diluted with ethyl acetate (40 mL), and filtered through silica gel. The filtrate is concentrated to give a crude that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:3, v/v) to afford 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one as a brown solid (4.01 g, 72% yield).