Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[Cu]>[N:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([OH:12])(=[O:11])=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(F)c(S(=O)(=O)O)c1
Agent: [Cu]
Product: Cc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 65.4 %

Procedure:
According to the method described in Example 1 of Japanese Patent Application Laid-Open No. 3-7263, 2-fluoro-5-methylbenzene sulfonic acid (0.76 g) was reacted with piperazine (3.44 g) in the co-presence of cuprous iodide (0.76 g) and copper powder (0.26 g) in a sealed tube at 160° C. for 8 hours. Then, the reaction product was purified on silica gel column chromatography (eluent=chloroform: methanol: acetic acid=100: 100: 3) to give anhydrous crystal of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative (0.67 g, yield=65.0%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][CH:32]([C:35]#[N:36])[C:33]#[N:34]>O1CCCC1>[NH2:36][C:35]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([OH:10])=[N:31][C:32]=1[C:33]#[N:34]
Reactant: O=C=NCc1ccccc1
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(O)n(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
Benzylisocyanate (25 g, 188 mmol) and N,N-diisopropylethylamine (23.5 ml, 130 mmol) were added to aminomalononitrile p-toluenesulfonate (45 g, 178 mmol) suspended in tetrahydrofuran. The mixture was stirred at room temperature for 14 hours and then the solvent was removed in vacuo. To the residue was added ethyl acetate and the solution was washed and the organic layer was dried on magnesium sulfate. The solvent was removed in vacuo. To the residue was added tetrahydrofuran and 1N aqueous sodium hydroxide. The solution was stirred at 50° C. for 20 minutes, and neutralized with 15% aqueous potassium hydrogen sulfide. The resulting crystals were filtered and dried to give the subject compound (41 g, 106%). The crude product was used for next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1
Reactant: c1ccc2c(c1)NCC21CCC1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC2(CCC2)c2ccccc21

Procedure:
214 mg (0.63 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 100 mg (0.628 mmol) spiro[cyclobutane-1,3′-indoline], 212 mg (0.66 mmol) TBTU and 168 μL (1.20 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and the acetonitrile was removed using the rotary evaporator. The precipitated substance was suction filtered, washed with 20 mL water and dried in the CAD at 50° C.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[CH2:11]O.[C:14]([O:18][C:19]([NH:21][O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([N:21]([CH2:11][C@H:3]1[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1([Cl:13])[Cl:1])[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON(C[C@H]1[C@H](c2ccccc2)C1(Cl)Cl)C(=O)OC(C)(C)C
Temperature: -42 °C
Yield: 94 %

Procedure:
A solution of KOH (3.36 g, 60 mmol) and the product of Step 1, above, (10.36 g, 40 mmol) in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and water (90 ml) was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with diethyl ether (100 ml+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 ml) and brine (50 ml), then dried over MgSO4. Evaporation of the solvent afforded (2,2-dichloro-trans-3-phenylcyclopropyl)methanol in quantitative yield. To a stirred solution of the alcohol thus prepared (4.34 g, 20 mmol), N,O-di-tert-butoxycarbonylhydroxylamine (5.83 g, 25 mmol), and triphenylphosphine (6.56 g, 25 mmol) in toluene (40 ml), cooled to −42° C. was added dropwise a solution of diethyl azodicarboxylate (4.35 g, 25 mmol) in toluene (5 ml) over 15 minutes under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature overnight, insolubles were removed by filtration and the filtrate concentrated under reduced pressure. The resultant residue was purified by column chromatography (SiO2, 300 g; 8% ethyl acetate in n-hexane) affording the title compound (8.09 g, 94% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](N[C@H](C(O)=O)C)[CH:5]=[CH:6][C:7]=1[OH:8].CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[NH2:30][C@H:31]([C:40]([OH:42])=[O:41])[CH2:32]C1C=CC(O)=CC=1>>[O:41]=[C:40]([C@H:31]([CH2:32][C:4]1[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=1)[NH2:30])[OH:42]
Reactant: C[C@H](Nc1ccc(O)c(O)c1)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reaction time: 6 h

Procedure:
After confirming stationary phase, DOPA (3,4-dihydroxyphenyl-L-alanine) was introduced to the concentration of 1 mM in the medium. After introducing DOPA, inducer IPTG(isopropyl-β-D-thiogalactopyranoside, 1 mM) was added to induce the expression of the above proteins. After adding IPTG, culture was conducted at 37° C. for additional 6 hours. For a positive control, tyrosine was introduced to the concentration of 1 mM instead of DOPA, and the expression of the proteins was induced with IPTG, and for a negative control, nothing was introduced. After culture, the cells were centrifuged at 4000 rpm for 10 minutes, and then, supernatant was removed, and the cells were recovered.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([F:25])=[N:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:9]1)=O)(C)(C)C.ClC1C=CC(CN)=CC=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[F:25][C:19]1[C:18]([CH2:17][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][CH:9]=2)=[CH:23][CH:22]=[C:21]([F:24])[N:20]=1
Reactant: CC(C)(C)OC(=O)n1cc(Cc2ccc(F)nc2F)c2cccnc21
Agent: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(Cc2c[nH]c3ncccc23)c(F)n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To 3-(2,6-difluoro-pyridin-3-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (536, 0.35 g, 1.0 mmol, prepared as described in Example 49, Scheme 164, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 532 with 1H-pyrrolo[2,3-b]pyridine in step 1) in N-methylpyrrolidinone (3.00 mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) and N,N-diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction was stirred at 50° C. for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude intermediate was dissolve in dichloromethane (15.0 mL) and trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give a white solid (P-0154, 0.18 g, 72%). MS (ESI) [M+H+]+=246.2.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[C:9]([I+]C1C=CC=CC=1)#[CH:10].[C:18]([O-:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C(Cl)Cl.O>[C:18]([O:26][C:9]#[CH:10])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])c1ccccc1
Reactant: C#C[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#COC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
Ethynyl(phenyl)iodonium trifluoromethanesulfonate (3.78 grams, 10 millimoles) dissolved in 10 milliliters of methylene chloride was mixed with sodium benzoate (7.2 grams, 50 millimoles) dissolved in 20 milliliters of water. The reactants were stirred for 5 minutes at 0° C. The organic layer was concentrated by evaporation and chromatographed on silica gel columns to isolate 0.77 grams of ethynyl benzoate (53% yield). The product was identified by spectroscopic means, and had a melting point of 43° C.(dec).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:16]([O:8][CH2:7][C@@H:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)CO
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
The compound of Example 68-1 (308 mg, 2.57 mmol) was dissolved in methylene chloride (10 ml), and thereto were added triethylamine (704 mg, 6.95 mmol), 4-dimethylaminopyridine (33 mg, 0.27 mmol), and t-butyldimethylsilyl chloride (524 mg, 3.48 mmol). The mixture was stirred at room temperature for 2 hours, and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (356 mg, 57%).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([OH:20])=[C:7]([CH:21]=[O:22])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([O:20][CH2:2][CH3:3])=[C:7]([CH:21]=[O:22])[CH:6]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Iodoethane (0.77 g) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.09 g), potassium carbonate (0.91 g), and DMF (20 mL), and the mixture was stirred at 60 C for 2 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.07 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][CH:14]([CH:15]=[CH2:16])[CH:4]([CH:5]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH:7]=[N:8][OH:9])[O:3]1.C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1([CH3:18])[O:3][CH:4]2[CH:5]([O:10][CH2:11][O:12][CH3:13])[CH2:6][C:7]3[CH:15]([CH2:16][O:9][N:8]=3)[CH:14]2[O:17]1
Reactant: C=CC1OC(C)(C)OC1C(CC=NO)OCOC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCOC1CC2=NOCC2C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 57 h
Yield: 0 %

Procedure:
4,5-(Dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal oxime (89.5 mg) was dissolved in 4 ml of methylene chloride, and 0.035 ml of triethylamine was added at 0° C. A 10 % sodium hypochlorite aqueous solution (2.6 ml) was added at 0° C., and the mixture was stirred at 0° C. for 57 hours. The reaction mixture was diluted with diethyl ether, and washed with saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to provide 0.0 mg of 4,5-(dimethylmethylenedioxy)-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following properties (yield 56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]1([C:45]2[O:49][N:48]=[C:47]([C:50]3[C:55]([Cl:56])=[CH:54][N:53]=[CH:52][C:51]=3[Cl:57])[C:46]=2[CH2:58]O)[CH2:44][CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:41]1([C:45]2[O:49][N:48]=[C:47]([C:50]3[C:51]([Cl:57])=[CH:52][N:53]=[CH:54][C:55]=3[Cl:56])[C:46]=2[CH2:58][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:42][CH2:43][CH2:44]1
Reactant: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 mg, 0.36 mmol), triphenylphosphine (94 mg, 0.36 mmol) and [5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (Example 9e) (0.11 mg, 0.36 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.064 mL, 0.36 mmol). The mixture was heated to 90° C. for 10 minutes and then allowed to stand overnight. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution followed by further purification (silica gel, 0-30% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (53 mg, 26%). 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.99 (m, 1H), 3.94 (s, 3H), 2.45-2.34 (m, 4H), 2.15-2.02 (m, 1H), 1.99-1.89 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[CH3:16][NH2:17].[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[CH:21][N:20]=1.Cl>>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:25][C:24]2[C:19](=[N:20][CH:21]=[N:22][CH:23]=2)[N:18]=1
Reactant: CN
Reactant: Nc1cncnc1N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Agent: Cl
Product: CNS(=O)(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 50 from 2-methoxy-4-chlorosulfonyl-benzoic acid, aqueous methylamine solution, and 4,5-diamino-pyrimidine. The crude free base was converted into the hydrochloride with 2N hydrochloride acid, and the hydrochloride was purified by boiling with methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[C:5]=1[OH:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (2.78 g) and 3,4-dihydro-2H-pyrane (1.81 g) in benzene (39 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at ambient temperature, and the mixture was stirred for 24 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform—methanol) and crystallized with n-hexane to give 2-nitro-6-(tetrahydropyran-2-yloxy)phenol (2.32 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:14][OH:15])[CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1ccc2c(c1)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC2=NO
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
5-Methoxy-2,3-dihydroinden-1-one (1 g, 6.17 mmol) was added to a solution of hydroxylamine HCl (730 mg, 10.5 mmol) in 10 ml of water. The mixture was brought up to 70° C. and a solution of sodium acetate (1.4 g, 16.7 mmol) in 7 mL of H2O, 14 ml of MeOH, 3 ml of THF was added. After stirring for 1.5 h at 70° C., 10 ml of H2O was added to produce a precipitate and the suspension was allowed to stir for 2 h. The precipitate was collected by filtration to give 5-methoxy-2,3-dihydroinden-1-one oxime almost quantitatively and was used in the next step without further purification. The oxime (0.5 g, 2.82 mmol) was dissolved in MeOH and a catalytic amount of Raney nickel and 25 mL of ammonia solution in MeOH (7N) was added. The reaction was stirred at r.t. overnight under H2. The slurry was filtered over celite and concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude title amine (yield, 45%). The crude amine was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[OH:15].C(N([CH2:21][CH3:22])CC)C.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:9]=1[O:15][C:9](=[O:15])[C:8]1[CH:13]=[CH:12][C:21]([CH3:22])=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Oc1cccc(CCCCCCBr)c1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Oc2cccc(CCCCCCBr)c2OC(=O)c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 180.8 %

Procedure:
To 9.0 g (0.033 mol) of 1-(6-bromohexyl)-2,3-dihydroxybenzene in 200 mL of anhydrous tetrahydrofuran and 13.7 mL (0.099 mol) of triethylamine stirred in an ice bath was added 10.9 mL (0.082 mol) of 4-methylbenzoyl chloride dropwise over 30 minutes. After 30 minutes, the bath was removed and stirring was continued at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was treated with sodium bicarbonate and the product was extracted with ether. The dried extract was concentrated to an oil which was purified by HPLC using 10% ethyl acetate-hexane to give 15.2 g (90% yield) of 1-(6-bromohexyl)-2,3-bis[(4-methylbenzoyl)oxy]benzene as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][N:19]=[CH:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:25]4[CH:24]=[CH:23][C:22]([N:17]5[CH:21]=[CH:20][N:19]=[CH:18]5)=[CH:29][CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(-n4ccnc4)cc3)nc(=O)c1-2
Temperature: 130 °C
Reaction time: 72 h
Yield: 94.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.18 g, 5.32 mmol), 4-(1-imidazolyl)benzaldehyde (1.37 g) and xylenes (8 ml) was warmed to 130° C. for 30 minutes, then to 160° C. for three days. The reaction mixture was cooled, and the product was collected by filtration and washed with Et2O to afford 1.88 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one as the 6,7-saturated derivative. This derivative was mixed with ethanol (300 ml) and 30% H2O2 (3.0 ml) and refluxed overnight. Additional 30% H2O2 (3 ml) was added and the mixture was refluxed for 8 hours. An additional 10 ml of 30% H2O2 was added and the mixture was refluxed overnight. Starting material was still present so an additional 10 ml of 30% H2O2 was added and the mixture was refluxed for 4 hours and then additional 30% H2O2 (10 ml) was added and the mixture was stirred for 1 hour, then was allowed to stand at room temperature overnight. The reaction mixture was stripped to a yellow liquid and purified by column chromatography on silica gel eluting with ethyl acetate (100%), then 5% methanol/ethyl acetate to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]-pyrazolo[3,4-d]pyrimidin-4-one 1/2 hydrate, m.p. >300° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[CH:12]([O:15][C:16](C)=[O:17])(C)[CH3:13]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:16]([O:15][CH2:12][CH3:13])=[O:17]
Reactant: CCOC(=O)c1cccnc1
Reactant: CC(=O)OC(C)C
Product: CCOC(=O)c1cccnc1C(=O)OCC

Procedure:
To a suspension of 2,3-pyridinedicarboxylic acid (200 g, 1.2 mol) in ethanol (800 ml) was added conc H2SO4 (100 ml) and this mixture was heated to reflux for 3 days (mechanical stirring). It was then cooled down to r.t. and added to crushed ice. Conc NH4OH (405 ml) was then added slowly and the pH was adjusted to 9 by addition of some aq. NH4Cl. The products were extracted into i-PrOAc, dried over Na2SO4 and concentrated to yield 182.48 g of an orange oil containing 88% of the diester (60% yield), 8.1% of ethyl 3-pyridinecarboxylate and 3.5% i-PrOAc. This mixture was used as such in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.O.[N-:10]=[N+:11]=[N-:12].[Na+]>O1CCOCC1>[N:10]([CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc(CCl)cs1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NCc1csc(N)n1
Yield: 70 %

Procedure:
To a solution of 4-chloromethyl-thiazol-2-ylamine (7.45 g, 50.0 mmol) in dioxane:water mixture (8:2) was added sodium azide (4.87 g, 75.0 mmol) and the reaction mixture was refluxed for 2-3 h. The mixture was concentrated in vacuo to remove all dioxane and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with water (2×200 mL), brine (2×200 mL), dried over (Na2SO4) and concentrated in vacuo to give 4-azidomethyl-thiazol-2-ylamine in 70-90% yield.