Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:1]1([C:7]2[C:8]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCNC2)ccc1-3
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(S(C)(=O)=O)C2)ccc1-3
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (43 mg, 0.091 mmol) in pyridine (0.5 ml) was added dropwise methanesulfonyl chloride (8.5 μl, 0.11 mmol), and the mixture was stirred at 0° C. for 2 hr. Toluene was added to the reaction mixture and the solvent was evaporated under reduced pressure. Hexane and ethyl acetate were added to the obtained residue, and the precipitate was collected by filtration, washed with hexane, and dried in vacuo to give methyl 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (47 mg, yield 94%).
Reaction SMILES: [Br:1]C1C=C(C2C=CC(C(OCC)=O)=CC=2)C=CC=1O.[H-].[Na+].C(OCCBr)(=O)C.[C:29]([O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:44][CH:43]=2)=[CH:38][C:37]=1Br)(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:44]([Br:1])[CH:43]=2)=[CH:38][CH:37]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)c(Br)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)cc2)cc1Br
Yield: 95 %

Procedure:
In a manner similar to that of Example 6a, by reacting 2 g (6 mmol) of ethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate with 320 mg (8 mmol) of 60% sodium hydride and 0.7 mL (7 mmol) 2-bromoethan-1-ol acetate, 2.2 g of ethyl 4′-(2-acetoxyethoxy)-3′-bromobiphenyl-4-carboxylate are obtained (yield=95%) in the form of a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[N:13]#[C:14][NH2:15].[N+:16]([O-:19])([OH:18])=[O:17]>>[N+:16]([O-:19])([O-:18])=[O:17].[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:14]([NH2:15])=[NH2+:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(-n2ccnn2)cc1
Reactant: N#CN
Product: NC(=[NH2+])Nc1ccc(-n2ccnn2)cc1
Product: O=[N+]([O-])[O-]

Procedure:
4-(1,2,3-triazol-1-yl)phenylguanidinium nitrate was prepared from 4-(1,2,3-triazol-1-yl)aniline (1.42 g, 8.87 mmol), cyanamide (635 mg, 15.1 mmol) and concentrated HNO3 (645 ml, 9.67 mmol) in a manner similar to the corresponding starting material of Example 1, as a white solid (1.0 g), m.p.>320°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][N:18]1[C:25](=[O:26])[CH2:24][C:22](=[O:23])[N:21]([CH3:27])[C:19]1=[O:20]>>[CH3:27][N:21]1[C:22](=[O:23])[C:24]2([CH2:4][C:3]3[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH:15]23)[C:25](=[O:26])[N:18]([CH3:17])[C:19]1=[O:20]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: CN1CCNCC1
Reactant: O=Cc1ccccc1F
Product: CN1CCN2c3ccccc3CC3(C(=O)N(C)C(=O)N(C)C3=O)C2C1
Yield: 55 %

Procedure:
In a manner similar to that described in Example 1, except starting with 2-fluorobenzaldehyde, 1-methylpiperazine and 1,3-dimethylbarbituric acid, 190 mg (55%) of the title compound is obtained. 1H NMR (400 MHz, CDCl3) δ 7.19, 7.04, 6.95, 6.80, 3.98, 3.62, 3.55, 3.39, 3.32, 3.10, 3.04, 2.82, 2.57, 2.23, 2.21, 1.86.
Reaction SMILES: N[CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[CH:10]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:6]([CH:2]1[S:19][C:18]([NH:17][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:20][C:3]1=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: NC(=S)NC1CCCCCC1
Reactant: CC(C)(C)C(N)C(=O)O
Product: CC(C)(C)C1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-3,3-dimethylbutanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: COC(=O)CC[C:6]1(C)[CH2:15][CH2:14][CH2:13][CH2:12][C:7]21OCCO2.CO[C:20](=[O:35])[CH2:21][CH2:22][C:23]1([CH2:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29][C:24]21[O:28][CH2:27][CH2:26][O:25]2.C([C:38]1(CC(O)=O)[CH2:43][CH2:42][CH2:41][CH2:40][C:39]1=O)C>>[CH2:33]([C:23]1([CH2:22][CH2:21][C:20]([C:6]2[CH:7]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[OH:35])[CH2:32][CH2:31][CH2:30][CH2:29][C:24]21[O:25][CH2:26][CH2:27][O:28]2)[CH3:34]
Reactant: CCC1(CC(=O)O)CCCCC1=O
Reactant: COC(=O)CCC1(C)CCCCC12OCCO2
Reactant: CCC1(CCC(=O)OC)CCCCC12OCCO2
Product: CCC1(CCC(O)(c2ccccc2)c2ccccc2)CCCCC12OCCO2

Procedure:
In the same manner but replacing 6-methyl-1,4-dioxaspiro[4.5]decane-6-propionic acid methyl ester with an equivalent amount of 6-ethyl-1,4-dioxaspiro[4.5]decane-6-propionic acid methyl ester, described in Example 7, 1-ethyl-2-oxocyclohexaneacetic acid, identical to the product of the same name in Example 5, is obtained via the respective intermediates, 6-ethyl-α,α-diphenyl-1,4dioxaspiro[4.5]decane-6-propanol, νmaxCHCl3 3450 cm, nmr (CDCl3) δ 0.75 (t, J = 7, 3H), 3.85 (s, 4H), 7.2-7.6 (m, 10H) and 2-ethyl-2-(3,3-diphenylallyl)cyclohexanone, νmaxCHCl33 1740 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@H:28]([C@H:36]([S:38][CH:39]([CH2:42][OH:43])[CH2:40]O)[CH3:37])[CH:29]([N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)O.O.C1(C)C=CC(S(O)(=O)=[O:52])=CC=1>>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:43][CH2:42][C@H:39]([S:38][C@H:36]([CH3:37])[C@:28]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[F:20])([OH:52])[CH2:29][N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH2:40][O:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](SC(CO)CO)[C@H](c1ccc(F)cc1F)C(O)n1cncn1
Reactant: N#Cc1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 1(2), a reaction was carried out using 4′-cyano-4-formylbenzanilide (75 mg, 0.30 mmol) obtained in Example 2(1), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)butanol (98 mg, 0.27 mmol) and p-toluenesulfonic acid monohydrate (62 mg, 0.32 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to give the trans isomer of the title compound (30 mg, yield 19%) as a white solid and the cis isomer (20 mg, yield 12%) as a white solid. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6]C(C)C.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:6])[OH:10]
Reactant: CCP(=O)(CCCN)OC(C)C
Agent: Cl
Product: CCP(=O)(O)CCCN
Reaction time: 14 h

Procedure:
A mixture of 7.73 g of isopropyl 3-aminopropyl(ethyl)-phosphinate and 40 mlof 20% hydrochloric acid is refluxed with stirring for 14 hours. The clear solution is evaporated to dryness and the residue is recrystallized from methanol/propylenoxide to give 3-aminopropyl(ethyl)phosphinic acid as a white solid, m.p. 233°-239°; 1H-NMR (D2O): 0.4-1.8 (m, 9H, PCH2CH2 and PCH2CH3); 2.7 (t, 2H, NCH2); 4.55 (s, 3H, OH, NH2).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:33])([F:35])[F:34]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1cc(Cl)c(OC(F)(F)F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (378 mg, 1.58 mmol) and 1,3-dichloro-2-(trifluoromethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (567 mg, 1.74 mmol) in DMF (10 mL) at rt was added TEA (176 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the final desired title compound 5-(5-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (310 mg; 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.91 (s, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 4.46 (d, J=18.4 Hz, 1H), 4.37 (d, J=18.0 Hz, 1H), 1.48 (s,6H) ppm; HPLC purity: 97.1% at 220 nm and 99.0% at 254 nm; MS: m/z=528.4 (M+, ESI+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S1C2C=CC=CC=2N=C1NC1CCN(CC2C3C(=CC=CC=3)C=CC=2[O:53]CC)CC1.C(=O)([O-])[O-].[K+].[K+].OO.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24](=[O:53])[NH2:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc2ccccc2c1CN1CCC(Nc2nc3ccccc3s2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C(N)=O)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
To a suspension of 4-(5-cyano-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 3.01 mmol, 1.0 equiv; intermediate T (2-(piperidin-4-ylamino)-benzooxazole-5-carbonitrile)/step 1) and 0.084 g (0.6 mmol) of potassium carbonate in DMSO (5 mL) was added a solution of 35% hydrogen peroxide in water (0.53 mL, 0.59 g, 6.02 mmol, 2.0 equiv) and the reaction mixture stirred at ambient temperature for 24 h. The solution was poured on crashed ice, the reaction mixture extracted with dichloromethane/2-propanol (4:1, 3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) containing 33% of NH4OH to yield 1.05 g (97%) of the title compound. MS (ESI): 361.2 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)O)cc1)C1CCC(C(C)(C)C)CC1)n2C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 14 Step C (0.2 mmol, 93 mg) in 2 mL of dioxane was added LiOH (2 mmol, 48 mg) in 1 mL of H2O. The reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford the acid as a white solid. HPLC A: 2.17 min.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[C:13](=[O:23])[N:12]([CH3:24])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:24])[C:13]1=[O:23]
Reactant: Cn1c(=O)n(CCCCBr)c(=O)c2c1ncn2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(CCCCBr)c(=O)c2[nH]cnc21
Yield: 89.7 %

Procedure:
A solution of 2.1 g (0.005 mole) of 95% 7-benzyl-1-(4-brombutyl)-3-methylxanthine in 50 mL methanol and 0.21 g of 20% palladium hydroxide on carbon is hydrated at 40° until cessation of hydrogen absorption (˜1.5 hours). The catalyst is filtered out and washed with hot methanol, then the filtrate is evaporated, yielding 1.35 g of 1-(4-brombutyl)-3-methylxanthine (VI, where R═H, R1=Me, n=4).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
4-(1H-Imidazol-1-yl)aniline (0.159 g, 1.003 mmol), triethylamine (0.101 g, 1.003 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.170 g, 1.003 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (2:1) to obtain the titled compound (0.140 g, 0.272 mmol, 41%).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.F[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=1.[C:38]([O:42][C:43]([C:45]1[CH:55]=[C:54]([OH:56])[C:48]2[CH2:49][CH:50]([CH2:52][OH:53])[O:51][C:47]=2[CH:46]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([C:45]1[CH:55]=[C:54]([O:56][C:27]2[CH:37]=[CH:36][C:30]([C:31](=[O:32])[N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:48]2[CH2:49][CH:50]([CH2:52][OH:53])[O:51][C:47]=2[CH:46]=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Reactant: CN(C)C(=O)c1ccc(F)cc1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(CO)O3)cc1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluoro-N,N-dimethylbenzamide (989 mg, 5.91 mmol) and 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (1.500 g, 5.633 mmol) to give a white solid (154 mg, 7% yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.59 Hz, 2 H) 7.20 (d, J=16.17 Hz, 2 H) 6.96 (d, J=8.59 Hz, 2 H) 4.87-5.03 (m, 1 H) 3.77-3.87 (m, 1 H) 3.71 (br. s., 1 H) 2.99-3.13 (m, 7 H) 2.90 (dd, J=16.55, 7.20 Hz, 1 H) 1.54 (s, 9 H); LCMS for C23H27NO6 m/z 358.20 (M-tBu+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:13]([CH3:17])[C:14](Cl)=[O:15])[CH3:12]>>[CH2:11]([N:13]([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CCN(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Product: CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 96.1 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-ethyl-N-methylcarbamoyl chloride, the reaction is carried out as in Example 1, whereby 1-ethyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 96.1%. Melting point is 88.5° to 89.5° C.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[C:17]([CH3:25])=[C:18](C(O)=O)[O:19][C:20]=1[CH3:21])=[O:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>N1C2C(=CC=CC=2)C=CC=1.CN1C(=O)CCC1>[CH3:21][C:20]1[O:19][CH:18]=[C:17]([CH3:25])[C:16]=1[C:4]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][N:7]([CH3:8])[C:3]=1[CH:1]=[O:2]
Reactant: Cc1oc(C(=O)O)c(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: c1ccc2ncccc2c1
Solvent: CN1CCCC1=O
Product: Cc1coc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Yield: 51.9 %

Procedure:
A mixture of 4-(5-formyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylfuran-2-carboxylic acid (45 mg, 0.13 mmol), phenantroline (9.53 mg, 0.05 mmol) and Cu2O (3.78 mg, 0.026 mmol) in quinoline (0.73 ml) and NMP (2.19 mL) was flushed with N2 and irradiated in the microwave at 190° C. for 15 min. HCl (1M) and CH2Cl2 were added and the phases were separated. The crude product was purified on preparative IIPLC to give 4-(2,4-dimethylfuran-3-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (20.0 mg, 51%).
Reaction SMILES: C([Sn](CCCC)(OCCCC)[O:6][Sn:7]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])CCC>C(O)CCC>[CH2:17]([Sn:7]([CH2:13][CH2:14][CH2:15][CH3:16])([O:6][CH2:9][CH2:10][CH2:11][CH3:12])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Solvent: CCCCO
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Reaction time: 0.1 h
Yield: 34.2 %

Procedure:
A feed pump was used to start feeding the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 110 at 4,600 g/Hr and the reactant 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from alcohol supply line 111 at 22,000 g/Hr. The holding time in the reactor was 6 minutes. The liquid temperature inside the reactor was adjusted to 120° C. Continuous supply was continued in this state for 2 hours, after which the pressure in the system reached a steady state. Low boiling point components flowed through the low boiling point component recovery line 116 for liquefaction at the condenser 117, and were thereby recovered from the liquid-phase recovery line 120 at 18,000 g/Hr. Furthermore, from the reactor lower portion 115, a dibutyltin alkoxide-containing component was recovered at 8,600 g/Hr from the extraction line 121. Analysis of the recovered liquid showed that, using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 34.2% dibutyl-di(butyloxy)tin and 65.7% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.015%. Meanwhile, the liquid recovered from the liquid-phase recovery line 120 was transparent and contained 2,000 ppm of moisture. The dehydration rate in the reactor was 2.5 mol/Hr, which was greater than the value 0.0061 mol/Hr calculated from expression (16).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH:20]O>C(O)(=O)C.[Pd].C(O)C>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:20])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Twenty grams of adenosine (commercialized by Sigma-Aldrich Corporation, St. Louis, Mo. USA, Product code: A9251-25G) was dispersed in one liter of acetic acid, admixed with 100 mL of hydrogen peroxide solution, and stirred at ambient temperature for five days. To the resulting solution was added five grams of 5% palladium on carbon, commercialized by Kawaken Fine Chemicals Co., Ltd, Tokyo, Japan, followed by decomposing an excessive amount of hydrogen peroxide, filtering the resultant to remove palladium carbon, drying the resulting solution in vacuo, adding ethanol to unstiffen the formed crystals, and filtering the resultant to obtain a crude crystalline adenosine N1-oxide. The crude crystals were dissolved by heating in two liters of ethanol, filtered, and ice chilled for crystallization, followed by repeating the recrystallization step twice to obtain eight grams of adenosine N1-oxide with a purity of 99.5%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:27][CH2:26]1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:25]1([CH2:28][O:29][C:30]2[N:31]=[CH:32][C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:34][CH:35]=2)[CH2:26][CH2:27]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc(OCC4CC4)nc3)n2n1
Temperature: 110 °C
Yield: 40.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (104 mg, 0.377 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (75-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (53.7 mg, 41%). 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.90 (d, J=2.5 Hz, 1H), 8.40 (dd, J=8.8, 2.5 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.98 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 5.19 (br. s., 1H), 4.22 (d, J=7.1 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H), 1.25-1.36 (m, 1H), 0.52-0.62 (m, 2H), 0.30-0.42 (m, 2H); ESI-MS: m/z 458.3 (M+H)+.