Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:78])([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:26]=2[CH2:34][O:35][C:36](=[O:63])/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:62])([F:61])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:78])([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[CH2:34][O:35][C:36](=[O:63])/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:62])([F:61])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57]([F:58])([F:59])[F:60])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ccc(N)cc2COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 87 %

Procedure:
9.22 g (8.38 mmol) of [4,4′-dinitro-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}-phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexa-hydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.59 g of [4,4′-diamino-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.CC#N.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:26][C:6]=3[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][CH2:9][C:10]=12)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Reactant: C#CC(C)(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#CC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 439 %

Procedure:
A mixture of 5 (300 mg, 0.732 mmol) available from procedure [0051] in triethyl amine (5 mL) and CH3CN (8 mL) was stirred with 3,3-dimethyl-1-butyne (12.3 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) acetate (38.3 mg, 0.051 mmol) and heated to reflux under nitrogen. After 5 hours, the reaction mixture was cooled to rt and filtered. The filtrate was concentrated under vacuum and the residue was treated with H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The organic layers were combined and washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified via flash chromatography (silica gel, EtOAc/hexanes: 1/1) to furnish the t-butylacetylene 24(XLi340) as a yellow powder (271 mg, 90%): mp: 155-156° C.; IR (KBr) 2358, 1717, 1489, 1248, 1074, 803, 668 cm−1; 1HNMR (CDCl3) δ 1.25 (s, 9H), 1.45 (t, 3H, J=7.1 Hz), 4.05 (d, 1H, J=12.3), 4.45 (2H, J=7.1 Hz), 5.95 (d, 1H, J=12.3 Hz), 7.3-7.7 (m, 8H), 7.95 (s, 1H); MS (EI) m/e (relativity intensity) 412 (M+, 46), 365 (46), 337 (100), 322 (8), 277 (16), 219 (14). Anal. Calcd. For C26H25N3O2.½H2O, C 74.26, H 6.23, N 9.99. Found. C, 74.50; H, 6.29; N, 9.89.
Reaction SMILES: N1C=CC(N2CCC([CH2:13][NH:14][C:15]3[C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=3)CC2)=CC=1.[NH4+].C(Cl)(Cl)=[O:26]>O1CCOCC1>[C:20]12[C:15](=[N:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13](=[O:26])[O:23][C:21]2=[O:22]
Reactant: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Cl)Cl
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2c(=O)o1
Reaction time: 2 h

Procedure:
A solution of ammonium 2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]pyridine-3-carboxylate (3.0 g, 9.12 mmol) in dioxane (45 mL) was treated with phosgene (1.9 M in toluene, 9.50 mL, 18.2 mmol), and the resulting mixture was heated at reflux. After 2 h, the mixture was concentrated yielding the corresponding aza-isatoic anhydride which was used without further purification. A solution of the crude anhydride (300 mg, 0.648 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with the magnesium salt of 2-amino-5-chloropyridine [2.60 mmol; freshly prepared by addition of methyl magnesium bromide (3.0 M in THF, 0.865 mL, 2.60 mmol) to 2-amino-5-chloropyridine (900 mg, 3.89 mmol) in THF (10 mL) at 0° C.]. After 17 h, the mixture was treated with a saturated aqueous solution of ammonium chloride and then partitioned between EtOAc and water. The aqueous layer was washed with EtOAc (3×) and the combined extracts were washed with water (1×), dried with sodium sulfate, and concentrated. The residue was purified by RPHPLC yielding 29 mg (9%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 12, piretanide can be reacted with chloromethyl pivalate, triethylamine and sodium iodide in DMF to yield_t-butylcarbonyloxymethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:16]([F:15])([F:26])[F:27])=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(C(F)(F)F)cc1
Yield: 57.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (1.0 g, 5.3 mmol), 4-(trifluoromethyl)benzoyl chloride (0.79 mL, 5.3 mmol), and pyridine (1.1 mL, 13 mmol) in acetonitrile (50 mL) provided N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)-4-(trifluoromethyl)benzamide (1.1 g). MS (ESI) m/z 358 ([M−H]); m/z 360 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:35]=[C:36]([F:38])[CH:37]=1.O>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][CH:42]([CH2:5][CH2:4][CH2:3][F:2])[CH2:41][CH2:40]2)[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Reactant: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FCCCC1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
THF in an amount of 100 ml was added to 12.5 g (31.0 mmol) of the 3-fluoropropyltriphenylphosphine bromide synthesized in the first step, and cooled down to 0° C. under nitrogen gas atmosphere. Solution of 3.4 g (31.0 mmol) of potassium-t-butoxide in 30 ml of THF was added thereto and stirred for 3 hours. To this reaction product was added dropwise a solution of 5.0 g (23.8 mmol) of the 4-(3,5-difluorophenyl)cyclohexanone synthesized in the second step in 50 ml of THF at 0° C., stirred at the temperature as it was for 1 hour, warmed up to room temperature, and then stirred for further 4 hours. Water in an amount of 100 ml was added to the reaction product, the product was extracted with ethyl acetate, the extract was washed with saturated aqueous sodium bicarbonate solution and water in turn, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was purified by column chromatography treatment using toluene as eluent. The purified product was subjected to hydrogenation in ethanol in the presence of 5% Pd/C catalyst. After termination of the reaction, the catalyst was filtered off, the ethanol was distilled off under a reduced pressure to obtain 1.3 g (5.1 mmol) of 4-(3,5-difluorophenyl)-1-(3-fluoropropyl)cyclohexane. Yield of this product from 4-(3,5-difluorophenyl)cyclohexanone was 21%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccccc1CN
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1CNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
25 g (0.177 mole) of 1-Flouro-2-nitrobenzene is added to a 500 ml round bottom flask containing a solution of 200 ml of anhydrous DMF and 24.28 g (0.177 mole) of 2-Methoxybenzylamine. 73.27 g (0.531 mole) of K2CO3 is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered through celite and washed with 400 ml of ethyl acetate. The filtrate is then washed twice with 200 mL saturated brine and twice with 200 mL water. The organic layer is dried over anhydrous Na2SO4 concentrated in vacuo to afford 32 g (0.13 mole, 76%) of (2-methoxy-benzyl)-(2-nitro-phenyl)-amine (1). 1H NMR (400 MHz, DMSO) 8.6 (m, 1H), 8.0 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 6.6 (m, 1H) 4.6 (m, 2H), 3.8(s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][OH:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:35]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:21]=[C:22]([CH2:30][O:31][CH3:35])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
After dissolving 322 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of dichloromethane, 364 mg of 1,8-bis(dimethylamino)naphthalene and 240 mg of Me3O+BF4 were added and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (169 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][C:23]=2[F:27])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:28]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]1>CCCCCCC.CCO.CO>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][C:23]=3[F:27])[C:2]([N:28]3[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Reactant: O[C@H]1CCNC1
Solvent: CCO
Solvent: CCCCCCC
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 5 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)nicotinamide (Stage 25.1) and (S)-3-pyrrolidinol to afford a white solid. HPLC (Condition 5) tR=5.69 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV 210 nm) tR=12.62 min, UPLC-MS (Condition 6) tR=0.97 min, m/z=468.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.81 (m, 1H) 1.81-1.92 (m, 1H) 3.02 (d, J=11.34 Hz, 1H) 3.24-3.37 (m, 2H) 3.40-3.49 (m, 1H) 4.23 (br. s, 1H) 4.89 (br. s, 1H) 7.32 (d, J=9.4 Hz, 2H) 7.76-7.98 (m, J=9.00 Hz, 3H) 8.03 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.20 (br. s, 1H) 12.99 (br. s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2cccc(C#N)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from the 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 23 and 3-cyanophenylboronic acid, 5-(3-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=59%).
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][OH:9].[C:32]1([CH3:39])[C:37](O)=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:39]
Reactant: Cc1ccccc1O
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Yield: 42.3 %

Procedure:
To a solution of 3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.065 g, 0.145 mmol) in toluene (4 ml) at ambient temperature was added o-cresol (0.020 g, 0.186 mmol) under Argon with stirring. The mixture was treated with polymer bound PPh3 (0.076 g, 0.228 mmol). After 15 minutes of stirring, the mixture was treated with DIAD (0.036 g, 0.178 mmol) and was stirred at ambient temperature overnight. The reaction mixture was filtered then concentrated, in vacuo, to dryness. The oil was dissolved in DMSO and was purified via reverse-phase HPLC to yield the title compound (0.033 g, 42%); MS (ES+) m/e 539 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:35]=[CH:36][C:29]=12.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][O:18][C:28]3[N:33]=[CH:32][N:31]=[C:30]4[N:34]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][O:38]5)[N:35]=[CH:36][C:29]=34)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Reactant: OCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OC(COc1ncnc2c1cnn2C1CCCCO1)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A toluene solution (30 mL) of 3-[4-[bis(4-fluorophenyl) methyl]-1-piperazinyl]-1,2-propanediol (3.98 g, 11 mmol) was added dropwise to a stirred mixture of 4-chloro-1-(tetrahydropyran-2-yl)-pyrazolo[3,4-d]pyrimidine (2.387 g, 10 mmol), powdered KOH (0.485 g, 8.51 mmol), 18-crown-6 (3, 90.2 mg, 0.34 mmol) in toluene (70 mL) over a 20 min period. The mixture was stirred at room temperature for 3 h and washed with water (3×70 mL). The organic layer was dried (Na2SO4), filtered and evaporated to dryness. The oily residue (7.0 g) was purified on a medium pressure silica gel column eluting with increasing proportions of methanol in methylene chloride. The title compound was obtained as the major product (1.49 g, 41%), mp 101°-105° C. IR (KBr) cm-1 : 2466, 2446, 2401, 1603, 1568, 1506, 1347, 1222. 1H NMR (CDCl3) δ: 8.35 (s, 1H, 3 or 6-H), 8.12 (s, 1H, 3 or 6-H), 6.9-7.4 (m, 8H, Ar--H), 5.0 (m, 1H, N--O--CH--C), 4.6 (m, 2H, OCH2), 4.23 [s, 1H, CH(O)2 ], 4.15 (m, 2H, HCOH, O--CHN), 3.8 (m, 1H, OCNH), 1.6-2.9 (m, 16H, CH2, NCH2 ; MS(DCI): 565 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%).
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>C(Cl)Cl>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:27]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)N(NC(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N'-t-butyl-N'-3-toluoyl hydrazine (4.03 g, 0.02 mole) in methylene chloride (25 ml) under nitrogen was added 4-chlorobenzenesulfonyl isocyanate (5 g, 80%, 0.02 mole) at room temperature. The exothermic reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil. A precipitate appeared after treating with ether. The pure product was collected by suction-filtration and washed with a small amount of ether affording 4.8 g of 1-t-butyl-1-(3-toluoyl)-4-(4-chlorobenzenesulfonyl)semicarbazide as a white solid. m.p. 184-188° C.