Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH3:5]C(C)([O-])C.[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1)#[N:12].CC(OC)(C)C>[Cl-].[Na+].O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:5][C@H:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccc(C#N)cc1
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A round bottom flask was charged with (CH3)3S(I)O (37.9 g, 172.4 mmol, 2 eq.) and DMSO (450 mL). With moderate stirring under N2, a clear yellow solution was formed. To this solution was added sodium tert-butoxide (16.5 g, 172.4 mmol, 2 eqs) and the resultant mixture was stirred at RT for 2 h. 21A (20 g, 86.2 mmol, 1 eq) was charged and the container of the acrylate was rinsed forward with DMSO (50 mL). Stirring of the reaction mixture was continued at RT for 16 h. The reaction mixture was analyzed for completion using 1H NMR spectroscopy. After confirming completion of the reaction, the reaction mixture was diluted by sequential addition of MTBE (500 mL) and brine (300 mL). The organic layer was separated, dried over MgSO4 and evaporated to dryness to give crude product. The crude product was purified by flash chromatography, eluting with 5-10% EtOAc in heptanes to give 11.6 g 21B (54% yield) (which was found by 1H NMR to contain a small amount of impurities). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.29 (m, 1H) 1.49 (s, 9H) 1.57-1.69 (m, 1H) 1.83-1.96 (m, 1H) 2.40-2.53 (m, 1H), 7.18 (d, 2H) 7.56 (d, 2H).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.O.[NH2:32][NH2:33]>O1CCCC1>[NH:32]([C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[NH2:33]
Reactant: NN
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)c2c(NN)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 60 °C

Procedure:
To a solution of the 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (30 mg, 0.062 mmol) in tetrahydrofuran (0.5 ml) was added hydrazine monohydrate (15 mL, 0.3 mmol). A yellow precipitate immediately formed and the heterogeneous mixture was heated to 60° C. for 1 hour during which time more solid separated from the reaction. After cooling, the solid product was collected by filtration, washed with ether and dried under vacuum (6 mg, 25%); 1H NMR (d6-DMSO) δ 9.70 (br s, 1H), 9.27 (br s, 1H), 6.85 (s, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.21 (d, J=8.5 Hz, 1H), 5.00 (br s, 2H), 3.73 (s, 6H), 3.71 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[CH:19]=1)=[O:17].[NH2:36][NH:37][C:38]([NH2:40])=[S:39]>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[N:36][NH:37][C:38]([NH2:40])=[S:39])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[CH:19]=1)=[O:17]
Reactant: NNC(N)=S
Reactant: Cc1cccc(C(=O)c2cccc(C(=O)c3cccc(C)c3)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1cccc(C(=O)c2cccc(C(=NNC(N)=S)c3cccc(C)c3)c2)c1
Reaction time: 12 h
Yield: 1.7 %

Procedure:
p-toluenesulfonic acid (0.018 g, 0.09 mmol) was added to a solution of 1-(3-methylbenzoyl),3-(3-methylbenzoyl)benzene 8 (0.300 g, 0.95 mmol) in anhydrous methanol (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.086 g, 0.954 mmol) was added to the reaction mixture and stirred for 12 h under an inert atmosphere of nitrogen gas. After 12 h, methanol was removed under reduced pressure and 10 mL of water was then added. The products were extracted with dichloromethane (2×30 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 90:10 to 80:20) afforded 1-(3-methylbenzoyl),3-(3-methylbenzoyl)benzene thiosemicarbazone 9 (0.063 g, 0.016 mmol) as a white solid in a 17% yield. HRMS (ESI) calculated for C23H21N3OSH+ (M+H)+ 388.14781, found 388.14793. The product was determined to be approximately 80% pure and was submitted for biological testing without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-])=O)(=[O:4])=[O:3].O.NN>C(O)C.CO.[Pd]>[NH2:14][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])[C:9]([OH:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1N
Yield: 70 %

Procedure:
4-methylsulfonyl-3-nitrobenzoic acid (0.90 g, 3.7 mmol) was dissolved in 10 mL ethanol. To it were added hydrazine monohydrate (0.46 mL, 15 mmol) and catalytic amount of 10% Pd/C. The mixture was refluxed for 1.5 hour, diluted with methanol, filtered through celite and concentrated in vacuuo to afford 3-amino-4-methylsulfonylbenzoic acid (>70%). ES-MS: (M+H)+ 216.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][CH3:18])=[C:6]([C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[C:7]([OH:9])=O)[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH2:31])[CH3:24].O(C(C)C)C(C)C>>[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH:31][C:7](=[O:9])[C:6]1[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[O:17][CH3:18])[CH3:24]
Reactant: CCCc1cc(OC)c(OC)c(C(=O)O)c1OC
Reactant: CCN1CCC[C@H]1CN
Solvent: O=S(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCCc1cc(OC)c(OC)c(C(=O)NC[C@@H]2CCCN2CC)c1OC

Procedure:
3-Propyl-2,5,6-trimethoxybenzoic acid (23 g, 0.09 mol) was treated with thionyl chloride and (2S)-(-)-1-ethyl-2-aminomethylpyrrolidine as described in example 4. Yield 10.6 g (32%). M.p. 68°-70° C. (i-Pr2O). 1H-NMR (CDCl3): δ6.73 (s,1H), 6.40 (b,1H), 3.85 (Sx2,6H), 3.76 (s,3H), 0.9-3.8 (m,21H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:27]([C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1)=[O:28])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Colorless solid (46%). MS (ESI): m/z=532.109 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:15][CH2:13][CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-chloro-2′,4′-difluoroacetophenone (10 g, 0.053 mol) and ethyl mercaptan (3.6 g, 0.058 mol) in methanol (200 ml), potassium carbonate (8.8 g, 0.064 mol) was added under ice cooling, followed by stirring at room temperature for 1.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ether. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting oil was distilled under reduced pressure (bp: 115 to 118° C., 2 mmHg), whereby 2′,4′-difluoro-2-(ethylthio)acetophenone (11.4 g, yield: 99.9%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)CC)C>CN1C(=O)CCC1>[N+:16]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26]2)[CH:29]=1)[C:6]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])([O-:18])=[O:17]
Reactant: CN(C)CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2cccc(Nc3ccc(C(=O)OCCN(C)C)cc3[N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 2-(dimethylamino)ethyl 4-chloro-3-nitrobenzoate (2.5 g, 9.1 mmol) and 2d (2.0 g, 9.1 mmol) in anhydrous NMP (5 ml) was added triethylamine (1.3 ml, 9.1 mmol), and the mixture was stirred at 80° C. for 4 hours. The cooled mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (4×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 v/v) as the eluent to yield 2-(dimethylamino)ethyl 3-nitro-4-(3-(1-acetylpiperazin-4-yl)anilino)benzoate (1 g, 24%). This intermediate product was dissolved in ethanol (50 ml) and was hydrogenated quantitatively at ambient pressure, using Pd (5% on activated carbon) as the catalyst. The resulting diamine was dissolved in THF (50 ml) and triethyl orthoformate (0.7 ml, 4.2 mmol) was added, together with a catalytic amount of pTSA. The mixture was heated to reflux for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between aqueous sodium carbonate (1M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure, and the residue was chromatographied on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1) as the eluent. The product isolated from the eluate was treated with activated carbon in refluxing ethanol and the product thus obtained was triturated with petroleum ether to yield 4i (0.18 g, 20%). M.p. 101-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Yield: 74.9 %

Procedure:
A mixed solution of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (7.70 g, 15 mmol), 4-fluorophenylboronic acid (2.52 g, 18 mmol) and sodium carbonate (3.97 g, 37.5 mmol) in toluene (50 mL), methanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (0.87 g, 0.9 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.16 g, 74.9%) as crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1)CCC>CC#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
To a solution of 0.500 g (2.70 mmol) of 4-bromobenzaldehyde and 1.00 g (2.67 mmol) of 2-tributylstannylthiazole in MeCN (25 mL), degassed by bubbling N2 through for 10 min, was added 0.100 g (0.140 mmol) of palladium dichloride bis(triphenylphosphine). The mixture was heated to 60° C. for 15 h. The mixture was cooled to room temperature and filtered through diatomaceous earth. The mixture was diluted with H2O and washed with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.400 g (79.1%) of 4-thiazol-2-yl-benzaldehyde as a yellow solid.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (45 mg, 0.05 eq.), (R)-BINAP (110 mg, 0.05 eq.) and 4-chloro-phenylboronic acid (1.20 g, 2.2 eq.). 100 mL of MeOH and 10 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (0.70 g). The reaction mixture was heated at 55° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.36 g (33%) of the title product as a light yellow oil. ES-MS m/e: 314.0 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:3])[CH3:2].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([CH:23]=O)=[CH:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH2:12][CH2:13]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: CC(C)Oc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
108 mg of the target compound (0.28 mmol, 50.8%) was obtained using 1-(2-isopropoxyphenyl)piperazine (240 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Na].[C:2]([C:5]1[N:10]=[C:9]([P:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[N:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:8]=[CH:7][CH:6]=1)([OH:4])=[O:3].C([O-])(=O)C.[Gd+3:34].C([O-])(=O)C.C([O-])(=O)C>O>[Gd:34].[C:27]([C:23]1[N:22]=[C:21]([P:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([OH:4])=[O:3])[N:10]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: [Gd+3]
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(P(c2cccc(C(=O)O)n2)c2cccc(C(=O)O)n2)n1
Agent: [Na]
Solvent: O
Product: [Gd]
Temperature: 90 °C

Procedure:
A reaction flask was equipped with a reflux condenser, agitator, addition funnel, nitrogen source and heating bath. The tris(6-carboxy-2-pyridyl)phosphine sodium salt (310 mg, 0.67 mmol, MW 463) from Example 9 was dissolved warm demineralized water (10 mL) and the resultant solution was filtered and charged to reaction flask. Gadolinium (III) acetate (260 mg, 0.64 mmol, MW 406 for tetrahydrate, 1 equiv) was dissolved in warm demineralized water (10 mL) and the resultant solution was filtered and charged to the addition funnel. The bath was heated to 90° C. and the gadolinium acetate solution was added dropwise with agitation over 30 min. Once the addition was complete, the reaction was cooled to ambient temperature and the white solids were isolated by filtration and washed with demineralized water. The solids were dried in vacuo to afford 130 mg of white solids (369 mg theoretical yield for anhydrous complex, 93% by HPLC area %), and having the structural formula shown below: ##STR14##
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:30]([NH2:32])=[O:31].O.C(O)(=O)C>CS(C)=O>[CH3:18][O:17][C:12]1[C:11]([CH3:19])=[C:10]([C:8]2[CH:9]=[CH:4][C:5]3[C:20]4[N:24]([C@H:25]5[CH2:29][CH2:28][O:27][CH2:26]5)[N:23]=[CH:22][C:21]=4[C:30](=[O:31])[NH:32][C:6]=3[CH:7]=2)[C:15]([CH3:16])=[CH:14][N:13]=1
Reactant: COc1ncc(C)c(-c2ccc(-c3c(C(N)=O)cnn3[C@H]3CCOC3)c(F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c1C
Reaction time: 0.83 h
Yield: 96.1 %

Procedure:
Sodium hydroxide powder (9.43 g) was added at one time to a solution of 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide (37.2 g) in DMSO (186 mL) at room temperature. The reaction mixture was stirred at the same temperature for 50 minutes and then at 70° C. for 45 minutes. Under water-cooling, water (600 mL) was added dropwise to the reaction mixture, and then acetic acid (13.5 mL) was added dropwise. The precipitated powder was collected by filtration. The collected subject was washed with water and MTBE and then dried under reduced pressure to give the title compound (34.0 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25](B(O)O)[C:20]=2[O:19][CH2:18]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:2]3[N:11]=[CH:10][C:9]4[NH:8][C:7](=[O:12])[CH:6]5[CH2:13][O:14][CH2:15][CH2:16][N:5]5[C:4]=4[N:3]=3)[C:20]=2[O:19][CH2:18]1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: OB(O)c1cccc2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: O=C1Nc2cnc(-c3cccc4c3OCO4)nc2N2CCOCC12

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 84 using 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 50 mg, 0.208 mmol), benzo[d][1,3]dioxol-4-ylboronic acid (51.7 mg, 0.312 mmol) and PdCl2(dppf) (7.60 mg, 10.39 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.96-3.09 (m, 1 H), 3.62 (m, 2 H), 3.93-4.01 (m, 1 H), 4.11-4.20 (m, 1 H), 4.36-4.46 (m, 1 H), 4.52-4.62 (m, 1 H), 6.12 (s, 2 H), 6.94 (t, 1 H), 7.02 (m, 1 H), 7.58-7.65 (m, 1 H), 7.83 (s, 1 H), 10.98 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C16H14N4O4, 327.10; found 327.3.
Reaction SMILES: N1(C([O-])=O)CCCCC1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][CH:32]([CH3:34])[CH3:33])[C:28]([C:35]2[O:36][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[N:38][N:39]=2)=[CH:27][N:26]=1>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][CH:32]([CH3:34])[CH3:33])[C:28]([C:35]2[O:36][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[N:38][N:39]=2)=[CH:27][N:26]=1.[Cl:24][C:25]1[N:26]=[CH:27][C:28]([C:35]2[O:36][C:37]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)=[N:38][N:39]=2)=[C:29]([NH:31][CH:32]([CH3:34])[CH3:33])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)Nc1cc(Cl)ncc1-c1nnc(S(C)(=O)=O)o1
Agent: O=C([O-])N1CCCCC1
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 90 °C

Procedure:
Synthesis of tert-butyl 445-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate (45): tert-butyl 4-aminopiperidine-1-carboxylate (8 mmol, 5 equiv.) was added to a stirred solution of 2-chloro-N-isopropyl-5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (44) (500 mg, 1.7 mmol) in Dioxan (5 mL) and heated at 90° C. for 4 h. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH:DCM as eluent to afford the desired compound, tert-butyl 4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.049 min; LCMS (ES-API), m/z 437.2 (M+H).