Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C(C)C)(C(C)C)[S:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1)(C)C.Cl>CCO>[SH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1CCc2ccc(S[Si](C(C)C)(C(C)C)C(C)C)cc2O1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(S)cc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 7-[(triisopropylsilyl)thio]chromane-2-carboxylate (5.6 g, 14.2 mmol) in EtOH (100 ml) was added concentrated HCl (4 ml) and the mixture was stirred at room temperature for 3 h. Evaporation to dryness gave the title compound. Yield: 3.4 g. MS m/z (rel. intensity, 70 eV) 238 (M+, 75), 165 (bp), 163 (56), 132 (50), 131 (43).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])[CH:2]=[CH2:3].Br[CH2:10][C:11]#[N:12].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][CH2:5][C:6]([O:8][CH2:10][C:11]#[N:12])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCOCC(=O)O
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOCC(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
2-(Allyloxy)acetic acid (0.500 g, 4.31 mmol) was dissolved in dichloromethane (20 ml), and 2-bromoacetonitrile (2.06 g, 17.18 mmol) and triethylamine (0.87 g, 8.61 mmol) were slowly added at room temperature. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford cyanomethyl 2-(allyloxy)acetate (0.40 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cn1cnc(-c2ccnc(N)c2)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: Cn1cnc(-c2ccnc(NC(N)=O)c2)c1-c1ccc(F)cc1
Temperature: 50 °C
Yield: 65.4 %

Procedure:
4-[5-(4-Fluoro-phenyl)-1-methyl-1H-imidazol-4-yl]-pyridin-2-ylamine (72 mg, 0.27 mmol) and benzoyl isocynate (59 mg, 0.40 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (56 mg, 0.40 mmol). The mixture is then heated at 80° C. for 35 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (45 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is washed with methanol (3×5 mL) and dried to give 55 mg of the titled product.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@H:8]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:7]1[C:22]([O:24][CH3:25])=[O:23].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[Na+].[Na+]>O>[O:10]=[C:9]1[NH:6][C@@H:7]([C:22]([O:24][CH3:25])=[O:23])[C@H:8]1[NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reaction time: 1 h

Procedure:
To 900 ml of acetonitrile, which had been thoroughly degassed with argon, was added 30.0 g (0.070 mole) of methyl cis-1-(2,4-dimethoxybenzyl)-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate and the solid was rinsed into the reaction vessel with an additional 50 ml of degassed acetonitrile. This solution was heated to 78° under argon and to it was added a degassed solution of 75.6 g (0.28 mole) of potassium persulfate and 37.5 g (0.14 mole) of sodium monohydrogen phosphate in 1400 ml of water. Addition of the aqueous solution was made in six portions of 250 ml over a period of 1 hour while maintaining the external temperature between 78° and 82°. After cooling the reaction mixture, the acetonitrile was removed by evaporation. Sodium chloride was added to the concentrated reaction mixture and it was extracted four times with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered and concentrated in vacuo to approximately 100-200 ml. Addition of ether (ca. 300 ml) followed by low temperature (-25° C.) crystallization afforded the title compound; tlc: silica gel GF, ethyl acetate, Rf=0.44; ethyl acetate:benzene (1:1), RF=0.21; mp 140°-141° (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([OH:23])=O)=[CH:16][N:15]=2)=[N:6]1.C(Cl)CCl.C1C=CC2N(O)N=[N:38]C=2C=1.N>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([NH2:38])=[O:23])=[CH:16][N:15]=2)=[N:6]1
Reactant: On1nnc2ccccc21
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)O
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 250 mg (0.688 mmol) of the compound from example 45A were initially charged in dimethylformamide (3.8 ml). Subsequently, 145 mg (0.757 mmol) of EDC and 116 mg (0.757 mmol) of HOBt were added, and finally 77 μl (1.03 mmol) of aqueous ammonia solution (25%) were added. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The organic phase was washed once each with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was admixed with tert-butyl methyl ether, and the solids were filtered off and dried under high vacuum. This gave 171 mg (66% of theory) of the title compound in solid form.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([Cl:77])[CH:72]=1)[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:73]1[CH:72]=[C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])[CH:76]=[CH:75][CH:74]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2cccc(Cl)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0661 g, 0.215 mmol), HATU (0.0744 g, 0.196 mmol), and DIEA (d 0.742; 0.0341 mL, 0.196 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(3-chlorophenyl)acetic acid (0.072 g, 0.196 mmol, see Example B, Step 3) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4), concentrated to an oil and purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(3-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.090 g, 0.154 mmol, 78.7% yield). LC/MS=3.79 minutes, (APCI+) m/z=584 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nn2ccccc2c1I
Reactant: Nc1ccc(B(O)O)cc1
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Solvent: O
Product: CC(C)c1nn2ccccc2c1-c1ccc(N)cc1

Procedure:
4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 4-aminophenylboronic acid monohydrate following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine as in Example 59 above (134 mg, 18%). 1H-NMR (250 MHz, DMSO-d6) δ 8.58 (d, J=7.0 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.14-7.04 (m, 3H), 6.77 (t, J=7.0 Hz, 1H), 6.67 (d, J=8.5 Hz, 2H), 5.15 (s, 2H), 3.23 (sept, J=6.8 Hz, 1H), 1.26 (d, J=7.0 Hz, 6H). LC/MS 252.3 m/z (M+H+). Compound 1101.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cnn(CCO)c3)n(-c3ccccc3)c(=O)c12
Yield: 8.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.12 mmol) was treated with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (66 mg, 0.28 mmol, prepared according to Perry, Benjamin Garfield; Sabin, Verity Margaret from PCT Int. Appl. (2009), WO 2009122148 A1 20091008), sodium carbonate (2M, 565 μl, 1.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.02 mmol) according to the method described in Example 3 to give 5 mg (8% yield) of the title compound. Purity 92%.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OOC(C)(C)C)(C)(C)C>>[CH:7]1([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCCCC1
Reactant: CCCCCO
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCOC1CCCCC1
Temperature: 90 °C
Yield: 40 %

Procedure:
Into a pressure vessel 1-pentanol (109 μL, 1 mmol, 1 eq) was added and diluted with cyclohexane (1.080 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing cyclohexane under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 40%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([OH:30])[CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:26][NH:25][C:23](=[O:24])[C:22]3[CH:21]=[C:20]([OH:19])[CH:29]=[C:28]([OH:30])[CH:27]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NNC(=O)c1cc(O)cc(O)c1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=C(C)NNC(=O)c1cc(O)cc(O)c1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3,5-dihydroxybenzoic hydrazide, 57.0 mg of the desired product was obtained in the same manner as in Synthetic Example 1 as a pale red solid (yield 73%).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[NH:15][C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[CH2:3]([CH:10]1[N:15]([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COCC(Cc2ccccc2)N1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COCC(Cc2ccccc2)N1C(CCN1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% NaH (80 mg, 2 mmol) in dry dimethylformamide (8 ml) was added 5-benzyl-3-morpholinone (880 mg, 2 mmol). The mixture was stirred at room temperature for 1 hour. To this were added 4-(3-chloro-3-phenylpropyl)morpholine (480 mg, 2 mmol) and dry dimethylforamide (1 ml). The mixture was then stirred overnight at 60° C. The stirred mixture was placed under reduced pressure to evaporate the solvent. Water was added to the residue, and extraction with ethyl acetate was performed. The extract was washed with a saturated aqueous brine and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to remove the solvent. The oily residue was placed on silica gel column and eluated with ethyl acetate/methanol (20/1) to yield the desired diastereomer A (168 mg, 21.3) and diastereomer B (156 mg, 19.8%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>CN(C)C=O.O>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:20](=[O:21])[CH:19]([Br:18])[CH3:23])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(Br)C(=O)Br
Reactant: CC(=O)c1cccc(N)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(NC(=O)C(C)Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred solution of 3-amino acetophenone (1.0 g, 7.35 mmol) in dimethylformamide (DMF) (10.0 mL) was added triethylamine (Et3N) (1.11 g, 11.03 mmol) at 0° C. followed by the slow addition of 2-bromopropionyl bromide (1.75 g, 8.08 mmol). The reaction was stirred at room temperature (rt) under N2 atmosphere for 3 h, diluted with water (50.0 mL) and the precipitated pale brown solid was filtered and dried to give the title product in 80% yield. 1H NMR (CDCl3, 400 MHz): 8.47 (br s, NH), 8.09-8.08 (m, 1H), 7.92 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.73 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 4.60 (q, J=6.8 Hz, 1H), 2.62 (s, 3H), 1.96 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): 198.0, 167.8, 137.8, 137.7, 129.5, 124.8, 124.6, 119.5, 44.8, 26.7, 22.7. ESI-MS calcd for C11H12BrNO2 (M+Na)+291.99. found 292.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12](CC3C=CC(OC)=CC=3)[CH2:11][CH2:10][C:9]=2[N:8]=1.O.[N+]([O-])([O-])=O.[NH4+].[Ce].S(NN)(C1C=CC(C)=CC=1)(=O)=O>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[NH:12][CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: COc1ccc(CN2CCc3nc(COc4cccc(F)c4)ccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: O
Solvent: CC#N
Product: O=C1NCCc2nc(COc3cccc(F)c3)ccc21
Yield: 35.3 %

Procedure:
2-((3-Fluorophenoxy)methyl)-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (300 mg, 0.77 mmol) from above was dissolved in CH3CN (5 mL) and water (2 mL) added. Cerium ammonium nitrate (419 mg, 0.77 mmol) was added and after 15 min, the reaction was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layers were concentrated and purified by RP-HPLC (0 to 90% CH3CN). Product containing fractions were treated with PS-TsNHNH2 (2 equiv) to give the compound as a solid (74 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.38 (1H, d, J=8), 7.56 (1H, d, J=8), 7.27 (1H, dd, J=16, 7.6), 6.77 (1H, dd, J=13.2, 2.0), 6.71 (2H, m), 5.96 (1H, br s), 5.20 (2H, s), 3.67 (2H, t, J=6.2H), 5.96 (1H, br s), 5.20 (2H, s), 3.67 (2H, t, J=6.8 Hz), 3.24 (2H, t, J=6.8 Hz); LC-MS (M+H)=273.2.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21]([NH:23][C:24]([NH2:26])=[NH:25])=[NH:22])=[CH:17][CH:16]=1>C(O)C>[ClH:11].[NH2:26][C:24]1[NH:23][C:21]([NH:20][CH2:19][C:18]2[CH:27]=[CH:28][C:15]([C:14]([F:13])([F:29])[F:30])=[CH:16][CH:17]=2)=[N:22][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:25]=1
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 4.4 ml (25.6 mmol) of 1-nonanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 26 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)) to give a residue, which was dissolved in 80% aqueous ethanol. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 2.3 g of a colorless resinous solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=1[CH:32]=O.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=1[CH:32]1[O:4][CH2:1][CH2:2][O:3]1
Reactant: OCCO
Reactant: COC(=O)c1cc(C=O)c(Cl)nc1C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2OCCO2)c(Cl)nc1C(=O)OC
Temperature: 25 °C
Yield: 93 %

Procedure:
Ethylene glycol (14.3 mL, 0.255 mol), and a catalytic amount of p-toluenesulfonic acid monohydrate is added to a solution of 6-chloro-5-formyl-2,3-pyridinedicarboxylic acid, dimethyl ester, 5-(dimethyl acetal) (15.46 g, 0.051 mol) and toluene. The reaction mixture is heated at reflux temperature for 3 hours, cooled to room temperature, treated with ether, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as an orange oil (14.27 g, 93%), identified by IR and NMR spectral analyses.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20][C@@H:21]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O.Br[C:39]#[N:40]>C(Cl)Cl.[Cl-].[Na+].O>[C:39]([N:25]1[CH2:24][CH2:23][CH:22]([C@H:21]2[N:16]3[N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20]2)[CH2:27][CH2:26]1)#[N:40]
Reactant: N#CBr
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC[C@H]2C1CCNCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCC([C@@H]2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of (S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (417 mg, 1 mmol) in DCM (20 mL) was added NaHCO3 (168 mg, 2 mmol) and water (5 mL), followed by BrCN (127 mg, 1.2 mmol). The mixture was stirred at RT for 16 h. To the mixture was added DCM (50 mL) and brine (20 mL). The organic phase was further washed with brine (100 mL), dried over Na2SO4. Concentrated and purified by Pre-TLC (DCM/MeOH, 50/1) to afford 330 mg (75%) of white solid. MS (ESI) m/e [M+1]+ 443.0.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[C:9]([OH:28])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN(CCO)CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(C)CCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound A-6 (333 mg, 51.4%) was obtained in the same manner as that in Reference Example 2, by using N-methyldiethanolamine (Tokyo Chemical Industry Co., Ltd.; 119 mg, 1.00 mmol) and oleic acid (Tokyo Chemical Industry Co., Ltd.; 621 mg, 2.20 mmol)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:22][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]#[N:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCOC(C#N)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(C#N)Cc1ccc(O)c(N)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 3-(4-benzyloxy-3-nitrophenyl)-2-ethoxypropanenitrile (0.54 g, 1.7 mmol) in ethanol (25 ml) and acetic acid (75 ml) containing 10% palladium on carbon (0.40 g) was hydrogenated at 45 psi for 1 hour. The catalyst was filtered and the solution concentrated. The residue was treated with 5% sodium bicarbonate (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml), dried over sodium sulfate and concentrated. The product was isolated by column chromatography (silica gel, 2% methanol in chloroform) as a solid (0.20 g, mp 114°-115° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)c1cn(C(C)C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=601 (M+1); 1H NMR (CDCl3) δ: 11.0 (s, 1H), 8.68 (s, 1H), 8.54 (d, 1H J=9 Hz), 8.5 (d, 1H, J=6 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.25-7.23 (m, 3H), 6.81 (dd, 1H, J=3.9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.96 (p, 1H, J=7 Hz), 4.05 (d, 6H), 3.83 (s, 3H), 1.47 (d, 6H, J=6 Hz).