Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:20].C(OCC)C>C(O)C>[C:12]1([C:11]2[C:2](=[S:20])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2cc1-c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCOCC
Product: S=c1[nH]c2ccccc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-phenylquinoline (3.4 g.) and thiourea (1.2 g.) in ethanol (20 ml.) was refluxed for one hour. The solution was allowed to cool to ambient temperature and diethyl ether (10 ml.) was added. The solid which precipitated was filtered off, dispersed in M-sodium hydroxide (70 ml.), and heated on a steam bath for 2 hr. The reaction mixture was acidified with 2 M-hydrochloric acid. The resulting mixture was filtered, and the solid residue was stirred with hot ethanol (50 ml.) and filtered. There was thus obtained as the solid residue 3-phenylquinolin-2-thione, m.p. 242°-4°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25]O)[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25][N:31]4[C:27](=[O:37])[C:28]5[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:30]4=[O:32])[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO)no1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCN2C(=O)c3ccccc3C2=O)no1
Reaction time: 0.58 h
Yield: 123.4 %

Procedure:
To a solution of 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethanol (S5, 5.3 mg), phthalimide (10.9 mg) and triphenylphosphine (19.4 mg) in tetrahydrofuran (1 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (39 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 35 minutes, and then stirred at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 84 to 35% hexane in ethyl acetate) to obtain 2-(2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethyl)isoindoline-1,3-dione (S6, 8.9 mg) as white solid.
Reaction SMILES: S1C(C=[O:7])=CC=C1C=O.C(O)(=O)C.[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][OH:27])=[CH:22][CH:21]=1)[CH3:15]>O>[CH2:14]([CH:16]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:7])=[O:27])=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCCCC(CC)COC(=O)c1ccc(NO)cc1
Reactant: O=Cc1ccc(C=O)s1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 160.6 %

Procedure:
To a 250 ml 3-necked flask was added 0.5 gm 2,5-thiophenedicarboxaldehyde, 30 ml acetic acid, 5.6 gm 2-ethylhexylesterphenyl hydroxylamine 3 and stirred for 20 hrs at room temperature. To the reaction mixture, 100 ml water was added and the mixture was filtered. The filtered product was washed with water and dried. A yield of about 1.6 gm of 2, 5-thiophene bis-2-ethylhexylesterphenyl dinitrone of Ex.2 was obtained with a HPLC purity of 98% (DSC: 205° C.).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:8][C:9]([O:11]C)=[O:10])(=[O:7])[CH:4]([CH3:6])[CH3:5]>O>[C:3]([CH2:8][C:9]([OH:11])=[O:10])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
Sodium hydroxide (0.4 g) was dissolved in water (10 mL), and methyl isobutyrylacetate (1.44 g: made by Fluka) was added and this was agitated for six hours at room temperature. The reaction product was washed with ether, then 10% dilute sulfuric acid (4.9 g) was added and the mixture was extracted with ether. The ether extract was dried by adding excess anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The ether was then removed with a rotary evaporator, yielding isobutyrylacetic acid (yield 1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]1=[O:15]
Reactant: COC(=O)CC1Cc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)CBr
Product: COC(=O)CC1Cc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 89 %

Procedure:
Following a similar N-alkylation procedure described in example 6, the (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.99 mmol) is alkylated with tert-butyl bromoacetate to give (1-tert-butoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as a colorless oil, after purification by silica gel chromatography (hexane/EtOAc). Yield: 89%. MS: (ES+): 356.2 [M+23].
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].C(O)(=O)C.[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH2:19][N:29]3[CH2:30][CH2:31][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a 250 ml round bottomed flask 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate B37) (780 mg, 2.60 mmol) was dissolved in 30 ml of DCM then acetic acid (0.446 ml, 7.79 mmol) and benzyl piperazine-1-carboxylate (1.503 ml, 7.79 mmol) were added. After few minutes sodium triacetoxyhydroborate (2.75 g, 12.99 mmol) was added and the mixture was stirred at r.t. The mixture was poured into 100 ml of DCM and 100 NaHCO3 sat. sol. then phases were separated and the organic one was concentrated to dryness to leave a brown oil that was immediately purified by chromatography eluting with Hexane\EtOAc mixtures to leave the title compound (903 mg, 1.790 mmol, 68.9% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[C@@H:6]([CH3:11])[O:5][C:3]1=[O:4].[OH-:12].[Na+]>CO>[NH2:1][C@@H:2]([C@H:7]([C:8]([OH:10])=[O:9])[C@H:6]([OH:5])[CH3:11])[C:3]([OH:12])=[O:4]
Reactant: [OH-]
Reactant: C[C@H]1OC(=O)[C@@H](N)[C@@H]1C(=O)O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@@H](C(=O)O)[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
2.07 g of 2(S)-amino-3(S)-carboxy-4(R)-pentanolide are suspended in 10 ml of methanol and dissolved by the addition of 13 ml of 2N aqueous sodium hydroxide solution with stirring at room temperature. The solvent mixture is distilled off and acetonitrile is added to the oily residue. The crystals which gradually form are filtered off, washed with a small amount of acetonitrile and dried under a high vacuum. The disodium salt of the title compound remains behind, [α]D20 =-9.0° (1% in water). 1H-NMR (D2O): 1.21 (3H, d 6.4 Hz), 2.54 (1H, dxd 6.4 and 8.4 Hz), 3.49 (1H, d 6 Hz), 3.97 (1H, dxq 8.4 and 6.4 Hz).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21](=[O:40])[N:22]4[CH2:27][CH2:26][N:25]([C:28]5[CH:33]=[CH:32][C:31]([C:34]6[N:39]=[CH:38][CH:37]=[CH:36][N:35]=6)=[CH:30][CH:29]=5)[CH2:24][CH2:23]4)[CH2:16]3)=[O:14])[CH:10]=2)[N:5]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:4]=1)#[N:2].[N-:49]=[N+:50]=[N-:51].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:49]1[C:1]([C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]4[CH2:19][CH2:18][N:17]([CH2:20][C:21](=[O:40])[N:22]5[CH2:27][CH2:26][N:25]([C:28]6[CH:29]=[CH:30][C:31]([C:34]7[N:35]=[CH:36][CH:37]=[CH:38][N:39]=7)=[CH:32][CH:33]=6)[CH2:24][CH2:23]5)[CH2:16]4)=[O:14])[CH:10]=3)[N:5]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:4]=2)=[N:2][N:51]=[N:50]1
Reactant: C[Si](C)(C)CCOCn1nc(C#N)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2nnn[nH]2)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 29 from Example 62 Step 4 (40 mg, 0.061 mmol) in DMF was added NaN3 (12 mg, 0.18 mmol) and NH4Cl (13 mg, 0.24 mmol). The crude was stirred at 100° C. for 18 hrs. The crude was cool, evaporated, and filtered through a plug of cotton. The crude was evaporated and purified via preparation plate to give 31 mg of a mixture of two isomers.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][CH2:12][CH:13]([CH2:20][CH2:21][CH3:22])[CH2:14][C:15](OCC)=[O:16].C(N(CC)CC)C.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:3]([CH2:4][N:11]2[CH2:12][CH:13]([CH2:20][CH2:21][CH3:22])[CH2:14][C:15]2=[O:16])=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: CCCC(CN)CC(=O)OCC
Reactant: Nc1ncccc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC1CC(=O)N(Cc2cccnc2N)C1
Temperature: 25 °C
Yield: 8 %

Procedure:
To a solution of 2-aminonicotinaldehyde x282 (8.19 mmol, 1 eq, 1 g) in 10 ml of EtOH, is added ethyl 3-(aminomethyl)hexanoate hydrochloride x31 (9.83 mmol, 1.2 eq, 2.06 g) and the resulting solution is stirred at room temperature for 1 h30. Then, triethylamine (9.0 mmol, 1.1 eq, 909 mg) is added and the mixture is stirred during 0.5 hour. Sodium borohydride is then added (9.83 mmol, 1.2 eq, 372 mg). The resulting mixture is stirred at room temperature for 20 hours, heated at 55° C. for 21 hours and then overnight at room temperature. Volatiles are removed under vacuum and CH2Cl2 (50 ml) and water (25 ml) are added. The organic layer is washed with water (25 ml) and dried over MgSO4. After filtration, volatiles are removed under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2 (v/v/v)) and recrystallized in AcOEt to afford 1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 230 as a white solid (152 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.C1N=C[N:31](C(N2C=NC=C2)=O)[CH:30]=1.CN>CN(C=O)C.C(Cl)Cl>[CH3:30][NH:31][C:26]([C:24]1[S:25][C:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]([CH3:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:5]=3)[N:20]=2)=[CH:22][CH:23]=1)=[O:27]
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid (Intermediate 62, 316 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added CDI (190 mg, 1.17 mmol). The mixture was stirred for 2 h and then heated at 50 C for 3 h. After this time more CDI (190 mg, 1.17 mmol) was added and the mixture heated at 65 C for 18 h. After cooling to room temperature, methylamine (2 M in THF, 3.5 mL, 7 mmol) was added and the mixture stirred at room temperature for 1 hr The reaction mixture was then diluted with DCM (20 mL), extracted with aqueous sodium hydroxide solution (1M, 20 mL), saturated brine (20 mL) and dried over sodium sulfate. Evaporation of the solvent gave an orange gum which was purified by preparative HPLC (Method A) and then by chromatography on silica eluting with 4% MeOH-DCM to give the title compound (27 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([CH2:31]Cl)=[CH:29][CH:28]=[C:27]([C:33]([F:36])([F:35])[F:34])[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:25]1[C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=[C:27]([C:33]([F:34])([F:35])[F:36])[N:26]=1
Reactant: FC(F)(F)c1ccc(CCl)c(Cl)n1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 70 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (200 mg, 0.62 mmol) and 2-chloro-3-(chloromethyl)-6-(trifluoromethyl)pyridine in anhydrous DMF (4.0 mL) at room temperature was added anhydrous K2CO3 (1.8 g, 13 mmol). The resulting yellow suspension was stirred at 70° C. for 3 h. Analysis by HPLC/MS indicated that starting 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 260 mg (81%) of the title compound as a yellow foam. This product (25 mg) was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 21 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.96 min, [M+H]+=516.1.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13](Cl)=[O:14].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:37])[C:28](=[CH:33][C:34]=1[O:35][CH3:36])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13]([NH:37][C:27]1[C:28](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=1)[C:29]([O:31][CH3:32])=[O:30])=[O:14]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
In a mixture of 3.2 g of methyl 4,5-dimethoxyanthranilate in 30 ml of chloroform is dissolved 3 ml of triethylamine, and to this solution is added a solution of 3.45 g of 3,4,5-trimethoxybenzoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from a mixture of dimethylformamide and ethanol to obtain 4.8 g of methyl N-(3,4,5-trimethoxybenzoyl)-4,5-dimethoxyanthranilate as pale yellow prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21][CH3:22])[CH:4]=1.OO.C(=O)([O-])[O-:26].[K+].[K+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:26])[CH:4]=1
Reactant: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCSC)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCS(C)=O)c1
Reaction time: 3.5 h

Procedure:
One gram of 8-[4-methoxy-2-(2-methylmercapto-ethoxy)phenyl]purine was dissolved in 10 ml of glacial acetic acid and mixed with 0.5 ml of 30% hydrogen peroxide. After standing for 3.5 hours at room temperature, the reaction mixture was diluted with water and made alkaline by means of potassium carbonate. The precipitate was recrystallized from isopropanol/ethanol in a volume ratio of 1:1.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[OH:24]O.[OH-].[NH4+]>C(O)=O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:15]=[CH:16][C@:17]2([OH:24])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 3 h
Yield: 149.6 %

Procedure:
Thebaine (100.0 g dry weight) was dissolved in 85% formic acid (252.3 g). 30% Hydrogen peroxide (43.6 g) was added over a period of about two hours. The mixture was stirred for three hours. Ammonium hydroxide solution was added to the mixture to increase the pH to 8–9. The solid precipitate was filtered and washed with water and ethanol. The solid was dried on the filter and in an oven. The product was 14-hydroxycodeinone (150.52 g damp, 75.32 g dry weight, 75% yield).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C1C=CC(COC([NH:34][C@H:35]([C:44](O)=[O:45])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=O)=CC=1>>[NH2:34][C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C:44]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:45]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method A, and employing ((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-tyrosine-OH as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 7.11 (d, 2H), 6.78 (d, 2H), 4.14-3.86 (m, 2H), 3.40 (dd, 1H), 3.22-3.03 (m, 2H), 3.01-2.88 (m, 1H), 1.94 (br.d, 2H), 1.86-1.58 (m, 6H), 1.51 (dd, 2H), 1.40-1.13 (m, 3H), 1.11-0.93 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.19. LCMS m/z: [M+H]+=399.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][CH2:39][CH:34]([CH2:33][OH:32])[CH2:35]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OCC1CCCNC1
Product: OCC1CCCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-hydroxymethylpiperidine (55.9 mg; 0.48 mmol) to give Example 140 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.55-7.48 (4H, m), 4.40 (1H, t, J=5.2 Hz), 3.61-3.48 (2H, m), 3.34-3.27 (1H, m), 3.25-3.17 (1H, m), 2.87 (1H, d, J=9.3 Hz), 2.74 (1H, d, J=10.9 Hz), 1.96 (1H, t, J=11.0 Hz), 1.76-1.62 (4H, m), 1.50 (1H, d, J=12.6 Hz), 0.92 (1H, d, J=12.3 Hz). LC/MS (Method C): 512 (M+H)+. HPLC (Method E) Rt 2.16 min (Purity: 99.3%).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[CH3:21][C:22]([CH3:50])([CH3:49])[CH2:23][N:24]1[C:28]2[N:29]=[C:30]([C:33]#[N:34])[N:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[CH2:35][N:36]1[C:40](=[O:41])[C:39]2([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[N:38]([CH3:47])[C:37]1=[O:48].Br[CH2:52][CH2:53][CH3:54]>CN(C=O)C>[CH3:21][C:22]([CH3:50])([CH3:49])[CH2:23][N:24]1[C:28]2[N:29]=[C:30]([C:33]#[N:34])[N:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[CH2:35][N:36]1[C:40](=[O:41])[C:39]2([CH2:42][CH2:43][N:44]([CH2:52][CH2:53][CH3:54])[CH2:45][CH2:46]2)[N:38]([CH3:47])[C:37]1=[O:48]
Reactant: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCNCC2
Reactant: CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)C(=O)N2C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a suspension of 27.4 mg (0.685 mmoles) of NaH and 6.5 mg (0.025 mmoles) of 18-crown-6 in 2.0 ml of DMF, 200 mg (0.488 mmoles) of 7-(2,2-Dimethyl-propyl)-6-(1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile is added at ambient temperature. After being stirred for 10 minutes, 75□l (0.823 mmoles) of 1-bromo propane is added at 0° C. and the reaction mixture is stirred for 5 hours at ambient temperature. The reaction mixture is quenched with cold H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated reduced pressure. The residue is purified by silica gel column chromatography to give 90.5 mg of desired 7-(2,2-dimethyl-propyl)-6-(1-methyl-2,4-dioxo-8-propyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 41% yield.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=O)=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)OCc1cccc(C(F)(F)F)c1
Product: O=Cc1cn(Cc2cccc(C(F)(F)F)c2)c2ccccc12
Yield: 95.2 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.68 g of (3-trifluoromethylbenzyl) methanesulfonate and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.98 g of 1-(3-trifluoromethylbenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 95%.