Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(=O)C1C(=CC=CC=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(N=NC(N(C)C)=O)=O.C([NH:62][C:63]1[S:64][CH:65]=[C:66]([CH2:68][CH2:69][O:70][C:71]2[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=2[C:73]([O:75][CH3:76])=[O:74])[N:67]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1COCC1.CO>[NH2:62][C:63]1[S:64][CH:65]=[C:66]([CH2:68][CH2:69][O:70][C:71]2[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=2[C:73]([O:75][CH3:76])=[O:74])[N:67]=1
Reactant: COC(=O)c1ccccc1OCCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(=O)c1ccccc1O
Solvent: CO
Product: COC(=O)c1ccccc1OCCc1csc(N)n1
Reaction time: 8 h

Procedure:
Ethyl 2-aminothiazole-4-acetate (931 mg, 5.0 mmol) was dissolved in DCM (10 mL) and TEA (0.765 mL, 5.5 mmol). Trityl chloride (1.53 g, 5.5 mmol) was added in portions. The mixture was left overnight at room temp and filtered. The filtrate was evaporated and the product purified by flash-chromatography on silica gel using 20% ethyl acetate/toluene as eluent: 1H NMR (CDCl3) δ 7.2-7.4 (m), 6.6 (s, 1H), 6.15 (s, 1H), 4.2 (q, 2H), 3.5 (s, 2H), 1.3 (t, 3H). A solution of the tritylated ethylester (5 mmol) in THF (18 mL) was added to lithium aluminiumborohydride (1.00 g, 26 mmol) in THF (100 mL) under cooling in ice. The mixture was stirred overnight at room temperature and then cooled in ice. Aqueous sodium hydroxide (10%, 15 mL) was added carefully. The solution was separated from the precipitate. The precipitate was washed with THF and ethyl acetate. The combined solutions were evaporated and the residue dissolved in ethyl acetate (80 mL) and washed with brine. Evaporation and chromatography on silica gel with 20% and 50% ethyl acetate in toluene gave 1.22 g product, 63% yield: 1H NMR (CDCl3) δ 7.2-7.4 (m), 6.4 (s, 1H), 6.0 (s, 1H), 3.75 (t, 2H), 2.7 (t 2H). This material (386 mg, 1.0 mmol), methyl salicylate (183 mg, 1.2 mmol) and triphenylphosphine (314 mg, 1.2 mmol) were dissolved in THF (5 mL). N,N,N′,N′-tetramethylazo-dicarboxamide (206 mg, 1.2 mmol) was added and the solution was left overnight. The mixture was filtered and the filtrate was purified by flash-chromatography on silica gel using toluene and ethyl acetate/toluene as eluent. Yield 418 mg, 80%: 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.4 (m, 1H), 7.18-7.38 (m), 6.95 (m, 2H), 6.5 (s, 1H), 6.15 (s, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.0 (t, 2H). MS-ES (pos) m/z 521.2. Methyl 2-{2-[2-(tritylamino)-1,3-thiazol-4-yl]ethoxy}benzoate (343 mg, 0.656 mmol) was mixed with methanol: conc. HCl 9:1 (50 mL) and heated to 60° C. for 24 h. The mixture was concentrated to 10 mL, filtered and the filtrate was made alkaline with aqueous sodium carbonate (1 M). The solution was extracted with chloroform. Evaporation gave a product that was purified by flash-chromatography on silica gel using 0-2% methanol/DCM as eluent. Yield 128 mg, 70% (partially crystalline): 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.42 (t, 1H), 6.96 (m, 2H), 6.35 (s, 1H), 4.29 (t, 2H), 3.85 (s, 3H), 3.05 (t, 2H). MS-ES (pos) m/z 279.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:14][C:13](=O)[C:12]2[C:11]3[C:10]([C:16](OC)=[O:17])=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1.[CH3:21]I.CN1C2CCCC3=[N:37][NH:38]C(=O)C4C(C=23)=C1C=CC=4>>[CH3:1][C:2]1([CH3:20])[CH2:14][C:13]2=[N:37][NH:38][C:16](=[O:17])[C:10]3[C:11]4[C:12]2=[C:4]([N:5]([CH3:21])[C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1
Reactant: Cn1c2c3c4c(cccc41)C(=O)NN=C3CCC2
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)(C)C3
Reactant: CI
Product: Cn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2

Procedure:
Compound 23 was prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate and methyl iodide according to the procedures for Compound 22 under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 9.86 (s, 1H), 7.42-7.53 (m, 2H), 7.12 (t, 1H, J=7.8 Hz), 3.66 (s, 3H), 2.67 (s, 2H), 2.20 (s, 2H), and 1.04 (s, 6H). MS (ESI) m/e [M+1]+ 268.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([NH:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[C:20]=2[CH3:27])=[O:17])[CH:10]=[CH:11][C:12]=1[F:13].C(N(CC)C(C)C)(C)C.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:25][C:21]2[C:20]([CH3:27])=[C:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][C:9]3[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1c(CO)cccc1NC(=O)CNc1ccc(F)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2cccc(NC(=O)CNc3ccc(F)c(F)c3)c2C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methane sulphonyl chloride (0.06ml) was added to a solution of the product of step (d) (0.12 g) and N,N-diisopropylethylamine (0.28 ml) in tetrahydrofuran (3ml). The reaction mixture was stirred at room temperature for 1.5 hours. A solution of 1-acetylpiperazine (0. 15 g) in tetrahydrofuran (1 ml) was added and the mixture was heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The crude product was triturated with ethyl acetate/isohexane to give the product as a pale yellow solid.
Reaction SMILES: C([CH:4]([CH2:12][CH2:13][CH2:14]C)[CH:5]([OH:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])C=C.[CH2:16](C(CC=C)C=O)[CH:17]([CH3:19])[CH3:18]>>[OH:11][CH:5]([CH2:4][CH2:12][CH:13]=[CH2:14])[CH:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCC(C=O)CC(C)C
Reactant: C=CCC(CCCC)C(O)CC(=O)OC
Product: C=CCCC(O)C(CC(C)C)C(=O)OC

Procedure:
The compound of interest (4.5 g, 61%) was obtained as an oil substance (diastereomeric mixture) in the same way as in paragraph (10-a) using 2-isobutyl-4-pentenal.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][P:6]([CH3:13])([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[O:7]>O>[CH3:5][P:6]([CH3:13])([CH:8]([OH:12])[C:9]([O-:11])=[O:10])=[O:7].[CH2:1]([NH3+:4])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CP(C)(=O)C(O)C(=O)O
Solvent: O
Product: CCC[NH3+]
Product: CP(C)(=O)C(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.9 g (0.15 mol) of propylamine are added dropwise to a solution of 15.2 g (0.1 mol) of 2-(dimethylphosphinoyl)-2-hydroxy-acetic acid in 30 ml of water. The temperature thereby rises from 23° C. to 38° C. The mixture is stirred at 25° C. for one hour and concentrated on a rotary evaporator and the residue is dehydrated for distillation several times with toluene. After removal of the toluene under a high vacuum, a syrup of nD22 =1.4869 initially forms, and solidifies as a wax after prolonged standing.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C1(C)C=CC=C(C)C=1.S(Cl)([Cl:24])=O>CCOC(C)=O.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:24])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)c1
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 100 %

Procedure:
In a flame dried rbf charged with nitrogen, a mixture of 2-naphthoic acid (0.516 g, 3 mmol), anhydrous m-xylene (14.83 mL) and thionyl chloride (11 mL) were refluxed for 2 hours. Rf=TLC (SiO2, 5% EtOAc/CH2Cl2) showed reaction was complete. The solvent was removed in vacuo resulting in 0.604 g of creamy white crystals of 2-naphthoyl chloride (100% yield). Fresh anhydrous m-xylene (5 mL) was added to 2-naphthoyl chloride (0.416 g, 2 mmol) and allowed to stir for 5 minutes, then a mixture of 2-amino-3-hydroxy-benzoic acid methyl ester (0.334 g, 2 mmol), triethylamine (3 mL) were added. The mixture was allowed to stir at room temperature for 4 hours, then the reaction mixture was heated to reflux and allowed to stir at refluxed temperature for 12 hours. The cooled mixture diluted with 100 mL of EtOAc and transferred to a separatory funnel, washed with of 0.1 M HCl (1×50 mL), H2O (1×50 mL) saturated NaHCO3 (1×50 mL), H2O (1×50 mL), and saturated NaCl (1×50 mL), respectively. The product was dried over Na2SO4; solvent was removed under pressure and concentrated in vacuo. The resulting 0.578 g of reddish-brown product was placed in a flame-dried rbf under N2 (g), then anhydrous m-xylene (14.4 mL), and PPTS (0.904 g, 3.6 mmol) were added. The reaction mixture refluxed for 4 hours. The cooled mixture was diluted with 100 mL EtOAc and transferred to a separatory funnel, washed with saturated NaHCO3 (1×50 mL), H2O (4×50 mL), and saturated NaCl (1×50 mL), dried over Na2SO4; solvent was removed under pressure and concentrated in vacuo using a coldfinger. The mixture was purified using flash chromatography Yield: 0.173 g tan solid (28% yield, 4 steps). Rf=0.40 (SiO2, 3% EtOAc/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 4.09 (s, 3H), δ 7.44 (t, J=7.8, 1H), δ 7.58-7.60 (m, 2H), δ 7.82 (dd, J=9.2 Hz, 1 Hz, 2H), δ 7.90 (d, J=7.3 Hz, 1H), δ 7.98-8.06 (m, 3H), δ 8.41 (dd, J=8.7 Hz, 1.8 Hz, 1H), δ 8.89 (s, 1H).
Reaction SMILES: [CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[N:9]1)[C:3](O)=[O:4].C[C@@](S(C)(=O)=O)(CCN1C(C2C=CC=CC=2)=C(C)N=N1)C(O)=O.CN1CCOCC1.O1CCCCC1[O:60][NH2:61].C(O)(C(F)(F)F)=O>C1COCC1>[OH:60][NH:61][C:3](=[O:4])[C@:2]([CH3:1])([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[N:9]1
Reactant: NOC1CCCCO1
Reactant: Cc1c(-c2ccccc2)nnn1CC[C@](C)(C(=O)O)S(C)(=O)=O
Agent: Cc1nnn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)nnn1CC[C@](C)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-methyl-4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoic acid and (2R)-2-methyl-4-(4-methyl-5-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanoic acid (115 mg, 0.341 mmol, 1 eq) in THF (5 mL) was added N-methyl morpholine (65.5 mg, 0.341 mmol, 1 eq), and CDMT (59.9 mg, 0.341 mmol, 1 eq). The reaction mixture was allowed to stir at RT for 1 h then O-tetrahydro-2H-pyran-2-yl-hydroxylamine (39.9 mg 0.341 mmol, 1 eq) was added and the reaction mixture was allowed to stir at RT for 2 days. Upon completion of the coupling reaction (as observed by LC-MS monitoring), 1 mL of TFA was added and the mixture was allowed to stir at RT for 3 h. The reaction mixture was concentrated and purified by HPLC to give (2R)—N-hydroxy-2-methyl-4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanamide (14 mg) as a 10:1 mixture with the corresponding regioisomer (2R)—N-hydroxy-2-methyl-4-(4-methyl-5-phenyl-1H-1,2,3-triazol-1-yl)-2-(methylsulfonyl)butanamide. 1H NMR (400 MHz, METHANOL-d4) δ 7.61-7.67 (m, 2H), 7.43-7.50 (m, 2H), 7.38 (d, J=7.42 Hz, 1H), 4.51-4.63 (m, 1H), 4.36-4.48 (m, 1H), 3.06 (s, 3H), 2.85-2.93 (m, 1H), 2.51 (s, 3H), 2.43 (ddd, J=13.42, 10.10, 5.37 Hz, 1H), 1.72 (s, 3H). LC-MS M+H+353.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:23][OH:24]>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[N:23][OH:24])[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC)c2C1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(CC)=NO)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a solution of 2-di-n-propylamino-8-propionyl-1,2,3,4-tetrahydronaphthalene (0.7 g, 2.4 mmol) (prepared as in Example 21) in methanol (40 ml) was added a solution of hydroxylamine hydrochloride (1.7 g, 24 mmol) in water (10 ml). The solution was stirred at room temperature overnight. The reaction was poured into water, the pH was adjusted to 12 and then extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give 760 mg of crude 2-di-n-propylamino-8-(1-oximinopropyl)-1,2,3,4-tetrahydronaphthalene sufficiently pure to be used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[C:20]([F:24])[CH:21]=[C:22]([F:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[C:20]([F:24])[CH:21]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cc(F)cc(F)c2n1
Product: FCc1cccc(C#CCCn2nc3cc(F)cc(F)c3n2)n1
Yield: 58333.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mol, 53%) of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4]CC.[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=[O:9])[CH3:8]>>[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: C=CCCCC
Reactant: C=CCCCCCCCOC(C)=O
Product: CCCC/C=C\CCCCCCCOC(C)=O

Procedure:
Reactions between 1-hexene and 8-nonenyl acetate were conducted using methods analogous to those described above using to form the pheromone derivative 17. When catalyzed by Ruthenium complex 1, the reaction proceeded in good yield (67%) with high Z-selectivity (91%) at a low catalyst loading (0.5 mol %).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][NH2:20])[N:14]=1)[CH3:3].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][NH:20][S:25]([CH3:24])(=[O:27])=[O:26])[N:14]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCNc2nc(CN)nn2C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)Cc1cccc(OCCCNc2nc(CNS(C)(=O)=O)nn2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-[[3-[3-[(Dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanamine (0.75 g) and methane sulphonyl chloride (0.18 ml) in dry pyridine (15 ml) was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in aqueous sodium carbonate and extracted with ethyl acetate. The organic solution was evaporated leaving the title compound (0.5 g). T.l.c. System B, Rf 0.6.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[F:23])=[O:4].O1CCCC1>C(O)C.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[C:10]2[CH:9]=[CH:8][C:7]([F:23])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:24])[CH:11]=2)=[N:14][CH:15]=1
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 128.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N-{2-fluoro-5-[methyl(5-nitropyridin-2-yl)amino]phenyl}acetamide (18.0 g, 50.2 mmol) in ethanol (100 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (1.8 g), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (1 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (21.2 g, 68%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=C1CCOc2ccc(Cl)cc21
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=C1COc2ccc(Cl)cc2C1=O
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 6-chloro-3,4-dihydro-4-oxo-2H-1-benzopyran (3.285 g), N,N-dimethylformamide dimethyl acetal (8.568 g), and triethylamine (2.727 g) in benzene (36 ml) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 1 hour. To the residue was added benzene (36 ml) and the solvent was distilled again. The residue was dissolved in a mixture of chloroform and ethyl acetate, treated with activated charcoal, and evaporated in vacuo. The residual solid was washed with a mixture of diethyl ether and ethyl acetate to give 6-chloro-3,4-dihydro-3-dimethylaminomethylene-4-oxo-2H-1-benzopyran (2.73 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N-:15][S:16](N1C=CC(=[N+](C)C)C=C1)(=[O:18])=[O:17])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:28][C:29]1[CH:30]=[C:31]([CH:53]=[CH:54][CH:55]=1)[CH2:32][C:33]1[C:34](=[O:52])[O:35][C:36]2[CH:44]=[C:43]([O:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])[C:42]([Cl:51])=[CH:41][C:37]=2[C:38]=1[CH2:39][F:40].O>ClCCl>[C:8]([O:12][C:13]([NH:15][S:16]([NH:28][C:29]1[CH:30]=[C:31]([CH:53]=[CH:54][CH:55]=1)[CH2:32][C:33]1[C:34](=[O:52])[O:35][C:36]2[CH:44]=[C:43]([O:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])[C:42]([Cl:51])=[CH:41][C:37]=2[C:38]=1[CH2:39][F:40])(=[O:18])=[O:17])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CF)c2cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)c(CF)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Triethylamine (34 μL, 0.25 mmol) and N-(tert-butoxycarbonyl)-N-{4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl}azanide (49 mg, 0.16 mmol) were added in series to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1h-1-3F) (33 mg, 0.082 mmol) in anhydrous dichloromethane (1.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was then obtained by vacuum concentration, and purified by preparative TLC (ethyl acetate:hexane=1:2) to yield the title compound (30 mg, 63%) as a white powder.
Reaction SMILES: C1(N2CCN3C(CC4(C5C=CC=CC=5)CCCC4)=NC(=O)C(O)=C3C2=O)CC1.C([O:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH:61]3[CH2:64][O:63][CH2:62]3)[C:59](=[O:60])[C:38]=12)C1C=CC=CC=1>>[OH:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH:61]3[CH2:62][O:63][CH2:64]3)[C:59](=[O:60])[C:38]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1COC1
Agent: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1COC1
Yield: 9.6 %

Procedure:
This compound was prepared following the same method as described for 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) from 9-benzyloxy-2-oxetan-3-yl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (298) (100 mg, 0.21 mmol). The product was obtained as a white solid (8 mg, 9.82%).
Reaction SMILES: N1C2C(=CC=CN=2)C=C1.C([O:17][C:18]1[C:19]([F:36])=[C:20]([C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[C:21]([F:24])=[CH:22][CH:23]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[F:36][C:19]1[C:18]([OH:17])=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]([C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:26]
Reactant: O=C(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncccc12
Agent: [Pd]
Agent: c1cnc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncccc12
Reaction time: 6 h

Procedure:
was prepared following the protocol of Scheme 43, substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with 7-azaindole. To a solution of (3-benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-1802, 0.5 g, 1.37 mol) in methanol (70 mL) and tetrahydrofuran (30 mL) was added palladium on carbon (120 mg, 10% wt., 0.58 mol). The mixture was stirred under hydrogenation (60 psi) for six hours. After removal of solvent, the residue was dried under vacuum, which provided (2,6-Difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone 651
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33]C)=[O:32])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:11]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([OH:33])=[O:32])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:11]=1
Reactant: COC(=O)Cc1ccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2ccc(CC(=O)O)cc2Cl)c1
Yield: 94 %

Procedure:
A mixture of methyl 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetate. (0.47 g), a 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and acidified with 1N hydrochloric acid. The precipitated solid was collected by filtration and dried with air to give crystals (0.43 g, yield 94%) of 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetic acid. Recrystallization from ethyl acetate-methanol gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>C(O)CC.ClCCl>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCCO
Solvent: ClCCl
Product: Cc1ccc(-c2cn3cc([N+](=O)[O-])ccc3n2)cc1
Yield: 22.9 %

Procedure:
81 g (0.38 mole) of 1-bromo-2-(4-methylphenyl)-2-ethanone and 53 g (0.38 mole) of 2-amino-5-nitropyridine are reacted in 900 ml of n-propanol. The solution is maintained under reflux, the reaction being followed by thin layer chromatography. When there is no further change, the mixture is evaporated to dryness. The residue is taken up with water and treated with ammonia solution until the pH>8. The insoluble material is filtered off and dried, and then treated with dichloromethane. The insoluble portion is recrystallized in ethyl acetate, which yields a first crop. The mother liquors are then combined with the portion soluble in dichloromethane, the mixture is concentrated and a second crop of product is obtained. The two crops are purified separately by chromatography. 22 g (23%) of yellow solid are obtained overall. M.p. 205°-206° C.