Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Reactant: NCCCN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(3-aminopropyl)morpholine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.75 (1H, br s), 10.7 (1H, br s), 10.20 (1H, br s), 8.17 (0.45H, s), 8.15 (0.55H, s), 7.45-7.21 (3H, m), 7.10-7.04 (1H, m), 4.02 (2H, s), 3.56-3.51 (4H, m), 3.31-3.24 (2H, m), 2.48-2.32 (6H, m), 1.65-1.61 (2H, m); HRMS calcd for C23H24F2N4O4+H+: 459.1844. Found 459.1856.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.S(Cl)([Cl:16])=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([Cl:16])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Cl)c1

Procedure:
Isophthalic acid mono methyl ester (200 mg, 1.10 mmol) was heated at reflux for 15 min in the mixture of thionyl chloride (2 ml) and DMF (cat.). The solvent was evaporated in vacuo, the residue was dissolved in DCM (5mi) and the solvent was evaporated to afford 3-chlorocarbonyl-benzoic acid methyl ester. To a solution of the product of step b above (435 mg, 1.00 mmol) and triethylamine (280 μl, 2.00 mmol) in DCM (10 ml) was added a solution of the previously prepared 3-chlorocarbonyl-benzoic acid methyl ester in DCM (2 ml). The reaction mixture was stirred at room temperature for 1h. It was washed with 5% aqueous potassium hydrogen sulfate (10 ml) and water (10 ml), dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/ethyl acetate 4:1) to afford the product as a white solid (310mg, 52%). 1H NMR (300 MHz, CDCl3) 8.53 (1H, s), 8.18 (2H, m), 8.07 (1H, d), 7.51 (1H, t), 7.30-7.21 (4H, m), 3.95 (3H, s), 2.91 (2H, m), 2.20 (3H, s), 1.94 (3H, br s), 1.66 (6H, m), 1.5 (6H, s), 1.38 (2H, m), 1.21 (9H, s).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.C(=O)(O)O.[NH2:16][NH:17][C:18]([NH2:20])=[NH:19].[OH-].[K+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[N:16]/[NH:17][C:18](=[NH:19])[NH2:20])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Agent: [K+]
Product: COc1ccc(/C=N/NC(=N)N)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of 4-anisaldehyde (2.0 g, 14.4 mmol), 20% hydrochloric acid (4 mL) was added to an aminoguanidine bicarbonate (1.96 g, 14.4 mmol) aqueous solution, and heated to reflux for 4 h. 40% aqueous potassium hydroxide (7 mL) was added and the mixture was heated at reflux for additional 10 min. The mixture was cooled in room temperature for 10 h and a yellow precipitate formed. The yellow precipitate was filtered, washed with hot water and recrystallized from ethanol to give 2-[(E)-1-(4-methoxyphenyl)methylidene]-1-hydrazinecarboximidamide (2.4 g, 87%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13](I)[CH3:14].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:10][C:5]1[C:4]([O:11][CH3:12])=[CH:3][C:2]([I:1])=[CH:7][C:6]=1[O:8][CH3:9])[CH3:14]
Reactant: COc1cc(I)cc(OC)c1O
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-iodo-2,6-dimethoxyphenol (JP61-207432A) (100.0 mg, 0.360 mmol) in dimethylformamide (1.0 mL) were added ethyl iodide (84.0 mg, 0.540 mmol) and a 50% dispersion of sodium hydride in mineral oil (19.0 mg, 0.40 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into 0.10 M hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 4-ethoxy-1-iodo-3,5-dimethoxybenzene as a colorless amorphous powder (102.0 mg, yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[NH:18][C:17](=[O:21])[CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[BH4-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([OH:7])[C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:19](=[O:20])[NH:18][C:17](=[O:21])[CH:16]=[N:15]3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Temperature: 10 °C
Yield: 35.2 %

Procedure:
A mixture of 2-[4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione (0.05 mol), ethanol (150 ml), water (150 ml) and NaOH (50%; 10 ml) was stirred at 10° C. A mixture of NaBH4 (0.05 mol), water (50 ml) and NaOH (50%; 2 ml) was added dropwise during 15 minutes. After stirring for 3 hours, 300 ml ice was added. The mixture was acidified with concentrated HCl. The product was extracted with CHCl3, yielding 5.8 g of 2-[4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione (interm. 31). The organic layer was dried, filtered and evaporated. The residue was crystallized with 2-propanol. The product was filtered off, washed with 2,2′-oxybispropane and dried, yielding a second fraction of 5.5 g of intermediate 31.
Reaction SMILES: C(OC1C=CS[C:5]=1[C:9]1[NH:10][C:11](=O)[C:12]2[N:17]([CH3:18])N=C(CCC)C=2N=1)C.ClS(O)(=O)=O.Cl[S:29]([C:32]1[S:36][C:35]([C:37]2[NH:38][C:39](=[O:50])[C:40]3[N:45]([CH3:46])[N:44]=[C:43]([CH2:47][CH2:48][CH3:49])[C:41]=3[N:42]=2)=[C:34]([O:51][CH2:52][CH3:53])[CH:33]=1)(=[O:31])=[O:30].ClS(C1SC(C2NC(=O)C3N(C)N=C(CCC)C=3N=2)=C(O)C=1)(=O)=O.CN1CCNCC1>CO>[CH2:52]([O:51][C:34]1[CH:33]=[C:32]([S:29]([N:10]2[CH2:9][CH2:5][N:17]([CH3:18])[CH2:12][CH2:11]2)(=[O:31])=[O:30])[S:36][C:35]=1[C:37]1[NH:38][C:39](=[O:50])[C:40]2[N:45]([CH3:46])[N:44]=[C:43]([CH2:47][CH2:48][CH3:49])[C:41]=2[N:42]=1)[CH3:53]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3sc(S(=O)(=O)Cl)cc3OCC)nc12
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3sccc3OCC)nc12
Agent: CCCc1nn(C)c2c(=O)[nH]c(-c3sc(S(=O)(=O)Cl)cc3O)nc12
Agent: CN1CCNCC1
Agent: O=S(=O)(O)Cl
Solvent: CO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3sc(S(=O)(=O)N4CCN(C)CC4)cc3OCC)nc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 4 (165 mg, 0.517 mmol) was added to chlorosulfonic acid (0.35 mL, 5.2 mmol) at 0° C. The mixture was stirred under nitrogen at 50° C. for 24 h. Ice was added and the mixture was extracted with a mixture of CH2Cl2 /MeOH (9:1), dried with Na2SO4. After evaporation of the solvent, a white solid was obtained which, by NMR analysis contained predominantly 5-(5-chlorosulfonyl-3-ethoxythiophene-2-yl)-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-7-one and a small amount of 5-(5-chlorosulfonyl-3-hydroxythiophene-2-yl)-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo-[4,3-d]pyrimidin-7-one. This white solid (90 mg, 0.456 mmol) was added to a solution of methylpiperazine (137 mg, 1.37 mmol) in methanol (abs. 15 mL) and stirred at rt for 4 days. The solvent was evaporated, and the residue was dissolved in CH2Cl2 /MeOH (9:1) and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 /MeOH (9:1). The organic layers were combined and dried with MgSO4. The residue obtained after evaporation of the solvent contained two compounds. Separation and purification was carried out by column chromatography (silica gel). Compound 5 was obtained as a white solid by elution with ethyl acetate; mp: 219-220° C.; 1H NMR (DMSO-d6) δ 0.94(t, J=7 Hz, 3H), 1.42(t, J=7 Hz,3 H), 1.74(sxt, J=7 Hz, 2 H), 2.18 (s, 3 H), 2.40 (m, 4 H), 2.76 (t, J=7 Hz, 2 H), 3.35 (m, 4 H), 4.14 (s, 3 H), 4.44 (q, J=7 Hz, 2 H), 7.72 (s, 1 H), 10.79 (br s, 1H); MS (m/z): 481 (MH+). The hydrochloride salt was prepared by adding a solution of HCl in dioxane (4.0 M, 0.2 mL) to a suspension of the free base (6.0 mg) in MeOH (1 mL) and stirring for 1 h. Following removal of the solvents under vacuum a white solid was obtained; mp: 225° C. (dec.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][N:17]1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)=[O:15])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C1COCCN1c1ccc(N)cc1

Procedure:
4-Fluoronitrobenzene and morpholine-3-carboxylic acid ethyl ester were allowed to undergo the reaction at 100° C. in DMSO in the presence of diisopropylethylamine, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(4-aminophenyl)morpholine-3-carboxylic acid ethyl ester. ESI: 251.
Reaction SMILES: [I:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH:8]([C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[C:4]([N+:25]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.Cl>CO>[NH2:25][C:4]1[CH:3]=[C:2]([I:1])[CH:24]=[CH:23][C:5]=1[CH2:6][O:7][CH:8]([C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: Cn1cncc1C(OCc1ccc(I)cc1[N+](=O)[O-])c1ccc(C#N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cn1cncc1C(OCc1ccc(I)cc1N)c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
A solution of Example 46B (0.8 g, 2.1 mmol) in methanol (50 mL) at room temperature was treated with SnCl2.2H2O (1.41 g, 6.3 mmol) and concentrated HCl (20 mL), stirred for 12 hours, and concentrated. The concentrate was treated with aqueous NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with CH2Cl2:CH3OH:NH4OH (100:3:3, v/v) to provide the desired product. MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH:22]=[CH:21][N:20]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:19]=[CH:18]2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.Cl>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH:18]=[CH:19][N:20]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:21]=[CH:22]2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3C=CN(S(N)(=O)=O)C=C3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3C=CN(S(N)(=O)=O)C=C3)c2c1
Yield: 58 %

Procedure:
40 mg 4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]-1-pyrazine sulfonamide obtained in Example 189 and 0.5 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 162, to give 14 mg of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:11]1([C@@H:14]2[CH2:18][CH2:17][N:16]([C@H](C3C=CC=CC=3)C)[CH2:15]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([C:11]1([C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CCN([C@@H](C)c3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(ethyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine (3.01 g, 8.40 mmol) was dissolved in ethanol (120 ml), and after adding a 10% palladium carbon catalyst (water content: 50%; 3.0 g), it was stirred at 40° C. for 5 hours under a hydrogen atmosphere at atmospheric pressure. After performing filtration through cellite (ethanol washing), the filtrate was concentrated under a reduced pressure. As a result, 2.16 g (quantitative) of the title compound was obtained in the form of a colorless syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Oc1ccccc1F
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3F)n2)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.3 g, 0.785 mmol), 2-fluorophenol (0.106 g, 0.942 mmol) and potassium carbonate (541 mg, 3.93 mmol) in dimethylformamide (3 mL) was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10–20% EtOAc-Hexane) to afford the title compound E28 as a pale yellow solid (0.2 g, 56%). mp 98–100° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 29.79 min, 99.82% purity; MS (CI): m/z 458 (M+H, 100).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].I[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[N:19]=[N:18][C:17]=1[O:28][CH3:29]>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[N:19]=[N:18][C:17]=1[O:28][CH3:29])[CH2:2][CH2:3][CH3:4]
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Reactant: [Li]CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.39 ml of n-butyllithium solution (1.6M in hexane) is added at −75° C. to a 0.5 M solution of zinc chloride in THF and the resulting mixture stirred for 30 min at room temperature. This solution is added via a syringe to a solution of 107 mg 3-iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole (9b) and 10 mg 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1:1 complex with CH2Cl2) in THF and stirred for 4 h at 70° C. The reaction mixture is quenched by adding saturated NH4Cl-solution and extracted with ethylacete. The combined organic layers are dried over MgSO4, the solvens removed in vacuo. Reversed phase chromatography (RP18, water (0.05% HCOOH)/acetonitrile (0.05% HCOOH)) 30 mg product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH:28]([CH2:33][C:34]#[CH:35])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH:28]([CH2:33][C:34]#[C:35][C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]3=[N:6][CH:7]=2)[CH2:27]1)=[O:25])([CH3:20])([CH3:22])[CH3:21]
Reactant: C#CCC1CN(C(=O)OC(C)(C)C)CCC1C
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Product: CC1CCN(C(=O)OC(C)(C)C)CC1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Yield: 85.5 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (1.67 g, 5.09 mmol) and (+/−)-4-methyl-3-prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 5.09 mmol) were reacted under the same conditions as described in example 4 above. The crude product was adsorbed onto silica (10 g) and purified by silica gel chromatography, eluting with 5% to 30% ethyl acetate in hexanes to afford 2.11 g of (+/−)-4-methyl-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow viscous oil. MS (M+H)+=485.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][OH:34])[C:29]([O:31][CH3:32])=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=1)C#CC.[H-].[Na+].[Br-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([CH:8]=1)[CH2:2][N:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:13])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH:28]([CH2:33][OH:34])[C:29]([O:31][CH3:32])=[O:30]
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(CO)C(=O)OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)C(CO)N(Cc1cc(F)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a solution was of 2-(bromomethyl)-4-fluoro-1-nitrobenzene (1.3 g, 5.56 mmol) at 0° C. was added tetrabutylammonium iodide (2.05 g, 5.56 mmol). The solution was stirred at 0° C. for 1.5 hours. In a separate flask, methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-hydroxypropanoate (1.73 g, 5.05 mmol) was dissolved in dimethylformamide and cooled to 0° C. Sodium hydride (0.21 g, 5.56 mmol, 60% dispersion in oil) was added and the reaction was allowed to stir at 0° C. for 0.5 hours at which time the solution of the bromide was added. The reaction was stirred overnight and then quenched with water. The mixture was extracted twice with ethyl acetate, washed with brine, dried over Na2SO4, concentrated in vacuo and chromatographed using 1.5:1 hexane:ethyl acetate as eluant to provide 1.88 g (77%) of the desired product as a white solid. mp 83-88° C. Anal Calc'd for C21H21N2O8FS: C, 52.50; H, 4.41; N, 5.83. Found: C, 52.44; H, 4.76; N, 5.56.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([OH:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Cl:56]CCl>CO.Cl>[ClH:56].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([OH:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1cc2c(cc(C(=O)O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: Cl
Solvent: CO
Product: CCc1cc2c(cc(C(=O)O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 0.25 h

Procedure:
5,7-Diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl]biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid (A) (165 mg) was dissolved in a mixture of methanol (4 ml), dichloromethane (1 ml) and concentrated hydrochloric acid (0.1 ml) and the mixture was stirred for 15 minutes. Volatile material was then removed by evaporation. The residue was dissolved in methanol (2 ml) and a solid was precipitated by the addition of ether. The solid was collected by filtration and purified by repeated precipitation from methanolic solution with ether to give 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylic acid hydrochloride (75 mg) as a solid; NMR (d6 -DMSO+d4 -acetic acid): 1.24(t, 3H), 1.34(t, 3H), 2.89(q, 2H), 3.29(q, 2H), 5.64(s, 2H), 7.1(d, 2H), 7.25(d, 2H), 7.41(s, 1H), 7.45-7.75(complex m, 4H), 8.95(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 481 (M+H)+ ; microanalysis, found: C, 57.8; H, 5.0; N, 14.3%; C27H24N6O3.HCl.2.5H2O.0.1(CH3CO2C2H5) requires: C, 57.6; H, 5.4; N, 14.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:8]1[C:7]([CH3:14])([CH3:13])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Yield: 38 %

Procedure:
A solution of 12.1 g of 6-methoxy-3.3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 67 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.64 g of educt, there were obtained 5.86 g (38%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1OC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester (35 mg, 0.12 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (2 eq), and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified with 1N HCl, and then extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzoic acid. To an ice-cold suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid and N,O-dimethylhydroxylamine hydrochloride (13 mg, 0.132 mmol) in CH2Cl2 (1 mL) was added N-methylmorpholine (0.015 ml, 0.132 mmol), and the resulting mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.132 mmol). The resulting mixture was stirred for 2 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=3/1) to give the title compound (28 mg, 80%).