Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]1[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Cc1ncn(Cc2ccccc2)c1C
Product: Cc1nc(CO)n(Cc2ccccc2)c1C
Temperature: 150 °C

Procedure:
A mixture of 8 g (43 mmol) of 1-benzyl-4,5-dimethylimidazole and 60 ml of 40% aqueous formaldehyde solution was heated in a sealed autoclave at 150° C. for 20 hours. The mixture was evaporated and the semi-solid residue was chromatographed on a column of 300 g of silica gel using a 20% solution of methanol in chloroform for the elution. Evaporation of the eluate yielded 6 g of 1-benzyl-4,5-dimethyl-2-hydroxymethylimidazole of melting point 156°-158° C. After recrystallization from methylcyclohexane, the melting point was 160°-162° C. A portion of the product was treated with a solution of hydrogen chloride in ethanol. Addition of diethyl ether precipitated 1-benzyl-4,5-dimethyl-2-hydroxymethylimidazole hydrochloride of melting point 162°-163° C.
Reaction SMILES: C([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][C:11](Br)=[C:6]2[CH:5]=[C:4]1[C:13]([OH:15])=[O:14])C.[CH2:16]([N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[C:20]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][C:6]=23)[C:20]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:19]1)[CH3:17]
Reactant: CCn1c(C(=O)O)cc2c(Br)ccnc21
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 6 with ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided title compound. ESMS [M+H]+: 378.2
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:52]=[N+:53]=[N-:54].CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][N:52]=[N+:53]=[N-:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H](CO)CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)OCc1ccccc1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H](CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-2-(benzyloxycarbonylamino)-3-(4-phenoxybenzene sulfonamido) propanol (0.45 g, 1.0 mmol) in toluene (10 mL) was added PPh3 (0.28 g, 1.1 mmol) and the mixture was stirred at RT for 5 min. After adding hydrazoic acid (1.25 M in toluene, 1.04 mL, 1.3 mmol), DEAD (0.17 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at RT for 30 min, filtered and solvent was evaporated. The crude residue was chromatographed (silica gel, 30% EtOAc in n-hexane) to afford (R)-2-(benzyloxycarbonylamino)-3-(4-phenoxybenzenesulfon amido) propyl azide as white solid in 60% (0.29 g) yield.
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C2(O)CCCc3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=CCCc3ccccc32)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 1-hydroxy-1-(4-methoxyphenyl)-tetralin (18 g., 0.071 mole) in toluene (250 ml.) was treated with para-toluenesulfonic acid (5 mg.) and the resulting solution stirred at reflux for 16 hours, with complete water removal accomplished by means of a Dean-Stark trap. The reaction mixture was then cooled to room temperature, washed sequentially with 10% aqueous sodium bicarbonate solution (100 ml.), water (100 ml.) and saturated aqueous sodium chloride solution (100 ml.), dried (MgSO4) and evaporated under vacuum to an oil, which was purified by silica gel chromatography (elution with a hexane-toluene gradient) to give 12 g. of the named compound (67% yield, oil).
Reaction SMILES: C([NH:3][C@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([OH:7])=[O:6])=O.[ClH:15]>>[ClH:15].[NH2:3][C@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([OH:7])=[O:6]
Reactant: C[C@@](NC=O)(C(=O)O)c1ccccc1
Agent: Cl
Product: C[C@@](N)(C(=O)O)c1ccccc1

Procedure:
The product of Example 445B (1.25g, 7.6 mmol)) in 1N HCl (12.5 mL) was refluxed for 1 hour. The reaction mixture was concentrated and dried at 40° C. under vacuum overnight to give (S)-2-amino-2-phenylpropanoic acid hydrochloride as a pale brown crystal (1.53 g). The intermediate amino acid (1.5 g. 7.5 mmol) was dissolved in EtOH (30 mL) was reacted with thionyl chloride (2.7 ml., 37.5 mmol) dropwise at room temperature then refluxed for 23 hours. The reaction was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer was washed with water (3×15 mL) and 10% aqueous NaHCO3 (1×15 mL), dried over MgSO4, concentrated to give the title compound (1.28 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][C@H:8]([CH2:23][NH:24][C@@H:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:56]1([CH3:65])[CH:61]=[CH:60][C:59]([C:62](Cl)=[O:63])=[CH:58][CH:57]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([CH2:23][N:24]([CH:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[C:62]([C:59]1[CH:60]=[CH:61][C:56]([CH3:65])=[CH:57][CH:58]=1)=[O:63])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@@H](NC[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of ((S)-1-{[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (250 mg, 0.37 mmol) in toluene (4 mL) was added triethylamine (0.10 mL, 0.74 mmol) followed by dropwise addition of p-toluoyl chloride (0.049 mL, 0.37 mmol). The reaction mixture was heated to 80° C. for 18 h, then reflux for 4 h. The reaction mixture was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and diluted with CH2Cl2 (10 mL). The extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes:ethyl acetate) to provide 235 mg (79%) of the title compound as a pale yellow powder. MS(ES+) m/e 794.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([OH:20])[C:18]#[CH:19]>>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:19]#[C:18][CH2:17][OH:20])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCO
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#CCO)cc1

Procedure:
In analogy to example 18.3, reaction of (4-Iodo-phenyl)-methyl-carbamic acid tert-butyl ester with propargylalcohol yielded [4-(3-Hydroxy-prop-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 261 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[N:27]=[C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)[S:29][CH:30]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)cs2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2nc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)cs2)cn1

Procedure:
Prepared from (2′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K75) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (75 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:10]1([NH:13][C:2]2[C:3]([C:8]#[N:9])=[CH:4][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: N#Cc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: N#Cc1cnccc1NC1CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
A mixture of 4-chloro-3-cyanopyridine (5.0 g, 36.1 mmol), cyclopropylamine (5.0 mL, 72.2 mmol, 2.0 eq), and potassium carbonate (5.2 g, 37.9 mmol, 1.05 eq) in isopropyl alcohol (130 mL) was stirred at 60° C. under N2 for 20 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 10-100% ethyl acetate in hexane). Trituration from hexane afforded the title compound as an off-white solid (4.55 g, 79.3%). 1H-NMR (400 MHz; DMSO-d6) δ ppm 8.43 (d, J=0.55 Hz, 1H), 8.29 (dd, J=6.10 Hz, 1H), 7.55 (s, 1H), 7.00-6.88 (m, 1H), 2.54 to 2.40 (m, 1H), 0.89-0.69 (m, 2H), 0.68-0.48 (m, 2H); LC-MS (method C): [M+H]+=160.2, RT=0.28 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13](Cl)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>C(N)C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)c2cnnc(Cl)c2n1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: NCc1ccccc1
Product: Cc1c(Br)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1.0 g (2.97 retool) of 1-benzyl-3 -bromo-7-chloro-2-methylpyrrolo [2,3-d]pyridazine in 5 ml of benzylamine is heated to 150° C. for 5 h and subsequently cooled to room temperature. The solution is then treated with 50 ml of water, adjusted to pH 6 with 2 N hydrochloric acid and extracted with 2×50 ml of dichloromethane. The organic extracts are dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: toluene/dioxane=2:1). After concentration of the fractions of Rf=0.25 and crystallization from diisopropyl ether, 1.01 g (84%) of the title compound are isolated. M.p.: 185°-188° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccn(Cc2ccccc2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Yield: 19.5 %

Procedure:
Benzyl 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1.08 g, 3.38 mmol) obtained in Step 2 was dissolved in a mixed solvent of methanol (7 mL) and water (7 mL), and sodium hydroxide (0.680 g, 16.9 mmol) was added thereto, followed by stirring under heating and reflux for 30 minutes. The reaction mixture was poured into water (50 mL), and 10% hydrochloric acid was added thereto to adjust the pH to 4.5, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to afford the entitled Compound w (151 mg, 20%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[OH:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1cc(O)ccc1O
Temperature: 60 °C

Procedure:
Methyl 2,5-dihydroxybenzoate (1 g) is dissolved in 10 mL of n-hexylamine. After overnight heating in an oil bath (60° C.), the mixture is cooled to room temperature. n-Hexylamine is removed under reduced pressure. The residue is dissolved in ethyl acetate and further extracted with 1 N HCl. The organic layer is extracted with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure to yield the product as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:23])[CH3:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Product: CC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 345.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([N:6]1[C:11]([F:13])([F:12])[C:10]([F:15])([F:14])[C:9]([F:17])([F:16])[C:8]([F:19])([F:18])[C:7]1([F:21])[F:20])[C:3]([OH:5])=[O:4].[OH-].[K+:24]>O>[F:22][C:2]([F:1])([N:6]1[C:7]([F:21])([F:20])[C:8]([F:18])([F:19])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[C:11]1([F:12])[F:13])[C:3]([O-:5])=[O:4].[K+:24]
Reactant: O=C(O)C(F)(F)N1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(F)(F)N1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F

Procedure:
Distilled water was placed in a three-neck flask equipped with a reflux condenser and a dropping funnel and a crude product of the electrolytic fluorination of methyl piperidinoacetate was added through the dropping funnel while the three-neck flask was kept cooled. The resultant hydrolyzate was extracted with ether from the reaction mixture, dried with anhydrous sodium sulfate, and then distilled under a vacuum in the presence of a small amount of concentrated sulfuric acid to obtain perfluoropiperidinoacetic acid (bp: 120° C./121 mmHg). This perfluoropiperidinoacetic acid was suspended in distilled water. The suspension was kept agitated by the use of a magnetic stirrer and an aqueous potassium hydroxide solution was added to the agitated suspension until pH 10. The resultant reaction mixture was deprived of water and low-boiling fractions by the use of an evaporator and then dried for one day with a vacuum pump to obtain white solid potassium perfluoropiperidino-acetate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](O)=[O:13])[CH3:8].C[N:21](C)C=O>C(Cl)Cl>[CH2:7]([O:9][C:10]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([NH2:21])=[O:13])[CH3:8]
Reactant: CCOc1ncc(I)cc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOc1ncc(I)cc1C(N)=O
Temperature: 25 °C
Yield: 95 %

Procedure:
Oxalyl chloride (6.60 ml, 75.1 mmol) was added to a solution of 2-ethoxy-5-iodonicotinic acid (prepared according to the procedure in WO0127112, 20.0 g, 68.3 mmol) in DCM (400 ml) and N,N-dimethylformamide (0.1 ml) at 0° C. The solution was warmed to room temperature over 18 h and then concentrated in vacuo. The resultant orange oil was dissolved in THF (200 ml) and cooled to 0° C. NH3 (410 ml of a 0.5 M soln. in dioxane, 205 mmol) was added and the mixture was warmed to room temperature over 4 h. The reaction mixture was concentrated in vacuo and triturated with water (150 ml). The solid was filtered and dried to afford the title compound as a beige solid (18.9 g, 64.9 mmol, 95%); m.p. 176-179° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)[CH2:30][N:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:28][CH:27]2[CH2:51]OS(C)(=O)=O)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:27]([CH2:51][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:28][N:29]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:30][CH:31]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:24][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cn2cncn2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A solution of 22 mg (0.32 mmol) of 1,2,4-triazole in 5 ml of DMF was cooled to 0° C. and treated with 15 mg (0.29 mmol) of sodium hydride (50% dispersion in refined oil). Subsequently, the mixture was left to warm to room temperature and was stirred for a further 1 hour. 70 mg (0.105 mmol) of tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methane-sulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate were added to this solution. The reaction mixture was heated to 100° C. for 24 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was partitioned between water and methylene chloride and the organic phase was separated, dried over sodium sulphate and evaporated. For purification, the crude product (70 mg) was chromatographed on silica gel using a 98:2 mixture of methylene chloride and methanol as the eluent. There were obtained 52 mg (77% of theory) of tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-[1,2,4]triazol-1-ylmethyl-piperidine-1-carboxylate as a colourless solid; MS: 663 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.COC1C=CC(CS[C:19]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=CC=1>O1CCCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][S:31]/[C:19](/[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8](/[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)\[CH2:9][CH3:10])=[CH:38][CH:37]=1
Reactant: CCCc1cc(Br)ccn1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SCc1ccc(OC)cc1)SCc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)/C(SCc1ccc(OC)cc1)=C(/CC)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 10.1 mL, 16.2 mmol) to a stirred solution of diisopropylamine (2.3 mL, 16.4 mmol) in tetrahydrofuran (25.0 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then recooled to −78° C. A solution of 4-bromo-2-propylpyridine (2, 2.94 g, 14.7 mmol) in tetrahydrofuran (25.0 mL) is added dropwise to this solution over a period of 30 min. The resulting deep red suspension is stirred at −78° C. for 1 h, after which time a solution of diethyl 2-[bis(4-methoxybenzylsulfanyl)methylene]malonate (1, 7.03 g, 14.8 mmol) in tetrahydrofuran (40.0 mL) is added dropwise over a period of 15 min. The resulting yellow solution is stirred at −78° C. for 1.5 h, −15° C. for 1.5 h, and room temperature for 30 min to give a dark orange solution. The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give 3 an orange oil. The product is purified by flash column chromatography (eluting with 5% ethyl acetate in methylene chloride.
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])[C:9]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)=[N:8][CH:7]([CH2:25][O:26]C(=O)C1C=C(OC)C=C(OC)C=1)[CH2:6]2.[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)=[N:8][CH:7]([CH2:25][OH:26])[CH2:6]2
Reactant: COc1cc(OC)cc(C(=O)OCC2Cc3cc(OC)c(OC)cc3C(c3cc(OC)cc(OC)c3)=N2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)cc(C2=NC(CO)Cc3cc(OC)c(OC)cc32)c1

Procedure:
A suspension of 98.4 g of [3S] 3,4-dihydro-6,7-dimethoxy-3-[(3,5-dimethoxybenzoyloxy)methyl]-1-(3,5-dimethoxyphenyl)-isoquinoline [Formula IIa: all of R1 to R4 =methoxy], 51 CH3OH and 207 ml aqueous lithium hydroxide, is stirred for 12 hrs. at room temperature. The obtained solution is concentrated under reduced pressure, treated with ethyl acetate and washed with H2O/Na2CO3. The organic phase is dried over K2CO3 and the solvent removed under reduced pressure. The residue is taken up in ethyl ether, crystallized, filtered and dried to yield the title compound: m.p.=59°-62° C., αD20 =-55.19° (c=0.5 in CH3OH).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1cccc(F)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1cccc(F)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 60 %

Procedure:
3-[(3-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 49-C) was reacted with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (60% yield); mp 119° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.87 (2H, s, NCH2), 6.99–7.35 (4H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52. Found: C, 57.04; H, 5.02; N, 9.42.