Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([S:12][CH3:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:14]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([S:12][CH3:13])=[N:10][N:11]=2)[CH2:14][NH:3]1
Reactant: CSc1nnc(NC(=O)N(C)N)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(N2CNN(C)C2=O)s1
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3 -one.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1cccc(-c2ccc(Cl)nc2)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(-c3cccc(C)n3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethyl-piperazine and 6′-chloro-6-methyl-[2,3]bipyridinyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:33]([C@H:30]3[CH2:31][CH2:32][C@H:27]([OH:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)[C@H]2CC[C@H](O)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(trans-4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using trans-4-hydroxycyclohexanecarboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 509.3 [M]+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]O.C(O)(=O)CC>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Solvent: O
Solvent: CCC(=O)O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 130 °C

Procedure:
A mixture of 100 parts of 3,3-dimethylacrolein, 200 parts of prenol and 150 parts of propionic acid is heated for three hours at 130°C, the water formed being distilled out azeotropically. The reaction product is worked up. 24 parts of citral is obtained. This is equivalent to a yield of 51°% of theory at a conversion of 26% (based on 3,3-dimethylacrolein).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][N:10]=[C:11]4[C:3]([CH3:19])([CH3:2])[C:4]3=[O:18])[CH2:13][CH2:14]1)[N:30]=[CH:29]2
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: Fc1ccc2nc(Cl)ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(C2CCN(c3ncc4cc(F)ccc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 35.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-fluoroquinazoline (0.063 g, 0.342 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The mixture was cooled, H2O was added, and the solid was collected, dried, and purified by ISCO (40% EtOAc/Hexanes) to give the title compound (43 mg, 35%). MS (M+1): 393. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (1 H, s), 8.08 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=3.1 Hz), 7.62-7.74 (2 H, m), 7.46-7.62 (1 H, m), 5.00 (2 H, d, J=13.5 Hz), 4.47-4.67 (1 H, m), 2.97-3.14 (2 H, m), 2.36-2.48 (2 H, m), 1.80 (2 H, d, J=9.6 Hz), 1.32 (6 H, s).
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)(CO)CCCC
Reactant: CI
Product: CCCCC(CO)(CCCC)COC

Procedure:
2,2-Di-n-butyl-3-methoxy-1-propanol was prepared from 2,2-di-n-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:23]#[N:24])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1
Reactant: N#C[Cu]
Reactant: CC1N=C(c2ccccc2F)c2cc(I)ccc2NC1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O

Procedure:
23.2 g (58.8 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-iodo-3-methyl-2H-1,4-benzodiazepin-2-one and 10 g (0.11 mol) of copper (I) cyanide in 250 ml of dimethylformamide are heated at 150° for 2 hours under argon. After cooling, 700 ml of water are added to the mixture and the resulting precipitate is filtered off. This is dissolved in 1 l of water/ethylenediamine (1:1) and extracted with 1 l of methylene chloride; the separated aqueous phase is extracted a further twice with methylene chloride. The combined organic extracts are washed with water, dried and evaporated. The residue gives, from cyclohexane, 5-(o-fluorophenyl)-2,3-dihydro-3-methyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile of melting point 216°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[C:3]=1[C:16]([F:19])([F:18])[F:17].[Si:20]([C:24]#[CH:25])([CH3:23])([CH3:22])[CH3:21]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:25]#[C:24][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 50 °C

Procedure:
A triethylamine (2.2 mL) solution of N-[4-chloro-2-iodo-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (0.413 g, 1.02 mmol) was treated with TMS acetylene (0.158 mL, 1.12 mmol) followed by copper iodide (0.019 g, 0.102 mmol) and PdCl2(PPh3)2 (0.021 g, 0.031 mmol). The reaction vessel was purged with N2, sealed and heated to 50° C. for 14 h. TLC at this time showed excellent conversion to the desired product. The cooled mixture was filtered through a plug of celite and partitioned between EtOAc (10 mL) and H2O (10 mL). The organic portion was dried (Na2SO4), filtered, and concentrated. Column chromatography (SiO2, EtOAc/hexanes) affored the title compound as a light brown solid: 1H NMR (CDCl3) δ 8.72 (bs, 1H), 8.64 (d, J=6.0 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 1.34 (s, 9H), 0.29 (s, 9H).
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)=[N:22][O:23][C:24]=3[CH2:25][OH:26])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of cyclopropylamine (62.0 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=8:2 to 1:0) to afford the title compound (27 mg, 25%) as a colourless oil. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:19]([O:25][CH2:26]Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([O:14][CH2:26][O:25][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1c(Cl)cccc1Nc1ncccc1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1Nc1ncccc1C(=O)OCOC(=O)C(C)(C)C
Yield: 77.4 %

Procedure:
To a stirred mixture of 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylic acid (26.3 g) in 400 ml of acetone, triethylamine (20.5 ml) was added. Thereafter pivaloyloxymethyl chloride (15 ml) was poured into the mixture and then it was refluxed 4 hours. Subsequently, the reaction mixture was cooled to 15°-20° C. poured into previously cooled distilled water (3000 ml) and maintained at 5°-7° C. for 4 hours. The cake was filtered by suction and the formed compound dried at 25°-35° C. under vacuum to obtain a yield of 77.4% (29.2 g) of pivaloyloxymethyl 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylate, m.p.: 91° C.-92° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(C)(=O)=O)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
Under a nitrogen atmosphere, methane sulfonic anhydride (550 mg) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (757 mg, 2.875 mmol), triethylamine (520 μL) and chloroform (11 mL). The reaction mixture was allowed to stir at ambient temperature for about 3 hours. The reaction mixture was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to provide crude product as a light yellow oil. The oil was purified by column chromatography (10 g of silica gel eluting with 2% methanol in chloroform containing 0.5 % triethylamine). The fractions containing product were combined and concentrated under reduced pressure. The residue was purified using Method A described above to provide 0.2753 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide.
Reaction SMILES: B1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)OCCCO1.Br[C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:23]([C:21]1[CH:20]=[CH:19][C:17]2[C:16](=[C:7]3[C:12](=[C:13]([NH2:14])[N:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:22]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)c1ccc2nc(N)c3ccccc3c2c1
Temperature: 25 °C

Procedure:
A 500 ml round bottom flask was charged with 12.2 grams (65.4 mmol) of 2-cyanophenylboronic acid propanediol ester, 14.0 g (65.4 mmol) of 2-bromo-4-isopropylaniline, 2.27 (2 mmol) tetrakis(triphenylphosphine)palladium, 18.0 g (131 mmol) of potassium carbonate, 150 ml toluene, and 50 ml ethanol. The reaction was heated to reflux under N2 for 18 hours. After cooling to room temperature the reaction was extracted with ethyl acetate and water. The organic washed with brine and then dried with magnesium sulfate. The solids were collected by filtration and the solvent removed from filtrate. The product was purified by silica gel chromatography using 94.5% dichloromethane, 5% methanol, 0.5% ammonium hydroxide as the eluent. The fractions containing the desired product were combined and the solvent removed. The product was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:39])([CH3:41])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (890 mg, 3.14 mmol), N-Me-Val-Tyr(3-tBu)-NH2 (1 g, 2.86 mmol) and CMPI (804 mg, 3.15 mmol) in THF (20 ml), TEA (1.2 ml, 7.16 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: acetone:n-hexane=1:2), giving Boc-Phe(4-F)-N-Me-Val-Tyr(3-tBu)-NH2 (1.5 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F

Procedure:
1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one is etherified with 4-fluoronitrobenzene in the presence of potassium carbonate in N,N-dimethylformamide to form 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound A). Compound A is then reduced with iron powder in acetic acid and water to produce 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound B). Acetone is added to a stirring mixture of Compound B in hydrochloric acid. The mixture is cooled to about 5° C., and a solution of an equimolar amount of sodium nitrite in water and a molar excess of methyl acrylate are added in succession. The resultant mixture is stirred for 15-20 minutes, after which copper (I) chloride is slowly added. The mixture is stirred at room temperature for approximately 30 minutes and then poured into ice water. The resulting mixture is then treated with an organic solvent (e.g., ethyl acetate) to extract the product, methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5H-5-oxo-tetrazol-1-yl]phenoxy]phenyl]propionate, which may then be purified, as by column chromatography on silica gel.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][S:30][C:31](SC)=[N:32][C:33]#[N:34].CCOCC>C(O)(C)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:31](=[N:32][C:33]#[N:34])[S:30][CH3:29])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CSC(=NC#N)SC
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 4 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.3 g) and dimethyl N-cyanoimidodithiocarbonate (2 g) in isopropanol (15 ml) were allowed to stand at room temperature for 4 hours. Ether (30 ml) was then added and the mixture was stood at room temperature overnight. The crystalline precipitate was filtered, washed with ether and dried, yield of the title compound 5.0 g, m.p. 177°-179°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](OCCCOC1N=CC(C2(O)CCN(C(OC(C)(C)C)=O)CC2)=CC=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:7][C:2]2[CH:3]=[CH:33][C:34]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:1]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(OCCCOCc3ccccc3)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 125 (g), by alkylating a 4:1 mixture of tert-butyl (3'RS, 4'RS)-6-(3-benzyloxy-propoxy)-3'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate and tert-butyl 6-(3-benzyloxy-propoxy)-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate with 2-bromomethylnaphthalene and subsequent separation of the isomers there was obtained tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:9]([C:11]2[CH:12]=[N:13][C:14]([C:20]3[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:28][CH3:29])=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])[OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.I[CH2:31][CH3:32].O>CN(C=O)C>[CH:3]1([CH:9]([O:10][CH2:31][CH3:32])[C:11]2[C:16]([O:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]3[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:28][CH3:29])=[N:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(OCC)C1CCCCC1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.3 mmol) is added to a solution of cyclohexyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol (74 mg, 0.2 mmol) in DMF (0.5 mL) at room temperature. The resulting mixture is stirred for 30 minutes. Iodoethane (31 mg, 0.2 mmol) is then added and the mixture is stirred for an additional 1 hour. Water (1 mL) is added to the above mixture and the aqueous layer is extracted with ethyl acetate (2×2 mL). The combined organic layers are dried and concentrated in vacuo. The crude product is purified with PTLC (hexanes/ethyl acetate 6:1) to give 5-(cyclohexyl-ethoxy-methyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine. 1H NMR: (CDCl3) 8.50 (s, 1H), 7.28 (t, 1H), 7.12 (d, 2H), 6.70 (S, 1H), 4.45 (d, 1H), 4.03 (q, 2H), 3.34 (m, 2H), 2.34 (m, 4H), 2.02 (br, 1H), 1.73 (m, 4H), 1.21 (m, 4H), 1.05 (m, 13H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O1CCOCC1>[C:6]([O:5][C:1](=[O:4])[NH:2][N:3]1[CH:12]=[CH:16][CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nn1cccc1
Yield: 12.5 %

Procedure:
A mixture of tert-butyl carbazate (5.51 g, 41.7 mmol), 2,5-dimethoxytetrahydrofuran (6.5 mL, 50.0 mmol) and acetic acid (33.6 mL) in dioxane (80 mL) was refluxed for 3 h; then cooled, the dark brown reaction mixture was concentrated, the resulting residue was directly silica gel column purified (eluents: 10% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product (951 mg) as white solid. 1H NMR (CDCl3, δ in ppm): 7.17 (s, br, 1H), 6.66 (m, 2H), 6.11 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[CH:28](O)([CH3:30])[CH3:29].O>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH:28]([CH3:30])[CH3:29])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Reactant: CC(C)O
Solvent: O
Product: CSc1ccc(C(CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)OC(C)C)cc1

Procedure:
This compound was prepared according to general procedure E, from 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxy-propyl]phenoxy]-2-methylpropanoic acid in 50/50 isopropyl alcohol/water at 70° C. for 32 hours;