Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C(O[C:16](=[NH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)C.Cl>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])=[NH:25]
Reactant: NN1CCc2ccccc2C1=O
Reactant: CCOC(=N)c1cccc(OC)c1
Agent: Cl
Product: COc1cccc(C(=N)NN2CCc3ccccc3C2=O)c1
Temperature: 125 °C

Procedure:
A mixture of 16.2 g. of 2-amino-3,4-dihydro-1(2H)-isoquinolinone (0.10 mole), 27 g. of m-methoxybenzimidic acid ethyl ester (0.15 mole) and 2.15 g. of the hydrochloride of m-methoxybenzimidic acid ethyl ester is heated under vacuum (200 mm Hg.) for 5 hours at about 90° C. and for 2 hours at about 125° C. Then 3.50 g. of m-methoxybenzimidic acid ethyl ester (0.02 mole) is added and the mixture is heated for a further 16 hours at about 125° C. under vacuum. All volatile materials are eliminated by distilling off at 125° C. and 5 mm Hg. The solid residue may be used as such for the cyclization step or, after washing with aqueous sodium bicarbonate and water, may be purified by crystallization from ethanol to isolate the intermediate III, 2-(m-methoxybenzimidoylamino)-3,4-dihydro-1-(2H)-isoquinolinone (m.p. 176°-177° C.). The crude reaction product is cyclized by heating for five hours in 150 ml. of ethanol containing 1.2 g. of 80% sodium hydride (0.040 mole). The reaction mixture is then evaporated to dryness in vacuo and then dissolved in dichloromethane. The organic solution after washing with water is evaporated and the crude residual compound is crystallized from 50% ethanol, yielding 20 g. (72%) of the title compound, m.p. 94°-96° C.
Reaction SMILES: C[CH:2]([CH3:4])[O-:3].[Al+3].C[CH:7]([CH3:9])[O-:8].CC(C)[O-].C(O)(=O)CCCCCCCC.[C:25]([O-:44])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]CCCCCCC.[K+]>>[C:2]1(=[O:3])[O:8][CH2:7][CH2:9][O:44][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:4]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CC(C)[O-]
Agent: CCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [K+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Yield: 89.3 %

Procedure:
Aluminum tripelargonate, obtained by reacting 0.5 mole aluminum isopropoxide and 1.5 mole pelargonic acid at 120° C., was combined with an equimolar amount, based on aluminum, of potassium stearate and the resulting mixed metal catalyst (1.7 weight percent) charged to a reactor with 76 g poly(ethylene brassylate). The depolymerization was conducted in the usual manner. Ethylene brassylate was obtained at a rate of 42 mls/hr. and yield of 89.3%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12]>C1COCC1>[C:11](=[O:12])([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1
Reactant: OC1CN2CCC1CC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN2CCC1CC2
Reaction time: 4 h

Procedure:
To a stirred solution of 3-quinuclidinol (3.00 g, 23.6 mmol) in THF (100 mL) was added 4-nitrophenyl chloroformate (5.94 g, 29.5). After stirring for 4 hours, the precipitate was filtered off, rinsed with THF and air dried on the frit under house vacuum. The filtercake was dissolved in ethyl acetate (150 mL) and washed with aqueous NaHCO3 (1×150 mL) and water (2×150 mL). The organic layer was dried (Na2SO4) and concentrated to afford crude 4-nitrophenyl quinuclidin-3-yl carbonate product, which was used in the next step without purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][C:10]=1[Si:16]([CH3:18])([CH3:17])[CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)C(=O)c1cccc(C)c1
Product: CCN(CC)C(=O)c1cc(C)ccc1[Si](C)(C)C
Yield: 46 %

Procedure:
These compounds were prepared from N,N-diethyl-3-methylbenzamide and 2.0 eq TMSCl according to General Method A. Purification by HPLC using 1:9 ethyl acetate/hexanes gave two products. Compound 63 was isolated as 6.0 g of a clear oil, a 46% yield. Compound 64 was isolated as 2.3 g of a clear oil, a 17% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH:22][NH2:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:23][N:22]([CH3:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Product: Cn1cc(-c2ccc(Br)cc2)c(-c2cc(Cl)c(O)cc2O)n1
Reaction time: 16 h
Yield: 73 %

Procedure:
An ethanolic solution (5 ml) of 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (100 mg, 28 mmol) was heated to boiling, methyl hydrazine (0.30 ml, 20 equiv.) added in one portion, and refluxing continued for 16 hrs. After cooling, the volatiles were evaporated under reduced pressure and water added to the residue causing a precipitate to form. This was filtered off and dried under vacuum in the presence of P2O5 to provide 78 mg (73% yield) as a tan coloured powder. Although pure by LCMS further purification by column chromatography, eluting with first 40% EtOAc in Hexane and increasing to 60%, gave a grey-white powder (6 mg). The exact regioisomer was confirmed by NOESY 1H NMR.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[C:4]([C:11]([F:14])([F:13])[F:12])=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:11]([F:14])([F:12])[F:13])[C:5]([C:8]([OH:10])=[O:9])=[CH:6]1
Reactant: O=C(O)c1c[nH]c(=O)cc1C(F)(F)F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cn1cc(C(=O)O)c(C(F)(F)F)cc1=O
Reaction time: 16 h

Procedure:
To a stirred suspension of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid (0.207 g) and potassium carbonate (0.553 g) in methanol (5 mL) was added methyl bromoacetate (0.104 mL) at room temperature. After 16 h, the reaction was not complete, so further methyl bromoacetate (0.15 mL) was added. After a further 16 h, the mixture was concentrated in vacuo before the addition of 1 N aqueous hydrochloric acid (30 mL) and extracted into ethyl acetate (3×25 mL), dried over Na2SO4, filtered, and concentrated in vacuo to leave a white solid (300 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (2 g, 0.007 1 mol), phenyl isothiocyanate (1.15 g, 0.0085 mol) and toluene (10 ml) was heated under reflux for 1.5 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 1.2 g (42%), m.p. 148°-149 ° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37]C)=[N:35][CH:36]=1>CN(C=O)C>[OH:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(O)nc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a solution of N-(4-(4-hydroxy-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (5-3, 1.92 g, 5.91 mmol) in DMF (15 mL) were added cesium carbonate (2.41 g, 7.39 mmol) and Cu (116 mg, 1.78 mmol, 0.30 equiv). The mixture was stirred at 80-90° C. for 60 min. 5-Bromo-2-methoxy-pyridine (9-1, 1.67 g, 8.87 mmol) was added to the solution and the reaction mixture was stirred at 100° C. for additional 24 hr. The solution was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 5 (0.97 g) in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.89 (d, J=5.0 Hz, 2H), 8.23 (d, J=5.0 Hz, 2 H), 8.02 (s, 1 H), 7.37 (d, J=3.0 Hz, 1 H), 6.89 (s, 1 H), 6.80 (d, J=9.0 Hz, 1 H), 6.69 (s, 2 H), 3.94 (s, 3H), 2.17 (s, 6 H), ESI-MS=m/z 433.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Product: O=C1CCCC1C(=O)OCc1ccccc1
Temperature: 175 °C
Yield: 93.1 %

Procedure:
To ethyl 2-oxocyclopentanecarboxylate (4 g, 25.6 mmol) was added benzyl alcohol (3.6 g, 33.3 mmol) and the resulting mixture was heated to 175° C. for 1 hour. The reaction mixture was concentrated under reduced pressure using a high vacuum pump to yield benzyl 2-oxocyclopentanecarboxylate (5.2 g, 23.84 mmol, 93% yield) as an oil. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC)=O.[C:23]([NH:32][NH2:33])(=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([NH:33][NH:32][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:20]
Reactant: CCCCCCCC(=O)NN
Reactant: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Product: C=C(C)C=Cn1c(=O)c(C(=O)NNC(=O)CCCCCCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 29 (0.66 mmols, 0.2 g); octanoyl hydrazine (0.73 mmols, 0.12 g). Yield: 0.125 g (22%), white solid, m.p.=114° C.-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-6-methylpyridine-4-carboxylic acid (0.52 g, 3.04 mmol) and borane-tetrahydrofuran complex (6.08 mL, 6.08 mmol) were combined in tetrahydrofuran (10.0 mL) at 0° C. After 15 min, the ice bath was removed and mixture stirred at room temperature for 4 h. The mixture was cooled to 0° C., and treated with methanol until no bubbles were observed. The solvents were removed and the crude mixture dissolved in ethyl acetate which was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 0.25 g (53%) which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 2.53 (s, 3H), 4.7 (s, 2H), 7.06 (s, 1H), 7.15 (s, 1H). Mass spec.: 158.0 (MH)+.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1)C.[OH-].[Na+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>O.C1(C)C(C)=CC=CC=1>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)Cc1ccc(O)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Oc1ccc(Cc2ncc[nH]2)nc1Cl

Procedure:
This hydrochloride was dissolved in water and the solution was neutralised with dilute sodium hydroxide solution and evaporated. The residue was extracted several times with hot toluene and the combined extracts were filtered and evaporated to give the corresponding free base. The base (3.70 g) and imidazole (1.5 g) were heated under reflux in xylene (50 ml) for 3 hours. The mixture was then evaporated and the resulting dark residue was extracted several times with hot water. The aqueous solution was evaporated and the residue was crystallised first from ethyl acetate and then from water to give 2-(1-imidazolylmethyl)-5-hydroxy-6-chloropyridine (0.88 g), m.p. 157°-158°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12]([CH2:13][C@@H:14]4[CH2:18][CH2:17][N:16]([C:19]([CH:21]5[CH2:23][CH2:22]5)=[O:20])[CH2:15]4)=[N:11][NH:10][C:9]3=[O:24])=[C:4]([F:25])[CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol) in 1,4-dioxane (1.5 mL) was treated with (4-acetylphenyl)boronic acid (0.244 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)-dichloromethane adduct (10 mg) and 2M aq potassium carbonate (0.733 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as an amorphous white solid (54%). MS(ES)+ m/e 449.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH2:16]COC[CH2:12]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:12][O:11][CH2:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: COCc1ccc(C(C)=O)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 31 %

Procedure:
To a mixture of 4′-bromoacetophenone (300 mg, 1.51 mmol) and 1,4-dioxane (4 ml) were added water (0.4 ml), cesium carbonate (1.48 g, 4.54 mmol), potassium methoxymethyl trifluoroborate (459 mg, 3.02 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (110 mg, 0.151 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 7 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain the title compound (76 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1.[ClH:31]>C(O)C.CCOCC>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-(2-fluorophenyl)-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Step B) (1.05 g, 2.43 mmol) in ethanol (20 mL) was added a solution of hydrogen chloride in ether (2 M, 12.2 mL). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure to provide the title compound as colorless solid (0.807 g)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[C:17]1([OH:27])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:27][C:17]3[C:26]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2cccc3c2CCCC3)cc2nc(-c3ccco3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. 5,6,7,8-tetrahydro-naphthalen-1-ol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 346 M+H+ (100%).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C.[Cl-].[NH4+]>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.[Cu](I)I.CN(C)C=O>[CH3:9][N:8]([CH3:10])[C:7]1[C:2]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)c1cccnc1Br
Reactant: C#Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1cccnc1C#Cc1ccncc1
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 2 g of (2-Bromo-pyridin-3-yl)-dimethyl-amine (9.95 mmoles), 1.24 g of 4-ethynyl pyridine (12 mmoles) in 120 mL of a 1/1 mixture of triethylamine and dimethylformamide is stirred under argon at room temperature. 750 mg of bis(triphenylphosphine)palladium dichloride and 400 mg of copper iodide are added to the reaction mixture which is further stirred at room temperature for 3 hours. The reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 1 g of Dimethyl-(2-pyridin-4-ylethynyl-pyridin-3-yl)-amine as orange oil.
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:17]=2[F:23])=[CH:12][C:11]1=[O:24])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[Br:22][C:18]1[C:17]([F:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:25])=[O:3])[C:11](=[O:24])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Br)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Br)c2F)=CC1=O
Temperature: 15 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
To a solution containing (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.260 g, 0.63 mmol) in tetrahydrofuran (8 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 1.5 mmol). The mixture was stirred at 15° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (0.250 g, 100%), as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C@H:5]([C@@H:25]([O:38][CH2:39][CH:40]=[CH2:41])[C@H:26]([O:34][CH2:35][CH:36]=[CH2:37])[C:27](=O)[CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:9]=1)=O)[CH:2]=[CH2:3].C([O-])=O.[NH4+].[BH3-]C#[N:48].[Na+]>CO>[CH2:35]([O:34][C@H:26]1[C@H:25]([O:38][CH2:39][CH:40]=[CH2:41])[C@@H:5]([O:4][CH2:1][CH:2]=[CH2:3])[C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[CH:9]=2)[NH:48][C@@H:27]1[CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[CH:36]=[CH2:37]
Reactant: C=CCOCC(=O)[C@@H](OCC=C)[C@H](OCC=C)[C@@H](OCC=C)C(=O)c1ccc(Cl)c(Cc2ccc(OCC)cc2)c1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C=CCOC[C@H]1N[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCC=C)[C@@H](OCC=C)[C@@H]1OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of compound from Step E (0.60 g, 1.03 mmol) in MeOH (12 ml) was added 4 Å MS followed by ammonium formate (0.13 g, 2.06 mmol). NaBH3CN (0.14 g, 2.3 mmol) was then added in one portion and the mixture stirred at room temperature for 1 hour 30 minutes. The reaction mixture was then filtered and concentrated. Purification by silica gel chromatography (10%-20% EtOAc/hexanes) afforded (2R,3R,4R,5S,6S)-3,4,5-tris-allyloxy-2-allyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-piperidine (155 mg, 0.27 mmol, 27%). MS (ES+) [M+H]+=568.
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12](#[N:14])[CH3:13].C([O:17][C:18](=O)[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>O1CCCC1>[CH2:21]([O:20][CH2:19][C:18](=[O:17])[CH2:13][C:12]#[N:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC#N
Reactant: CCOC(=O)COCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 151.1 %

Procedure:
In a stream of argon, 156.2 ml (0.248 mole) of a solution of 1.6 moles of n-butyllithiumhexane was added to 150 ml of anhydrous tetrahydrofuran. The mixture was cooled to -78° C., and a solution of 15.8 ml (0.293 mole) of acetonitrile in 50 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 1 hour. A solution of 55.2 g (0.248 mole) of ethylbenzyloxyacetate in 100 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 15 minutes and at room temperature for 50 minutes. The mixture was then poured into 200 ml of ice water. The aqueous layer was washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 70.9 g of crude 4-benzyloxy-3-ketobutanenitrile.