Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[CH3:19][C:20](=[O:23])[CH:21]=[CH2:22].[OH-].[K+]>CO.O>[O:23]=[C:20]1[CH2:21][CH2:22][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:19]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
A solution of 0.98 g (3.96 mmol) benzyl 4-formylpiperidine-1-carboxylate (prepared by the method from Eur. J. Med. Chem. 1991, 26, 625) and 0.28 g (4.0 mmol) 3-buten-2-one in a mixture of 1 ml methanol and 1 ml water was added dropwise to a boiling solution of 0.015 g (0.27 mmol), potassium hydroxide in 1 ml methanol. After 1 hour heating with reflux the cooled mixture was poured into 50 ml water, and it was extracted with tert.-butylmethylether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained from the remaining oil by HPLC on silica gel with hexane/acetone 4:1.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH3:7].O.C(=O)=O>C(O)C>[CH2:6]([O:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc(N)cc1
Yield: 81.9 %

Procedure:
Under nitrogen, 17.5 g (19.4 mmol) lithium-cobalt (I) phthalocyanine×4.5 THF and 663 mg (3 mmol) p-nitro cinnamic ethyl ester are agitated in 100 ml ethanol for 65 hours at 20° C. The green reaction mixture is mixed with 10 ml water; CO2 and air are passed into it for 5 min. and the blue precipitate is centrifuged which is washed out with ethanol and ether. The centrifugate collected is concentrated and the residue separated into methylene chloride and water. Concentration of the organic phase, dried with sodium sulfate, produces 470 mg (82%) p-amino cinnamic ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 4-aminotetrahydropyran (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (38 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][NH:25][O:26][CH3:27]>CCOCC>[CH:1]1([CH2:4][C:5]([N:25]([O:26][CH3:27])[CH3:24])=[O:7])[CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(O)CC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A 500 mL round bottom flask was charged with cyclopropylacetic acid (9.87 g, 98.6 mmol) (available from Oakwood) and DCM (200 mL). To the stirred solution was added 1,1′-carbonyldiimidazole (19.2 g, 118 mmol) portionwise (vigorous gas evolution). The yellow solution was stirred for 30 minutes at room temperature, and to it was added N,O-dimethylhydroxylamine hydrochloride (11.5 g, 118 mmol) (available from Aldrich) in one portion. The heterogeneous, white mixture was stirred overnight and diluted with ether (300 mL). The organics were washed with 1 N HCl (2×150 mL), saturated aqueous NaHCO3 (2×150 mL) and brine (1×150 mL), dried (MgSO4), and concentrated to afford 84.B (11.9 g, 84.3% yield) as a colorless liquid. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[O:5]CC1C=CC(Cl)=CC=1Cl>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[OH:5]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 3 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L of methylene chloride that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL of methylene chloride while stirring. After maintaining the solution at about 3° C. for approximately 27 hours, another 5.031 mL of stannous chloride (SnCl4) (0.04282 mol) was added and the solution was kept at about 3° C. overnight. After a total reaction time of approximately 43 hours, the reaction was quenched by carefully adding the solution to 1.9 L of a saturated NaHCO3 solution. Tin salts were removed via filtration through Celite after which the organic phase was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g. The crude oil was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:14])[C:11]([Cl:13])=[O:12]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([Cl:13])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(Cl)C(=O)c1c[nH]c2ccccc12

Procedure:
reacting indole with oxalyl chloride to give 3-indoleglyoxylyl chloride;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](Cl)[C:9]3=[CH:13][C:14]([CH3:16])=[CH:15][N:8]3[CH2:7][C:6]=2[CH:17]=1.Cl.[CH3:19][C:20]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][C:20]([CH3:32])([CH3:19])[C:21]([O:23][CH3:24])=[O:22])[CH2:31][CH2:30]3)[C:9]3=[CH:13][C:14]([CH3:16])=[CH:15][N:8]3[CH2:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Yield: 97.4 %

Procedure:
To a suspension of 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (34.0 g, 128.23 mmoles) in acetonitrile (300 mL) add methyl 2,2-dimethyl-3-(piperazin-1-yl)-propionate hydrochloride (2.1 equiv; 63.75 g, 269.29 mmoles) and potassium carbonate (4 equiv; 70.89 g, 512.93 mmoles). Heat the mixture at reflux overnight. Evaporate to dryness. Partition the residue between water (500 mL) and EtOAc (2×500 mL). Combine the organic layers and wash with water (500 mL) then brine. Dry over sodium sulfate, filter and evaporate to a brown oil. Add iso-hexane (˜150 mL) and a seed crystal of Preparation 50. Allow to crystallize over 2 h, then transfer the flask to a fridge and allow to stand. Collect the resulting heavy crystalline solid by filtration, washing with cold iso-hexane. Dry in a vacuum oven at 40° C. for 1 h, to give methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (53.6 g, 97% yield). MS (m/z): 429.18 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([NH:26]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C>CCCCCC.CC(O)C>[NH2:26][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:11]([OH:13])=[O:12])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CC(C)O
Product: N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)O)C(=O)O
Yield: 4.6 %

Procedure:
1.56 g (3.25 mmol) (2S)-2-tert.-Butoxycarbonylamino-5-(4-hydroxy-benzyl)-hexanedioic acid di-tert.-butyl ester (Example 41b) were purified by chiral HPLC (Chiralpak AD-H 5 μm 250×300 mm; hexan/2-propanol; 40 mL7 min). Two isomers were isolated (isomer 1: 362 mg and isomer 2: 424 mg). 0.15 g (0.31 mmol) isomer 1 and 0.15 g (0.31 mmol) isomer 2 were individually deprotected according to the procedure described in Example 41c, yielding 42 mg (51%) (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioic acid—Isomers C5-1 and 40 mg (48%) (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioic acid—Isomers C5-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].COCCO[Al+]OCCOC.[Na+].[H-].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)c(Cl)c2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Methyl 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate (0.67 g) was dissolved in toluene (5 mL). To the obtained solution was added dropwise a mixture of a 70% solution (0.81 g) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene and toluene (2 mL) at 0° C. and the mixture was stirred at 0° C. for 1 h. To the reaction mixture was carefully added a 10% aqueous solution (50 mL) of potassium sodium (+)-tartrate tetrahydrate and the mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration, washed successively with a 10% aqueous solution of potassium sodium (+)-tartrate tetrahydrate, pure water and isopropyl ether, and air-dried to give the title compound as crystals (0.46 g, 74%). Recrystallization from acetone-hexane gave pale-yellow prism crystals. melting point: 140-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.CC([O-])(C)C.[K+]>CC(N(C)C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccc(N)cc2)c1

Procedure:
4-Aminophenol was reacted with 4-methoxy-2-chloropyridine in the presence of KOtBu/8-Crown-6/DMA at 150° C. for 5 hrs to give 2-(4-aminophenoxy)-4-methoxypyridine. The product was purified by chromatography.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CN(C)C=O.O1CCOCC1>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 24.7 %

Procedure:
To a solution of 1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamine (50.0 g) in N,N-dimethylformamide (150 ml) and 1,4-dioxane (500 ml) was added 3,4,5,6-tetrachloro-1,4-benzoquinone (84.0 g) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 4.5 hours. To the reaction mixture was added a 2M aqueous solution of sodium hydroxide (400 ml) under ice-cooling over 25 minutes, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite to remove the insoluble substance, and eluted with ethyl acetate (250 ml×3), and then the filtrate was extracted with ethyl acetate (300 ml). The resulting organic layer was sequentially washed with water (300 ml) and a saturated aqueous solution of sodium chloride (300 ml). The separated aqueous layer was extracted twice with ethyl acetate (300 ml). To the combined organic layer were added anhydrous sodium sulfate (50 g) and silica gel (50 g), and the mixture was stirred at room temperature for 1 hour. This mixture was filtered with silica gel (100 g) on Celite, and subjected to elution with ethyl acetate (250 ml×3). The filtrate was concentrated, and diisopropyl ether (500 ml) was added to the resulting residue, and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, washed twice with diisopropyl ether (100 ml), and dried under reduced pressure to give the titled compound (12.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[OH-].[Li+].[H][H]>O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (20 g) in water (100 ml) was adjusted to a pH of 8 by the addition of 1N lithium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmosphere hydrogen pressure, using a palladium-on-carbon catalyst (0.6 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the filtrate by the addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol and drying, the melting point was 255°-256° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].Cl.CO[C:12](OC)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:7][C:2]1([CH2:5][OH:6])[CH2:3][O:4][C:12]([CH3:14])([CH3:13])[O:8][CH2:1]1
Reactant: COC(C)(C)OC
Reactant: NC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(N)(CO)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
Tris hydrochloride (51 g, 324 mmol) was suspended in dry DMF (100 ml) and 2,2-dimethoxypropane (39 g, 374 mmol) was added followed by para-toluenesulfonic acid (2.6 g, 13.5 mmol). The mixture was stirred in a sealed flask for 18 h at ambient temperature when a clear solution resulted. Triethylamine (2.5 ml) was added and solvent evaporated. The viscous crude was dissolved in triethylamine (40 ml) and ethyl acetate (750 ml) added and the white precipitate of ammonium salts was filtered off after stirring for 30 mins. The filtrate was evaporated to give the product as a colourless liquid in approx. 85% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(Cl)Cl.O1CCOCC1>[ClH:23].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1Cc2ccccc2C12CCNCC2
Yield: 75 %

Procedure:
295 mg (0.92 mmole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine]-2-oxide [prepared as described in step (a) above] were dissolved in 3 ml of methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added, whilst ice-cooling. The mixture was stirred, whilst ice-cooling, for 1 hour, and then the crystals which deposited were collected by filtration, to give 173 mg (yield 75%) of the title compound as white crystals.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O.C(N(CC)CC)C>ClCCl.CCOCC>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[O:25][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccco1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: BrC(Br)=Cc1ccco1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
Carbon tetrabromide (20 mmole) was dissolved in anhydrous diohloromethane (200 mL), and kept at 20° C. under argon atmosphere. Triphenylphosphine (20 mmole) in dichloromethane (200 mL) was added dropwise. After 15 minutes of stirring, the reaction flask was kept at −60° C., followed by the addition of furaldehyde (10 mmole) and triethylamine (10 mmole) in dichloromethane (100 mL). The reaction mixture was brought to room temperature, and two volumes of ether were added. The precipitate was filtered, and the filtrate was dried. The crude material was purified by Si gel column chromatography (>50% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a cold (−20° C.) solution of Rac-(1S,3R)-3-Hydroxy-cyclopentanecarboxylic acid tert-butyl ester (0.905 g) in dichloromethane (12 mL) was added methanesulfonylchloride (0.664 g) and triethylamine (0.636 g). The reaction mixture was stirred 10 min at −20° C. then poured into ice-water. Organic layer was washed with brine and dried over sodium sulfate then concentrated in vacuo to afford the title compound (1.15 g, 89%) as light yellow oil, used without further purification in the next step. MS (EI): 282 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Product: C[Sn](C)(C)c1cccnc1

Procedure:
The 3-trimethylstannylpyridine reagent was prepared from 3-bromopyridine by reacting the latter with n-butyllithium under nitrogen at -78° C., followed by addition of one equivalent of trimethylstannyl chloride. Aqueous work-up and concentration in vacuo gave 3-trimethylstannylpyridine in 79% yield.
Reaction SMILES: [Na].C[C:3]([CH3:13])([CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[C:4]#N.O1CCCC1.[Cl-].[NH4+]>C(O)C>[CH3:13][C:3]1([CH3:4])[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH:9]1[NH2:10]
Reactant: CC(C)(C#N)CCC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 35 g. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The sodium was then mixed with 400 ml. of ether and a mixture of 32.8 g. (0.20 mole) 2,2,5,5-tetramethyladiponitrile, prepared by the method of Coffman et al., J. Am. Chem. Soc., 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess sodium decomposed by dropwise addition of saturated aqueous ammonium chloride, the organic layer washed with water, dried (Na2SO4) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentylimine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) sodium shot. An additional 75 ml. ethanol was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of sodium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60°-61° C. (20 mm.).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.[C:20]([CH:23]1[CH2:28][CH2:27][C:26]([O:29][CH3:30])=[CH:25][CH2:24]1)(=[O:22])[CH3:21].C[O-].[Na+].CC(=O)CCCCCC>C1C=CC=CC=1.O>[CH3:30][O:29][C:26]12[CH2:27][CH2:28][CH:23]([CH2:24][CH2:25]1)[C:20](=[O:22])[CH2:21]2
Reactant: COC1=CCC(C(C)=O)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: CCCCCCC(C)=O
Solvent: O
Product: COC12CCC(CC1)C(=O)C2

Procedure:
A mixture of 13.2 g. of p-toluenesulfonic acid and 0.9 g. of hydroquinone in 540 ml. of benzene was heated at reflux under a Dean Stark trap until no more water was evolved. A solution of 90.6 g. of 1-Acetyl-4-methoxy-3-cyclohexene in 750 ml. of benzene was then added to the refluxing soltuion over 6 hrs. Following an additional hr's heating the mixture was cooled and treated with 16 ml. of 4.64N methanolic sodium methoxide. The mixture was washed twice with water and the solvent evaporated in vacuum. The residual oil was distilled at 0.45 mm to afford 64.2 g. of bicyclic ketone 4-Methoxybicyclo[2,2,2].octan-2-one, bp 77°-82°.
Reaction SMILES: O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47](OC)=[O:48])=[N:44][CH:45]=3)=[CH:36][CH:35]=2)[CH2:27][CH2:26]1.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[O:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:58][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:48])=[N:44][CH:45]=3)=[CH:38][CH:39]=2)[CH2:29][CH2:30]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.