Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25](OB(O)O)=[C:24]([O:33][CH3:34])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH3:34][O:33][C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Reactant: COc1cc(C)cc(C)c1OB(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
After dissolving tert-butyl N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0 g) in 1,2-dimethoxyethane (60 mL) and water (30 mL), 4,6-dimethyl-2-methoxyphenylboric acid (1.33 g), tetrakis(triphenylphosphine)palladium(0) complex (865 mg) and barium hydroxide octahydrate (2.34 g) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 124.9 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (100 g, 0.52 mol) in anhydrous THF (550 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (210 mL, 0.52 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (120 g, 0.44 mol) in anhydrous THF (500 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (178 g), which was used immediately for next step without purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[N:64]1[CH2:68][CH2:67][CH:66]([C:69](O)=[O:70])[C:65]1=[O:72]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:69]([CH:66]1[CH2:67][CH2:68][N:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[F:57])[C:65]1=[O:72])=[O:70]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccccc2F)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccccc2F)C1=O
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.349 g; 0.672 mmol), N,N-diisopropylethylamine (0.232 mL; 1.34 mmol) and 1-(2-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.078 g (44%) of the title compound as a white solid.
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH3:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][OH:8]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 97.6 %

Procedure:
A solution of product from step (c) (13.56 g) in ethyl acetate (68 mL) was stirred under a hydrogen atmosphere with 5% palladium on carbon (1.36 g, wet paste) for 3 hours. The catalyst was then removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (10.93 g). GC retention time 15.2 mins
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][C:7]=1[F:14]>CN(C=O)C>[N:1]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[C:7]([F:14])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(CBr)ccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Br)c(F)c1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
Add sodium azide (2.912 g, 44.8 mmol) to a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol) in anhydrous DMF (127 mL) at room temperature under nitrogen. Heat the mixture at 90° C. for 1 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the combined organics extracts with iced-water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (4.92 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([F:8])=[N:6][CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>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>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH2:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(F)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(N)cnc1F
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-3-bromo-2-fluoropyridine (3.25 g, 17.0 mmol) from step 131b above in toluene (20 mL) was added tributyl(vinyl)tin (7.64 g, 20.4 mmol) followed by tetrakis(triphenylphosphine)palladium (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the title compound as a beige solid (2.30 g, 98%): 1H NMR (CDCl3, 300 MHz) δ3.61 (br s, 2H), 5.44 (d, J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[Cl:18])(=[O:3])[CH3:2].[Cl:19][C:20](Cl)([Cl:24])[CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([O:17][CH2:22][CH:21]=[C:20]([Cl:24])[Cl:19])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
A solution of 25.3 grams (0.086 mole) of 4-(2,6-dichloro-4-hydroxyphenoxy)butyl acetate in 250 mL of DMF was stirred, and 19.5 grams (0.1 mole) of 1,1,1,3-tetrachloropropane was added, followed by 18 grams (0.13 mole) of potassium carbonate. Upon completion of addition the reaction mixture was heated at 80° C. during a 17 hour period. After this time the reaction mixture was cooled to ambient temperature, stirred with 350 mL of water and extracted with four 150 mL portions of diethyl ether. The combined extracts were washed with two 100 mL portions of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 27.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Br:2])=[CH:8][CH:7]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus tribromide (1.3 ml) was added, dropwise, to a solution of 4-chlorophenethyl alcohol (5.0 g) in carbon tetrachloride (30 ml). The mixture was stirred at room temperature for 10 minutes then heated under reflux for 2 hours. Ice (50 g) was added and the mixture partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, yield 3.0 g.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:25]=[CH:24][C:11]([O:12][CH:13]([CH3:23])[C:14]([O:21][CH3:22])=[CH:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H-].O>CCOCC>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:25]=[CH:24][C:11]([O:12][CH:13]([CH3:23])[C:14]([O:21][CH3:22])=[CH:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a slurry of LiAIH4 (100 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (500 mg) in ether. After addition is complete, the reaction mixture is stirred for about 20 minutes. Excess of the hydride is decomposed using wet ether and water. Filtration and evaporation of filtrate gives the C-1 alcohol, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol, MS m/e 440 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH:44]=O)[CH:36]=1.[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:44][CH2:43][CH2:42][CH2:41][C:37]1[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=CCCCc1cccnc1
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reaction time: 0.71 h

Procedure:
A dry flask containing 3.00 g (7.93 mmol) of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (prepared essentially as described in Example 7.1 Step A), 4.76 g (39.7 mmol) of anhydrous MgSO4, and a magnetic stirring bar was fitted with a septum and needle adapter leading to a Firestone valve. The flask was thoroughly purged with N2, and the mixture was cooled in an ice-MeOH bath at -10° to -5° C. and stirred vigorously as a solution of 1.32 g (8.88 mmol) of 4-(pyridin-3-yl)butyraldehyde in 15 ml of dry CDCl3 was added gradually by syringe over 10-15 minutes. The resulting mixture was stirred under N2 at -10° to -5° C. for 40-45 minutes. Then the septum was removed just long enough to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under N2 at -10° to -5° C. as 10 ml of dry MeOH was added dropwise by syringe over several minutes. After 30 minutes, the mixture was removed from the cooling bath and partitioned between 90 ml of EtOAc and 90 ml of H2 O. The organic layer was washed with 2×30 ml of brine, then dried over anhydrous Na2SO4. The filtered solution was concentrated in vacuo, and the residue was flash chromatographed of silica gel (gradient elution with 0-10% MeOH in CH2Cl2). Fractions containing product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of light beige, stiff foam, used directly in the next step without further purification or characterization.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]1([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1>CO.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH:8]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: C1CN(C2CC2)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
4.0M HCl in dioxane (42.7 mL, 170.78 mmol) was added to a stirred solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g, 34.16 mmol) in a mixture of methanol (50.0 mL) and ethyl acetate (200 mL). The resulting suspension was stirred at room temperature for 24 h under nitrogen. The white solid filtered off to give 1-cyclopropylpiperazine dihydrochloride (6.30 g, 93%).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:19](N(CC)CC)C.CO>CN(C=O)C>[CH3:19][O:2][C:1]([C:4]12[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:7][C:6]([OH:14])([CH2:12]3)[CH2:5]1)[CH2:13]2)=[O:3]
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
10 mmol of the 1-carboxy-3-adamantanol produced by the method of Preparation Example 5 under a nitrogen atmosphere was dissolved in 10 ml of DMF, and 15 mmol of thionyl chloride was dropped into the solution for 30 minutes. The temperature was elevated so that the solution starts its reflux at the end of dropping. After two hours of reflux, the reactant mixture was cooled, added 20 mmol of triethylamine, the temperature of the mixture was maintained at 10° C. or below, and 11 mmol of methanol was added dropwise for 30 minutes and stirred for 2 hours. And, at the result, the 1-carboxy-3-adamantanol was converted into a 1-methoxycarbonyl-3-adamantanol (yield: 95%) with a conversion of 99%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>C(Cl)Cl>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:23](=[O:24])[CH3:22])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (200 g, 1 mol) and Et3N (150 g, 1.5 mol) in DCM (3000 mL) was added Ac2O (102 g, 1 mol) dropwise over 1 h, while maintained the temperature at 0° C. After addition, the mixture was stirred 0° C. for another 2 h, at which time TLC showed the reaction was completed. The solution was quenched by addition of water (1 L). The organic phase was collected and washed with saturated aqueous NaHCO3 (1 L), dried (Na2SO4) and concentrated to give crude product. Four batches were run in parallel and produced a combined crude product weight of 670 g. This crude was used directly in the step. LCMS (m/z): 243.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccn(CCc2ccccc2)n1
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-1-phenethyl-1H-pyrazole (90 mg, 0.41 mmol) in ethyl acetate (2 mL) and ethanol (2 mL) was added 10% Pd—C (20 mg), the resulting mixture was stirred under hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound as colorless oil. LC-MS (ES, Pos.): 188 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.10 (t, J=7.2 Hz, 2H), 3.64 (br s, 2H), 4.12 (t, J=7.2 Hz, 2H), 5.51 (d, J=2.3 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H), 7.08-7.11 (m, 2H), 7.20-7.30 (m, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][N:6]=1>O1CCOCC1.O>[Br:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(Br)nc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred solution of NaCN (117 g, 2.38 mol) in dioxane (1 L) and water (1 L), was added the above crude 2-bromo-5-bromomethylpyridine (275 g) and the mixture was stirred at rt for 15 h. The reaction mixture was quenched with cold water (15 L) and extracted with EtOAc (3×1 L). The organic layer was washed with water (3×1 L), brine (2×1 L), dried with Na2SO4 and concentrated under reduced pressure to give crude title compound. The crude residue was purified by column chromatography over silica gel (pet. ether/ethylacetate, 7:3) to give 95 g (6-bromopyridin-3-yl)acetonitrile as a pale yellow solid (49%). [TLC, Rf=0.5, pet. ether/ethylacetate 7:3]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5°-57.5° C; NMR (CDCl3) δ 3.74 (s, 2H), 7.54 (d, J=8Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (191 mg, 42%) as a white solid. To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was added aqueous sodium hydroxide (1 M, 36.0 mL, 36.0 mmol). After heating at reflux for 2 h it was cooled to ambient temperature and concentrated. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by washing with tert-butylmethylether (100 mL). The aqueous phase was acidified with aqueous hydrogen chloride (conc.) to pH=1 and extracted with tert-butylmethylether (100 mL). The organic layer was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL). Drying over sodium sulfate and concentration afforded the title compound (1.68 g, 45%) as an off white solid. MS: m/e=309.3 [M−H]−.
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.N(OCCC(C)C)=O.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:11]1([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccccc1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Agent: CC(C)CCON=O
Product: c1ccc(-c2ccc3nc(-c4ccccc4)oc3n2)cc1

Procedure:
A mixture of 180 mg. of 5-amino-2-phenyloxazolo[5,4-b]pyridine, 10 ml. of benzene and 0.2 ml. of isoamyl nitrite was refluxed for 11/2 hours. The hot solution was filtered and concentrated to dryness. The residue was extracted with ether and the extract was filtered through aluminum oxide and concentrated to dryness. The crystalline residue was recrystallized from ethyl acetate to give 2,5-diphenyloxazolo[5,4-b]pyridine, m.p. 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=1)=[O:9]
Reactant: Cc1ncc(C(=O)O)c(O)c1Br
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
The compound 20 (138 g, 0.596 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 g, 0.775 mol), and 1-hydroxybenzotriazole (100 g, 0.656 mol) were dissolved in dimethylformamide (970 ml), and 4-fluorobenzylamine (79 ml, 0.715 mol) was added. After the reaction solution was stirred at room temperature for 9 hours, water (2000 ml) was added, and crystals were collected by filtration, followed by washing with ether. 5-Bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 21 (156 g, 77%) was obtained as a colorless crystal.