Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].[H][H]>C(O)(=O)C.[Pd]>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[N:3][CH:2]=[C:7]([CH3:8])[CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cnnc(-c2cccc(Cl)c2)c1

Procedure:
3-Chloro-6-(m-chlorophenyl)-4-methylpyridazine (7.2 g) is partially dissolved in 150 mL of acetic acid containing 1.5 g of 10% palladium on carbon. The mixture is shaken on the Parr hydrogenator until the theoretical amount of hydrogen is consumed.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([CH2:17][CH3:18])[N:13]=[CH:12][N:11]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=[O:34])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1>C1COCC1>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([CH:17]([CH3:18])[C:27]([C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])([OH:34])[CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ncnc(Cl)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of LDA (13.6 mmol) in THF (50 ml) (prepared by a similar method to that used in Example 1) at -70° C. was added dropwise 4,5-dichloro-6-ethylpyrimidine (the product of part (ii)) (2.37 g, 13.3 mmol) and the resulting solution was stirred at this temperature for 10 minutes. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.97 g, 13.3 mmol) in THF (50 ml) was added to the reaction mixture at such a rate so as to maintain the reaction temperature below -50° C. After stirring at -70° C. for 1 hour and at -50° C. for a further 1 hour the reaction was quenched by the addition of 10% aqueous acetic acid (11 ml).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:8][N:7]1[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CO)n(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(COS(C)(=O)=O)n(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (0.60 g, 3.51 mmol) and triethylamine (1.22 mL, 8.77 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.41 mL, 5.26 mmol). The reaction mixture was stirred in the ice bath for 15 minutes and then the mixture was allowed to warm to room temperature. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:22]Cl>C(O)(=O)C>[CH3:21][C:16]1[CH:17]=[C:18]([F:20])[CH:19]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([Cl:22])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cn2cccc(OCc3c(C)cc(F)cc3C)c2n1
Reactant: ClCl
Solvent: CC(=O)O
Product: Cc1cc(F)cc(C)c1COc1cccn2c(Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 8-(2,6-dimethyl-4-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (0.6 g, 2.1 mmol) in acetic acid (13 ml) was added dropwise 1.1 M Cl2 in acetic acid (2.2 ml, 2.43 mmol). The reaction mixture was stirred for 2 h. at room temperature and the solvent was evaporated under reduced pressure. The residue weas solved in methylene chloride and was washed with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:ethyl acetate (100:4) as eluent. Treating the residue with diethyl ether and filtration gave 0.3 g (45%) of the title compound.
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](O)=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1>C1C=CC=CC=1>[Cl:8][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMF (10 ml) and thionyl chloride (14 ml) are added successively to 4-fluoro-2,6-dinitrophenol (26.00 g) in benzene (50 ml). The resulting solution is stirred at room temperature for 5 min (an intermediate precipitates) and then heated under reflux for 1.5 h (or until the starting material has reacted completely). The reaction mixture is cooled to room temperature, concentrated and the residue is poured onto ice/water. The precipitate is collected by filtration, washed three times with water and dried. After recrystallization from ethanol 23.50 g (83% of theory) of product are obtained in crystalline form.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16](=O)[CH2:17]Br)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.C(OCC)(=O)C>C1COCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[N:3]=[CH:1][S:2][CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: NC=S
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2cscn2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixture was stirred at r.t. for 2 h. Ethyl acetate was then added and the organic phase was washed with saturated aqueous NH4Cl, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[CH3:19]I.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][CH3:19])[N:7]2[N:8]=1
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=Nc2ccccc2Cc2nc(C)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension is added a solution of 5.4 g of methyl iodide in 35 ml of tetrahydrofuran dropwise at 0° over a period of 15 minutes. The mixture is stirred at room temperature for 1 hour, poured into water and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-methylthio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Br:15]N1C(=O)CCC1=O.O>C1COCC1>[Br:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrant was washed with THF, dried under vacuum at 60° C., and recrystallized from ethyl acetate/hexanes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CN(C=O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Piperazine (12.9 g) was dissolved in DMF (100 mL), and a solution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was added dropwise. The mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to give 1-(2-nitrophenyl)piperazine (7.7 g) as a red oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[CH:55](=[O:64])/[CH:56]=[CH:57]/[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[C@H:15]([CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:34])([CH3:36])[CH3:35])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:55]([OH:64])[CH:56]=[CH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(C)(C)[Si](OCCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@H](O)C=Cc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
To a stirring solution of (R)-4-benzyl-3-[5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-oxazolidin-2-one (1.64 g, 3.19 mmol) in dry methylene chloride (15.9 mL) in a flame dried round bottom flask under N2 at 0° C. was added titanium(IV) chloride (386 μL, 3.51 mmol). After 5 min, (−)-sparteine (1.83 mL, 7.97 mmol) was added. After 20 min, trans-cinnamaldehyde (442 μL, 3.51 mmol) was added dropwise to the purple suspension, and the resulting pale green-yellow solution was stirred for 1 h . The reaction was quenched by the addition of 50% saturated ammonium chloride (50 mL), diluted with water (100 mL), and then extracted with methylene chloride (3×30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 15-30% ethyl acetate in hexanes) to yield 1.72 g (83.1%) of the desired product as a white solid. MS (APCI), m+/z: (M+H)+=648.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]=[C:16]([C:22]([O:24]CC)=[O:23])C(OCC)=O)=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:31]#[N:32].[K+]>O>[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]([C:31]#[N:32])[CH2:16][C:22]([OH:24])=[O:23])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#N
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Temperature: 70 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (20 mL) and water (5 mL). To the stirred solvent was added diethyl [4-(benzyloxy)-2-methoxybenzylidene]propanedioate (0.775 g, 2.02 mmol), followed by potassium cyanide (0.262 g, 4.04 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.62 g, yield: 100.0%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(F)cc2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(F)cc2n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A 1.0 g portion of ethyl 6-fluoro-2-indolecarboxylate was dissolved in 50 ml of dimethylformamide, mixed under ice-cooling with a suspension consisting of 0.3 g of 60% sodium hydride and 10 ml of dimethylformamide, stirred at the same temperature for 30 minutes, further mixed with 5.0 g of N-(2-bromoethyl)phthalimide and then stirred for 24 hours while gradually returning to room temperature. After terminating the reaction by adding water, this was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated. The thus obtained residue was applied to a silica gel column chromatography and developed with a hexane-ethyl acetate (9:1) mixed solvent, thereby obtaining 0.74 g of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:11][CH:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][N:13]2[CH2:14][CH2:15]3)[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][NH2:27]>CO>[C:1]1([C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:11][CH:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][N:13]2[CH2:14][CH2:15]3)[C:8]([NH:26][NH2:27])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Reactant: NN
Solvent: CO
Product: NNC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
According to this method, 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octan (IV) is treated with a butyl lithium solution in the presence of N,N,N',N-tetramethylethylenediamine followed by methyl chloroformate to yield 2,2-diphenyl-3-(1-azabicyclo[2.2.2]-oct-2-yl)propionate (V). Then the propionate (V) is treated with a solution of H2NNH2 in CH3OH to yield 2,2-diphenyl-3-(1-azabicyclo[2.2.2]-oct-2-yl)propionic acid hydrazide (VI). The hydrazide (VI) is then mixed with CH3C(OC2H5)3 to provide the product (VII), i.e., 2-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-2,2-diphenylethyl]-1-azabicyclo 2.2.2 octane.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17]>>[CH2:1]([O:19][C:18](=[O:20])[C@H:16]([CH3:17])[NH:15][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH:2]([CH3:11])[CH3:3]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc2ccccc2c1

Procedure:
Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine is iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128°-129° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: C1=CCCCC1
Reactant: Oc1ccc(Br)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Boron trifluoride etherate (5.83 mL) was added to a mixture of 4-bromophenol (39.8 g) and cyclohexene (187 mL) in toluene (160 mL) to form bright orange-red solution. The mixture was stirred at 40° C. under nitrogen for 5 hr. The mixture was quenched with 2N NaOH aq. (40 mL) and water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (46.3 g) as pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([O:14][Na])([CH3:13])[CH3:12]>CC(O)C>[O:14]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)O[Na]
Solvent: CC(C)O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A freshly oven dried 500 mL round-bottom flask was charged with 2-chloro-5-nitropyridine (5.0 g, 31.6 mmol) and anhydrous iPrOH (50 mL). The resultant solution was cooled in an ice bath and iPrONa (50 mmol) in iPrOH (250 mL) added slowly, followed by stirring at the same temperature for 30 min and then at room temperature for 14 h. The reaction was quenched with H2O (5 mL), filtered through celite, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-nitropyridine (4.6 g, 79%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1H), 8.30 (dt, 1H), 6.75 (d, 1H), 5.40 (sep, 1H), 1.38 (d, 6H); MS (ES) (M++H) expect 183.1, found 183.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:10]([CH2:9][O:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)[CH:7]=[N:6][CH:5]=1)#[N:11]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: N#CCOc1cncc(Br)c1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cncc(OCC#N)c3)cc2s1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A dry 15 mL, one neck round bottom flask was charged with 2-(5-bromopyridin-3-yloxy)acetonitrile (0.162 g, 0.762 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.2021 g, 0.635 mmol), 5 mL THF and a stirbar. The flask was flushed with Ar for 2 minutes, and fitted with an inert atmosphere inlet. To the stirring solution was added tetrakis(triphenylphosphine)palladium (0.147 g, 0.127 mmol) followed by 2 M sodium carbonate (0.953 ml, 1.91 mmol). The slurry was refluxed overnight, and cooled to room temperature. The mixture was poured onto 15 mL water and extracted with DCM (3×20 mL). The DCM extracts were Loaded onto an unbuffered Varian Chem elute CE1010 (100 mL, PN 12198010). The tube was extracted with DCM (4×20 mL). The combined extracts were concentrated in vacuo, and the residue was taken up in 1 mL DCM. A precipitate formed, which was collected using a course glass filter fitted with a 0.22 μm syringe filter. The solid was dried at 60° C. at <1 mmHg for 1 h to afford N-(6-(5-(Cyanomethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (15 mg, 7.3%). 1H NMR (300 MHz, Pyr) δ ppm 2.36 (s, 3H) 4.98 (br. s., 1H) 5.56 (s, 2H) 7.75 (dd, J=8.40, 1.90 Hz, 1H) 7.93 (dd, J=2.81, 1.86 Hz, 1H) 8.02 (dd, J=8.44, 0.48 Hz, 1H) 8.27 (dd, J=1.90, 0.44 Hz, 1H) 8.77 (d, J=2.85 Hz, 1H) 8.93 (d, J=1.83 Hz, 1H). 13C NMR (75 MHz, Pyr) δ ppm 23.71 (s, 1 C) 55.20 (s, 1 C) 116.92 (s, 1 C) 120.84 (s, 1 C) 121.15 (s, 1 C) 122.27 (s, 1 C) 126.25 (s, 1 C) 133.18 (s, 1 C) 134.41 (s, 1 C) 137.61 (s, 1 C) 138.12 (s, 1 C) 143.50 (s, 1 C) 150.53 (s, 1 C) 154.29 (s, 1 C) 160.70 (s, 1 C) 170.19 (s, 1 C). HPLC-MS: retention time=1.34 min (93.6%@215 nm; 96.7% @254 nm; m/z=325.6, calculated for C16H12N2O4S+H+=325.1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:42]2[CH2:43][CH:40]([O:39][CH3:38])[CH2:41]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1N
Yield: 58.6 %

Procedure:
HATU (2.70 g, 7.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidine hydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) in THF (15 mL) at room temperature. THF was removed under reduced pressure, and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 4% MeOH in DCM to afford the title compound (728 mg, 59%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:2]1([CH2:1][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(CNc2ccccc2)cc1

Procedure:
Benzaldehyde (31.84 g, 0.300 mol) and aniline (27.94 g, 0.300 mol) in benzene (100 ml) were heated to remove the water using a Dean-Stark trap. After 5.4 ml of water had been collected, the benzene was stripped off and the residual oil poured into a beaker. On treating with petroleum ether (10-20 ml) the oil crystallized. This mass was suction filtered and washed with some additional petroleum ether. Recrystallization from hexane gave off-white needles.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21]O)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:24].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][Br:24])[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nsc(CBr)n2)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
To a solution of (3-(2-(benzyloxy)-4-chlorophenyl)-1,2,4-thiadiazol-5-yl) methanol (0.35 g, 1.05 mmol) in toluene (10 ml) was added PBr3 (0.16 ml, 1.58 mmol) and the resulting reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.33 g, 79% crude yield), that was carried forward as such for the next step. MS: 395.05 (M+H)+.