Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:15][N:16](CC2C=CC=CC=2)CC2C=CC=CC=2)([CH2:13][F:14])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[NH2:16][CH2:15][C:10]1([CH2:13][F:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: FCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC1(CF)CCNC1

Procedure:
1-Benzyl-3-(dibenzylaminomethyl)-3-fluoromethylpyrrolidine (4.55 g) was dissolved in ethanol (40 ml), and 10% palladium-carbon (1 g) and hydrazine monohydrate (2.15 g) were added. The mixture was refluxed for 1 hour. After the completion of the reaction, the catalyst was removed, and the mixture was concentrated to give the object compound as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.O>CN(C=O)C>[O:25]1[CH2:26][CH2:27][O:28][CH:24]1[CH2:23][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: BrCC1OCCO1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ccn(CC3OCCO3)c(=O)c2c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.5 g, 1.72 mmol) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.6 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.62 mL, 6.03 mmol). The reaction mixture was heated at 140° C. and stirred for 5 h. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.32 g, 64%). LC-MS: (FA) ES+ 290.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].C(O)C.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([NH:23][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cccc(C(O)CNCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
In a 250 mL round-bottomed flask, 2-bromo-1-(3-methoxyphenyl)ethanone (3 g, 13.1 mmol) was combined in CHCl3 (55.0 ml) and ethanol (11.0 ml) to give a colorless solution. The solution was cooled to 0° C. Benzylamine (5.61 g, 5.72 ml, 52.4 mmol) was added. After stirring for 0.5 h at 0° C. and then 2 h at room temperature, LCMS indicated that the reaction was mostly complete. (M+H)+=256 m/e. The reaction was cooled again to 0° C. and NaBH4 (743 mg, 19.6 mmol) was added. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2.5 h until reaction was complete. The reaction mixture was quenched with 1M HCl (25 mL) at 0° C. followed by stirring at room temperature for 1 h. The reaction mixture was poured into 150 mL 1 M NaOH and extracted with ethyl acetate (3×150 mL). Combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 100% ethyl acetate) to yield 2-Benzylamino-1-(3-methoxy-phenyl)-ethanol (1.95 g, 58%). (M+H)|=258 m/e.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][C:17]([C:24]#[N:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][OH:32].CCN(C(C)C)C(C)C>C(O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][C:17](/[C:24](/[NH2:25])=[N:31]/[OH:32])=[C:18]([C:20]([F:22])([F:23])[F:21])[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(C#N)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(/C(N)=N/O)s1
Temperature: 60 °C

Procedure:
A mixture of 2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile (Example 404, 177 mg, 0.42 mmol), hydroxylamine hydrochloride salt (145 mg, 2.1 mmol), DIPEA (732 μL, 4.2 mmol) in ethanol (5 mL) was heated at 60° C. for 5 h. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was separated and evaporated to give the crude product. Purification of the crude product by flash chromatography (silica, 0-80% EtOAc/hexane gradient) gave Example A53a (120 mg) as white crystals. (M+H)+=452.1.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[NH:6][CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5](=[O:14])[NH:6][CH:7]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:9]=1
Reactant: CC(C)(C)c1c[nH]c(=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1c[nH]c(=O)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
3-Nitro-5-tert-butyl-1H-pyridin-2-one (360 mg, 1.83 mmol) was dissolved in methanol/ethyl acetate (2:1, 3 mL) and placed in a Parr hydrogenation vessel. Pd (10% on carbon, 36 mg) was added and the reaction was placed under a hydrogen atmosphere (50 psi) and shaken at room temperature for 2 h. The solution was then filtered through diatomaceous earth and concentrated in vacuo. The residue was redissolved in diethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to 10 with NaHCO3 and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 3-amino-5-tert-butyl-1H-pyridin-2-one (195 mg, 64%) as a pale green solid: ESI MS m/z 166 [C9H14N2O+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2)C.[H-].[Na+].[CH2:19](I)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:9]1[C:10]2[C:6]3[C:5](=[CH:16][CH:15]=[CH:14][C:7]=3[C:8]1=[O:13])[C:4]([S:3][CH3:1])=[CH:12][CH:11]=2)[CH2:20][CH2:21][CH3:22]
Reactant: CCSc1ccc2c3c(cccc13)C(=O)N2
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCN1C(=O)c2cccc3c(SC)ccc1c23

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 12), 0.6 g of 60% sodium hydride and 1.7 ml of butyl iodide in 70 ml are reacted as described in Example 16 giving 1.85 g of the desired product as a solid, m.p. 75°-77° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:24](O)=[O:25])[NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O.[ClH:35].[N:36]1C=CC=CC=1>>[ClH:35].[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:24]([NH2:36])=[O:25])(=[O:12])=[O:13]
Reactant: c1ccncc1
Reactant: Nc1ccc(C[C@@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 20 h

Procedure:
A solution. of.0.7 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (Example 35a) in 5 ml of pyridine is treated with 1 ml of acetic anhydride and left to stand at room temperature for 20 hours. After the addition of water and conc. HCl (ice-cooling) the separated product is filtered off under suction, dissolved in ethyl acetate, washed with water, dried and evaporated. The product is dissolved in 20 ml of methanolic 1N NaOH and left to stand. The solution is evaporated, the residue is dissolved in water, acidified with conc. HCl, the precipitated product is filtered off under suction, dissolved in ethyl acetate and washed with water. After evaporation the residue is reacted analogously to Example 5 and gives 146 mg of (R)-p-acetamido-N-[(RS)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonamido)hydrocinnamamide hydrochloride, FAB-MS: 551 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7](C)[N:6]=[CH:5]2.F[C:36](F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH3:36])[N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cnn(C)c12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn(C)nc12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (27 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 18 mg (79%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.28-7.32 (m, 4H), 7.19-7.23 (m, 1H), 7.10 (d, J=1.8 Hz, 1H), 4.74 (q, J=6.4 Hz, 1H), 3.97 (s, 3H), 3.36 (d, J=9.2 Hz, 1H), 3.23 (d, J=9.2 Hz, 1H), 2.87-2.89 (m, 2H), 2.70-2.76 (m, 2H), 2.13-2.16 (m, 2H), 1.83-1.90 (m, 2H), 1.44 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 144.1, 136.3, 132.5, 128.4, 128.3, 127.2, 126.8, 126.2, 126.1, 125.2, 119.4, 78.2, 42.7, 41.8, 39.9, 33.6, 33.4, 23.4. Mass spec.: 384.17 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C(C(OOOC(=O)C2C=CC=CC=2)=O)=CC=CC=1>[Br:13][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C(=O)OC)cc1
Agent: O=C(OOOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)Br)cc1
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
To a solution of methyl 4-ethylbenzoate (5.12 g) in carbon tetrachloride (50 ml) were added perbenzoic anhydride (0.20 g) and N-bromosuccinimide (6.07 g) in turn, and the mixture was heated and refluxed. After 30 minutes, the mixture was allowed to cool, and the precipitate was separated by filtration, and washed with carbon tetrachloride. The filtrate and the washings were combined, and concentrated under reduced pressure to give the title compound (8.28 g)
Reaction SMILES: [C:1]([CH:3]([N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:31]>C(Cl)Cl>[ClH:31].[NH2:11][CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)(C)NC(=O)C(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)C(N)C#N
Temperature: 60 °C

Procedure:
2-Cyano-N-(1,1-dimethylethyl)-2-[(diphenylmethylene)amino]acetamide 4 (900 g, 2.818 mol), ethyl acetate (4.5 L) and aqueous HCl (1 N, 4.5 L) were placed into a 12 L three-necked flask equipped with a nitrogen inlet, a gas outlet tube, reflux condenser, thermometer, mechanical stirrer, and maintained under a positive pressure of nitrogen. The mixture was heated on an oil bath at 60° C. for 4 hours with vigorous stirring, gradually cooled to room temperature, and then slowly diluted with CH2Cl2 (4 L). (Thin layer chromatography (EtOAc/hexanes=1/4) indicated no more starting material was present.) The resulting layers were separated and the aqueous phase was extracted with CH2Cl2 (4 L). The combined organic solutions were extracted with aqueous HCl (1N, 2×0.5 L). The aqueous extracts were combined and concentrated under reduced pressure to yield 490 g (2.557 mol) of 2-amino-2-cyano-N-(1,1-dimethylethyl)-acetamide hydrochloride 5.HCl.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11]CC)=O)[C:4]([O:6]CC)=O)[CH3:2].[H-].[Na+].Br[CH2:17][C:18](OCC)=O.[O:23]1CCCC1>>[CH2:17]([C:3]([CH2:4][OH:6])([CH2:1][CH2:2][OH:23])[CH2:9][OH:11])[CH3:18]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCC(CO)(CO)CCO
Reaction time: 2 h

Procedure:
To a flask were added 1.5 g diethyl ethylmalonate and 80 ml of tetrahydrofuran and the solution was cooled to 5 C. 0.38 g Sodium hydride were added in small portions and the reaction was stirred for 2 hours at 22 C. After cooling to 5 C, 1.6 g of ethyl bromoacetate were added drop wise and the reaction mixture was allowed to stir at 22 C under nitrogen for 16 hours. After quenching with a few drops of water, the solvent was removed and the crude oil was dissolved in 20 ml tert-butanol and 0.91 g sodium borohydride were added. The mixture was heated to reflux under nitrogen and 1 ml methanol was added drop wise. After stirring for 30 minutes at reflux, the mixture was cooled to 22 C and made acidic with slow addition of 3M hydrochloric acid. Following removal of solvent, the product was purified by silica gel chromatography using pure ethyl acetate resulting in a clear, colorless oil, 0.4 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:4]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:2]([C:3]1[N:8]=[C:7]([O:9][C:10]2[C:15]3[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[N:4]=1)=[O:1]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(CO)n3)cccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C=O)n3)cccc2s1
Temperature: -78 °C

Procedure:
To a solution of N-(4-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (80 mg, 0.174 mmol, Example 98) in DCM (2 mL) was added oxalyl chloride (0.35 mL, 2M solution in DCM, 0.7 mmol, Aldrich). The mixture was cooled to −78° C., and a solution of DMSO (0.1 mL, 1.4 mmol) in DCM (0.5 mL) was added dropwise with stirring. The reaction mixture was stirred at −78° C. for 2 h, TFA (141 mg, 1.4 mmol) was added dropwise, and the mixture was allowed to reach room temperature. The reaction mixture was partitioned between water (10 mL) and DCM (10 mL). The organic phase was separated, washed with sat. aqueous solution of sodium bicarbonate, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 459 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 42.1 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.24 g, 3.23 mmol) (obtained as described in Reference Example 59(3)) in methylene chloride (62 ml) were added methanesulfonyl chloride (0.30 ml, 3.88 mmol) and triethylamine (0.54 ml, 3.88 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (649 mg, yield 42%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:5]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/S(C)(=O)=O)c(OCCc2cccc(C)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCS(C)(=O)=O)c(OCCc2cccc(C)c2)c1
Yield: 99.5 %

Procedure:
250 mg of 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester were dissolved using 10 ml of methanol and hydrogenated under an 1.5 bar atmosphere of hydrogen using 50 mg of Pd/C (10%, 50% water) for 30 minutes. The catalyst was then removed by filtration and the solution evaporated to yield 250 mg of the title compound that was used without further purification.
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:4]1([CH:1]([CH3:3])[CH3:2])[O:8][CH2:7][CH2:6][O:5]1)(=[O:22])=[O:21]
Reactant: CC(C)C1(CCO)OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH2Cl2 (120 mL) was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was finished. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (12 g, crude), which was used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:8][C:9]1[CH:10]=[C:11]([O:18]C)[C:12](=[CH:16][CH:17]=1)[C:13]([O-:15])=[O:14].[C:20](=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:18][C:11]1[CH:10]=[C:9]([I:8])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:20])=[O:14])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(I)ccc1C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(I)ccc1C(=O)OC
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
Ethyl bromoacetate (80 mL; 0.72 mol, Aldrich, 98%) was added to a solution of 4-iodo-methylsalicylate (200 g, 0.72 mol; 1.0 eq), potassium carbonate (198 g, 2 eq, 1.44 mol) and potassium iodide (17.8 g 0.107 mol 0.15 eq) in acetone under nitrogen. The reaction was stirred at 50° C. for 5 h and at r.t. for 16 h. The reaction mixture was filtered and the solid was washed with acetone. The liquors were concentrated to a dark brown oil and dried under house vacuum to afford 241 g of methyl 2-(2-ethoxy-2-oxoethoxy)-4-iodobenzoate. 1H-NMR (400 MHz, CDCl3): δ 1.31 (t, 3H), 3.89 (s, 3H), 4.28 (q, 2H), 4.70 (s, 2H), 7.22 (d, 1H), 7.41 (dd, 1H), 7.54 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:26][CH3:27])=[CH:11][CH:10]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].Cl.C(N(CC)CC)C.O>CN1CCCC1=O>[CH2:26]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:30][N:29]=[N:28][N:2]=3)=[CH:10][CH:11]=2)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[N:18]=1)[CH3:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
10 g (0.027M) of 3-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine, 5.3 g (0.081M) of sodium azide and 5.6 g (0.041M) of triethylamine hydrochloride were suspended in 70 ml of N-methylpyrrolidone. The temperature of an oil bath was raised to 150° to 160° C. over a period of 20 min while stirring with a stirrer. The temperature was returned to room temperature after 6 hr, and water was added thereto. The mixture was washed with ethyl acetate (50 ml×3). The watery phase was acidified with acetic acid and extracted with ethyl acetate (100 ml×5). The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The blackish brown oleaginous substance as the residue was purified by medium pressure column chromatography (SiO2, ACOEt:EtOH=40:1→20:1→10:1). The yield was 11 g. Brown oleaginous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(Oc2ccnc(Cl)c2)c1
Yield: 93.8 %

Procedure:
Using the method of Example 3, Step A, ethyl 4-methyl-3-hydroxybenzoate (1.70 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.48 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide ethyl 4-methyl-3-(2-chloropyridin-4-yloxy)benzoate (2.59 g, 94% yield) as a clear oil. 1H NMR (CDCl3) δ 8.24 (d, 1H), 7.90 (d, 1H), 7.69 (s, 1H), 7.38 (d, 1H), 6.73 (d, 2H), 4.37 (quartet, 2H), 2.23 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].CO[C:12](=[O:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:17]([C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a 2 1 four-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser, and a nitrogen-inlet tube, 32 gm (0.8 mol) of 60% sodium hydride, 79 gm (0.79 mol) of pinacolone, and 700 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream. To this solution, 70 gm (0.36 mol) of dimethylterephthalate in 300 ml of tetrahydrofuran was added dropwise over one hour. After the addition, the reaction mixture was refluxed with heating for 6 hours, and was cooled to room temperature. After addition of 180 ml of 2N aqueous hydrochloric acid, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. The crude product was recrystallized using hexane to obtain 78 gm of the target compound as colorless scales (yield: 66%).