Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][O:3]C(C)=O.C(Cl)(Cl)Cl.[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].[CH:19]1[CH2:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:2][O:3][C:17]1[C:15](=[O:16])[CH:14]2[CH:13]([C:11](=[O:12])[CH:18]=1)[CH:23]1[CH2:19][CH:20]2[CH:21]=[CH:22]1
Reactant: CCOC(C)=O
Reactant: Oc1ccc(O)cc1
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC1=CC(=O)C2C3C=CC(C3)C2C1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
The procedure employed was a modification of that used by Okamato et al. (Chem. Pharm. Bull 32:4593-4599 (1984)). To a vigorously stirred solution of NaIO4 (15.4 g, 72.2 mmol, Baker) in water (500 mL), there was added solid 2-methoxyhydroquinone (37, 3.20 g, 22.8 mmol) in portions. The reaction immediately became dark orange. The reaction was allowed to stir for 1 h at rt and was extracted with CH2Cl2 (3×100 mL). The extract was washed with half saturated brine (1×100 mL), filtered through cotton and the solvent removed in vacuo to yield 17 as an orange solid (3.07 g, 97%), which was of sufficient purity (TLC analysis, 10% EtOAc, 90% CHCl3) for further reaction. The crude 17 was combined with hydroquinone (300 mg, Mallinkrodt), toluene (20 mL) and freshly distilled cyclopentadiene (15 mL, from the distillation of dicyclopentadiene, Aldrich). The reaction was allowed to stir at rt for 35 min at which point an orange homogeneous solution was present. TLC analysis (10% EtOAc, 90% CHCl3) indicated total conversion of the 2-methoxybenzoquinone to the lower Rf adduct. The lower boiling volatiles were removed in vacuo to give an orange liquid. Washing the liquid with ice cold hexanes yielded a beige solid (4.4 g). This was purified chromatographically (silica gel, 2.5×25 cm, CHCl3 elution) to yield an oil. Trituration with hexanes (50 mL), ice cold ether (3×10 mL) and hexanes (1×10 mL) yielded 46 as a pinkish powder (3.00 g, 64%, pure by TLC and 1H NMR); mp 95°-97° C., lit. (Okamato et al.) 97°-99.5° C.; 1H NMR (CDCl3) δ1.44 (d, J=9.0 Hz, 1H), 1.55 (m, 1H), 3.24 (m, 2H), 3.55 (m, 2H) 3.72 (s, 3H), 5.89 (s, 1H), 6.07 (m, 2H).
Reaction SMILES: OCC[O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7].[H-].I[CH3:32].[CH2:33]1[CH2:37][O:36][CH2:35]C1>CN(C=O)C>[CH3:35][O:36][CH2:37][CH2:33][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH:17]([C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)[CH3:32])=[N:15][N:16]=2)[N:13]=1)\[CH3:7]
Reactant: CI
Reactant: C1CCOC1
Reactant: C/C(=N\OCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCO/N=C(\C)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1

Procedure:
A solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime (31.0 mg, 0.078 mmol) (example 54), sodilum hydride (6.85 mg, 0171 mmol) and iodomethane (221 mg, 1.556 mmol) in 5 mL of THF and 0.5 mL of DMF was stirred at it for 3 h. The reaction was quenched by addition of 3 mL of methanol slowly. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.45 (dd, 1H), 8.26 (d, 1H), 7.70-7.65 (m, 2H), 7.60 (dd, 1H), 5.26 (q, 1H), 4.30 (dd, 2H), 3.58 (dd, 2H), 3.23 (s, 3H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]+=427, tR=5.50 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH:31]=[O:32].O>O1CCCC1.ClCCl>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH:31]([OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)CCCC=O
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)CCCC(=O)OC)n1
Reaction time: 0.17 h

Procedure:
A solution of 326 mg of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 5 ml of tetrahydrofuran is mixed with 1.25 ml of n-butyllithium (1.6 molar in hexane) at -78° C. with stirring and under argon atmosphere. After 10 minutes, a solution of 5-oxo-pentanoic acid methyl ester in 1 ml of tetrahydrofuran is added at -78° C. and stirred for 2 hours at this temperature. The reaction mixture is mixed with water, shaken out with dichloromethane, dried on sodium sulfate, concentrated by evaporation and the crude product is chromatographed on silica gel With hexane/ethyl acetate 98/2. 188 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C)C(=O)C.C(O)(=O)C>[C:1]([C:9]1[CH:13]=[C:12]([Br:14])[S:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1csc(Br)c1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
3.0 g of 3-benzoylthiophene was dissolved in 10 ml of N,N-dimethylacetamide and 1 ml of acetic acid, and 2.83 g of N-bromosuccinimide was added thereto, followed by stirring overnight. Water was added to the reaction solution, followed by extracting with diethyl ether. The extract was washed with an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium and then evaporated. The residue was subjected to silica gel column chromatography and eluted with 10% ethyl acetate/hexan, to give 2.7 g of the target compound.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[C:20]([NH2:25])[N:19]=[CH:18]4)=[C:13]([CH3:26])[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C:20]1[N:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][C:13]=3[CH3:26])[CH:16]=2)[N:21]=1
Reactant: COc1ccc(COc2nccc(C)c2-c2ccc3nc(N)ncc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc[nH]c(=O)c1-c1ccc2nc(N)ncc2c1

Procedure:
To a solution of 6-(2-(4-methoxybenzyloxy)-4-methylpyridin-3-yl)quinazolin-2-amine (0.650 g, 1.75 mmol) in CH2Cl2 (1 mL) at RT was added TFA (1.00 ml, 13.0 mmol). After 10 min the solvent and excess acid was removed in vacuo. The residue was taken up in EtOAc and saturated NaHCO3 was added. The resulting white precipitate was removed by filtration. The solid material, 3-(2-aminoquinazolin-6-yl)-4-methylpyridin-2(1H)-one, was dried in vacuo and used without further purification. M+H+=253.1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22]N=NN=2)=[CH:13][CH:14]=1)=[O:6].[CH3:33]OC(=O)[C@H](C(C)C)NCC1C=CC(C2C=CC=CC=2C#N)=CC=1.C(Cl)(=O)CCCC.C(N(CC)CC)C>ClCCl>[CH3:33][O:32][C:30](=[O:31])[C@H:26]([CH:27]([CH3:28])[CH3:29])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]#[N:22])=[CH:11][CH:10]=1)[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
Briefly, the process for the preparation of valsartan comprises of the condensation of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of Formula II with valeryl chloride of Formula III in the presence of triethylamine and dichloromethane, followed by flash chromatography, to give the compound N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester of Formula IV. The compound of Formula IV on tetrazole formation using tributyltin azide and subsequent hydrolysis using sodium hydroxide, followed by flash chromatography, gives valsartan of Formula I.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.C1([Li])C(C)=C(C)C=C(C)C=1C>C1COCC1.CCOCC>[C:2]1([B:17]([OH:20])[OH:18])[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11]
Reactant: COB(OC)OC
Reactant: Cc1cc(C)c(C)c(Br)c1C
Agent: [Li]CCCC
Agent: [Li]c1c(C)c(C)cc(C)c1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(C)c(B(O)O)c1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.2 mol of 3-bromodurene is reacted in 800 ml of absolute THF by means of 0.25 mol of butyllithium under inert conditions at −78° C. On completion of the BuLi addition, the reaction mixture is stirred at −78° C. for another 1 h and then allowed to thaw. A 2 l flask is then initially charged with 500 ml of absolute ether and 0.3 mol of trimethyl borate at −78° C. and the duryllithium prepared beforehand is added dropwise within a period of 30 min. The mixture is then allowed to thaw and the reaction mixture is stirred for another 12 h. Finally, the reaction mixture is poured onto 2 N HCl-ice mixture and hydrolyzed for 12 h, the organic phase is extracted and concentrated, and the residue is admixed with pentane to precipitate out the product. The product is filtered off with suction and dried under reduced pressure mp: 101-3° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 45 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 4-methoxybenzenesulfonyl chloride (0.0420 g, 0.205 mmol) to obtain 4-(4-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0194 g, yield 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O.Cl>C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 2a (1 mmol) in THF (10 mL) was treated with 1N LiOH in water (2 mL, 2 mmol), and stirred 16 h at room temperature (when reactions were slow, the temperature was elevated to 50° C.). The solution was neutralized with 1N HCl (2 mL, 2 mmol) and the organic solvent evaporated to afford an aqueous solution with an insoluble product. If the insoluble was a solid, it was filtered and dried to afford the final product. If the insoluble was an oil, it was extracted with EtOAc (30 mL). The organic solution was separated, washed with water (2×30 mL), dried, filtered, and evaporated to afford the final product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H][H].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=[O:14]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[C:13]([OH:15])=[O:14]
Reactant: Oc1cccc(Cl)c1
Reactant: [H][H]
Reactant: O=C1OCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1COc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mol) is suspended in 60 ml. of dry dimethylformamide and 0.1 mol of 3-chlorophenol in about 60 ml. of dimethylformamide is added dropwise maintaining the temperature at 25° C. When hydrogen evolution is completed, 0.1 mol of phthalide in about 60 ml. of dimethylformamide is added slowly at 25° C. The mixture is refluxed for two hours, stirred at room temperature overnight, poured into ice-water and extracted with ether. The aqueous fraction is acidified with concentrated hydrochloric acid and extracted with ether. The combined ether fraction is dried and concentrated to give 2-(3-chlorophenoxymethyl) benzoic acid, m.p. 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[SH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc([N+](=O)[O-])c4)nc3n2)CC1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc(N)c4)nc3n2)CC1
Temperature: 25 °C

Procedure:
4-[2-(3-Nitro-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (330 mg, 0.75 mmol) was dissolved in 6 mL of MeOH and 2 mL of water along with 210 mg of sodium hydrosulfide hydrate (3.75 mmol). The reaction mixture was stirred under reflux for 4 hours. The reaction appeared to be complete based on LC/MS. The reaction mixture was cooled to room temperature and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-[2-(3-amino-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N+:18]([C:5]1[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)=[CH:7][C:2]([O:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: NC(=O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: OCCN1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=O)[C@H]1CC[C@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (3.00 g, 10.04 mmol) was suspended in toluene (30 mL). 1-Piperidine ethanol (6.62 mL, 50.2 mmol), 18-crown-6 (3.98 g, 15.06 mmol) and cesium carbonate (9.82 g, 30.1 mmol) were then added to the reaction. The resulting reaction mixture was heated at 80° C. overnight followed by additional heating at 90° C. for 8 hours. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was concentrated under vacuum to yield 6.43 g of crude material as a yellow oil/residue. The sample was purified by flash chromatography, eluting with 0-100% 90:10:1 dichloromethane/methanol/NH4OH:dichloromethane to afford 1.62 g of trans-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide (41.2% yield) as a yellow solid. Mass cal'd: 391.2; MS (ESI pos. ion) m/z: 392.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35](O)=[O:36])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1.CCN=C=NCCCN(C)C.[CH3:51][C:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([NH:58][S:55]([C:52]5([CH3:51])[CH2:54][CH2:53]5)(=[O:57])=[O:56])=[O:36])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Compound 7e (100 mg, 0.187 mmol) was dissolved in DCM (5 ml), and EDAC (43 mg, 0.224 mmol) was added. The reaction mixture was stirred at RT for 1 h. Methylcyclopropanesulfonic amide (28 mg, 0.206 mmol) and DBU (59 μl, 0.393 mmol) were added and the reaction mixture was stirred at RT over night. Citric acid was added and the organic layer was separated, washed with brine, dried, filtered and evaporated. Purification of the residue by preparative HPLC provided the pure title compound (110 mg, 90%), MS (M+H)+652.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:14])[CH2:12]Br)[CH:5]=1.[CH:16]([C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1O)([CH3:18])[CH3:17].C(=O)([O-])[O-:28].[K+].[K+]>CC(=O)CC>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:15])=[O:14])=[CH:23][C:24]=1[CH3:25])([CH3:18])[CH3:17]
Reactant: Cc1cccc(O)c1C(C)C
Reactant: COC(=O)c1cccc(NC(=O)CBr)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)C)c(C)c2)c1
Reaction time: 12 h

Procedure:
A solution of 3-(2-bromo-acetylamino)-benzoic acid methyl ester (1.80 g, 6.61 mmol), 4 isopropyl-3-methylphenol (1.00 g, 6.61 mmol) and potassium carbonate (1.00 g, 7.23 mmol) in 2-butanone (15 mL) was heated to reflux under inert atmosphere with stirring for 12 h. After cooling, the mixture was partitioned between water and ethyl acetate (50 mL each). The aqueous phase was extracted with ethyl acetate, and the extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The residual material was separated on a column (silica gel) with 20:80 ethyl acetate-hexane, and the eluant containing the product was evaporated to afford pure methyl 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate, as a glassy solid (1.64 g, 4.80 mmol 73%). TLC RF 0.41 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): δ 8.39 (1H, br s), 8.05 (1H, t, J=1.8 Hz), 7.99 (1H, ddd, J=8.0, 2.2, 1.1 Hz), 7.80 (1H, dt, J=7.7, 1.3 Hz), 7.42 (1H, t, J=7.9 Hz), 7.18 (1H, d, J=8.8 Hz), 6.81–6.77 (2H, m), 4.57 (2H, s), 3.90 (3H, s), 3.07 (1H, heptet, J=7.0 Hz), 2.32 (3H, s), 1.18 (6H, d, J=7.0 Hz). MS (ESI): m/e 344 (3), 343 (22), 342 (100).
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[C:9](#N)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:21]2[C:22]([CH2:29][N:30]3[C@@H:34]([CH3:35])[C@@H:33]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:46])([F:45])[F:44])[CH:37]=4)[O:32][C:31]3=[O:47])=[N:23][C:24](SC)=[N:25][CH:26]=2)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1>O.COC(C)(C)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:21]2[C:22]([CH2:29][N:30]3[C@@H:34]([CH3:35])[C@@H:33]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:44])([F:46])[F:45])[CH:37]=4)[O:32][C:31]3=[O:47])=[N:23][C:24]([S:1]([CH3:9])(=[O:6])=[O:2])=[N:25][CH:26]=2)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC#N
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium peroxymonosulfate (972 mg, 1.581 mmol) was added to an acetonitrile (4 mL)/water (2 mL) solution of (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-5-[3-(trifluoromethoxy)phenyl]-1,3-oxazolidin-2-one (INTERMEDIATE 19, 380 mg, 0.702 mmol) at 25° C. The reaction was stirred for 16 hours at 25° C. followed by dilution with 100 mL methyl-t-butyl ether and 100 mL water. The organic layer was washed with 100 mL of aqueous NaCl three times. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated to give the title compound as a white solid, which can be used without further purification. LCMS (M+H)+: 573.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:35].CO.C(=O)([O-])[O-].[NH4+:42].[NH4+]>ClCCl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 73 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 73% of theory, C2H25N7O3 (471.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=472; (M+H+Na)++=247.8.