Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14]
Reactant: Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of tert-butyldimethyl(m-tolyloxy)silane (1.31 g, 5.9 mmol) in CCl4 (30 mL) was added N-bromosuccinimide (1.13 g, 6.5 mmol), followed by benzoyl peroxide (55 mg, 0.2 mmol). The reaction was refluxed for 1 h, then cooled to room temperature. It was filtered and filtrate was concentrated and purified by column chromatography on ISCO with 10% ethyl acetate in hexanes to yield (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane as a colorless oil (1.1 g, 62%). HPLC retention time (Method C)=4.44 min. LC/MS (ESI) (M+H)+=301.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[C:6]([C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[C:6]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:2][CH3:1])[CH:15]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)c1ccnc(Cl)c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1cc(C(=O)c2ccccc2)ccn1
Reaction time: 1 h

Procedure:
While heating under reflux a 28% sodium methoxide methanol solution mildly, a mixture of 135 g of 4-benzoyl-2-chloropyridine and 150 ml of methanol was added dropwise thereinto over one hour, followed by heating under reflux for further 2 hours. After cooling as it was, the reaction solution was filtered to remove insoluble matters and the solvent was removed. To the residue was added an aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then the solvent was removed, to give 130 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 70 mg (0.61 mmol) methanesulfonyl chloride and 72 μL (0.91 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added and the reaction mixture is extracted three times with 4 mL ethylacetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 32 mg (18%). HPLC-MS: M+H=404; tR=0.65 min.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:26]1([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]3[NH:16][C:12]4[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]5[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=5)[C:11]=4[CH:18]=3)=[CH:24][CH:23]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: COc1ccc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1ccc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c[nH]1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To 84 mg (0.20 mmol) of (6-methoxy-pyridin-3-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine and 10 ml chloroform in an ampoule under N2-atmosphere, 0.1 ml (0.73 mmol) Me3Sil is added. After stirring for 6 h at 70° C., diluted NaHCO3 solution and EtOAc is added to the suspension at RT. Stirring, filtration and washing with water yields the title compound; TLC (THF/methanol/conc. ammonia 90:10:1) Rf=0.23; MS-ES+: (M+H)+=403; HPLC (conditions see Examples 67-78) tR=4.7 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].B(F)(F)F.[CH3:21]COCC>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:21])=[O:15]
Reactant: CCOCC
Reactant: COc1ccc2ccc(C(=O)O)c(O)c2c1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc2ccc(OC)cc2c1O
Temperature: 0 °C
Yield: 92.3 %

Procedure:
A suspension of 6.2 g (0.028 mole) of 1-hydroxy-7-methoxy-2-naphthalenecarboxylic acid in 75 ml of methanol under a nitrogen atmosphere was treated over 15 minutes with 15.0 ml (17.3 g; 0.12 mole) of boron trifluoride etherate. The mixture was stirred at reflux for 45 hours, cooled, and added slowly to 500 ml of ice cold 5% aqueous sodium bicarbonate solution. The precipitated product was filtered, and washed with water to yield 6.0 g (92% yield) of the ester, mp 80°-83°, suitable for further synthetic use. A sample purified by chromatography (silica gel, dichloromethane elution) was analytically pure, mp 79°-81° (a mp of 81°-82° is given by M. E. Alonso, A. W. Chitty, S. Pekerar, and M. de L. Borgo, J. Chem. Soc. Chem. Comm., 1542 (1984).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].CCN(CC)CC>C1COCC1.[Cu]I>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[C:30][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24])[CH3:26]
Reactant: C#CC(OCC)OCC
Reactant: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.10 g, 0.247 mmol), propargylaldehyde diethyl acetal (0.48 mg, 0.370 mmol), copper(I) iodide (0.001 mg, 0.005 mmol) and Et3N (1 ml) in THF (1 ml) were placed in a glass tube for microwave synthesis. The mixture was degassed with argon and Pd(Cl2) (PPh3)2 (0.007 g) was added. The tube was sealed and heated with stirring at 60° C. (150 W) in a microwave heater for 20 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and was then purified on silica to give the title compound (28 mg, 25%).
Reaction SMILES: C1(S(O[CH2:11][C:12]([O:14]CCCC)=[O:13])(=O)=O)C=CC=CC=1.[OH-].[Na+].[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>O.CO>[C:21]1([CH3:29])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCOC(=O)COS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(CC(=O)O)c(C)c1
Yield: 85 %

Procedure:
8.0 g (0.06 tool) and 5.4 g (0.0198 mol) of n-butyl phenylsulfonyloxyacetate are reacted in 60 ml of mesitylene by the method of Example 7, and the reaction mixture is hydrolyzed with 5 g of NaOH in 15 ml of water and 50 ml of methanol to give the acid. 3.0 g (85% of theory) of mesitylacetic acid are isolated.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: OCC(CO)CO
Solvent: c1ccncc1
Product: CC(=O)OCC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (1 g, 9.4 mmol) in pyridine (7.5 mL) at 0° C. was added acetic anhydride (0.89 mL, 9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:9) to give 510 mg of pure 2-acetoxymethyl-1,3-propanediol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12](=[O:16])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][CH:12]([OH:16])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(O)CC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
386 mg of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-octan-7-one synthesized in accordance with the method described in Tetrahedron, 49, 5047 (1993) was dissolved in 20 ml of ethanol. After adding 65 mg of sodium borohydride, the resulting mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 319 mg of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][NH:17][CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)c(F)c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.74 g (5.42 mmol) of the compound from Example 92A were initially charged in 80 ml of dichloromethane and cooled to 0° C., and admixed with 1.5 ml (1.09 g, 10.8 mmol) of triethylamine and 1.09 g (5.42 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. It was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 2.4 g (87% of theory)
Reaction SMILES: [ClH:1].O1CCOCC1.C(O)=O.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]([C:31]3[O:32][C:33](=[O:58])[C:34]4[C:39]([C:40]=3[C:41]3[CH2:46][CH2:45][N:44]([CH:47]5[CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48]5)[CH2:43][CH:42]=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:30])[N:19]=[C:20]([C:21]3[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[C:13]=12>O1CCOCC1CO.C(O)=O.O.CC#N>[ClH:1].[ClH:1].[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:29]([C:31]3[O:32][C:33](=[O:58])[C:34]4[C:39]([C:40]=3[C:41]3[CH2:46][CH2:45][N:44]([CH:47]5[CH2:50][NH:49][CH2:48]5)[CH2:43][CH:42]=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:30])[N:19]=[C:20]([C:21]3[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[C:13]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Agent: OCC1COCCO1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C2CNC2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
4.0 M HCl in 1,4-dioxane (0.5 ml, 2.000 mmol) was added to a solution of tert-butyl 3-(4-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridin-1(2 H)-yl)azetidine-1-carboxylate formate (70 mg, 0.100 mmol) in 1,4-dioxane-methanol 3:1 (4 ml). The mixture was stirred for 6 hrs at rt, then volatiles were removed under reduced pressure. Purification by RP-flash chromatography (Biotage 30 g C18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (57 mg, 0.091 mmol, 91% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:13][C:12]3([CH2:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C5CCCCO5)=[O:27])[CH:19]=4)[O:14]3)[CH2:11]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][C:12]3([CH2:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2)NO
Yield: 91.1 %

Procedure:
(E)-3-{1′-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (85 mg, 0.18 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-hydroxy-acrylamide (65 mg, hydrochloride salt) as as a light brown solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C1COCC1>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14][B:10]([C:7]2[CH:8]=[CH:9][C:4]([NH:1][C:2](=[O:3])[NH:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:5][CH:6]=2)[O:11]1
Reactant: NCC(N)=O
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)NCC(N)=O)cc2)OC1(C)C
Yield: 88.5 %

Procedure:
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.22 mmol) was dissolved in dry THF and stirred with 2-aminoacetamide hydrochloride (108 mg, 1.46 mmol) and triethylamine (drops) at 60° C. overnight. The mixture was reduced in vacuo, yielding the title compound (345 mg, 1.08 mmol, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](OCC)=[O:20])=[C:13]([N+:24]([O-])=O)[N:12]=2)[CH2:6]1)=[O:4]>C(O)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][C:19](=[O:20])[NH:24][C:13]=3[N:12]=2)[CH2:6]1)=[O:4]
Reactant: CCOC(=O)COc1ccc(N2CC(C(=O)OC)CC2=O)nc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)C1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Reduced iron (55.7 mg, 0.996 mmol) was added to a solution of 1-[5-(2-ethoxy-2-oxoethoxy)-6-nitropyridin-2-yl]-5-oxopyrrolidin-3-carboxylic acid methyl ester (122 mg, 0.332 mmol) in acetic acid (1.2 ml) and the mixture was stirred at 85° C. for 2 hours. After cooling, the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, a saturated sodium hydrogen carbonate aqueous solution was added thereto and the mixture was stirred for 10 minutes. The organic layer was separated, dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure to yield 81 mg (84%) of the title compound in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2F)[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]2[C:16]3[C:15]([CH:13]([CH3:14])[N:12]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:11])=[O:10])[C:23]=2[CH:24]=1)=[CH:20][C:19]([F:21])=[CH:18][CH:17]=3
Reactant: COc1cccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccc(F)cc3C2C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A stirred suspension of 3-methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzenesulfonamide (0.88 g, 2.1 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in N,N-dimethylformamide (5 mL) was heated for twelve hours at 100° C. The reaction mixture was cooled and poured into distilled water. After stirring overnight at room temperature, a precipitate was filtered and dried under high vacuum. The title compound (0.81 g, 2.0 mmol, 96%) was obtained as a colorless, fine, crystalline powder, m.p. 147-149° C.;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate (0.59 g, 1.9 mmol), THF (13.5 mL) and methanol (8.5 mL) was added aqueous lithium hydroxide (9.3 mL, 2.0 M). The solution was maintained at 50° C. for 15 h. The solution was cooled to room temperature, adjusted to below pH 4 with aqueous HCl (22 mL, 1.0 N) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with brine (15 mL), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid as white solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.99 (s, 1H), 7.93 (d, J=8.55 Hz, 1H), 7.80 (d, J=2.44 Hz, 1H), 7.59 (dd, J=8.55, 5.49 Hz, 2H), 7.32 (t, J=8.70 Hz, 2H), 7.11 (dd, J=8.85, 2.44 Hz, 1H), 3.82-3.87 (m, 3H). LCMS: retention time: 1.532 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 303 (MH+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:43][O:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.C(N(CC)CC)C>[C:50]([O:49][C:48](=[O:54])[NH:47][CH2:46][CH2:45][O:44][NH:43][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of the carboxylic acid (6b, 1.34 g, 4.87 mmol) of Example 9 or 16 in methylene chloride (35 mL) were added triethylamine (2.71 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole.monohydrate (1.15 g), and tert-butyl 2-(aminooxy)ethylcarbamate (1.12 g) described in Reference Example 9, followed by agitating at room temperature overnight. To the residue resulting from concentrating the reaction solution under reduced pressure was added water, followed by extracting with ethyl acetate. The resulting organic layer was washed with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2-0/10) to afford 1.77 g of the title compound (yield 84%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][N+:14]([O-:25])=[CH:15][CH:16]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1

Procedure:
To a stirred solution of 28.8 g of 4-(tert-butyl-dimethysilyloxyethyl)-pyridine in 300 ml of methylene chloride is added 24 g of m-chloroperbenzoic acid. After 4 hours the solution is washed with aqueous sodium carbonate solution and water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:12]=[C:13]=[O:14])[CH3:11].[Si:15]([O:22][C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:26]=[CH:25][C:24]=1[C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClC(Cl)C>[CH2:10]([NH:12][C:13](=[O:14])[O:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([C:24]2[CH:25]=[CH:26][C:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31])=[CH:28][C:23]=2[O:22][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[CH2:42][CH2:41]1)[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine (199 μl) and ethyl isocyanate (90 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a solid (55 mg, 95%); Rf (ethyl acetate/petrol, 1:2 v/v) 0.65.