Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[CH2:17][CH2:16][CH2:15]2)#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:17][CH2:16][CH2:15]2)#[N:11]
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC=C2n1ccnc1
Reaction time: 7 h

Procedure:
175 μl of thionyl chloride are added dropwise to a solution of 272 mg of imidazole in 2.5 ml of methylene chloride. 342 mg of 6-cyano-1-tetralone are added in portions to the resulting white suspension, and the reaction mixture is stirred for 7 hours at 40° and then for 24 hours at room temperature. 386 mg of potassium carbonate in 1.6 ml of water are added to the reaction mixture, which is then extracted with chloroform. After drying the organic phase over sodium sulfate, concentration is carried out under reduced pressure. The resulting crude product is purified by column chromatography (0.04-0.063 mesh SIO2, hexane/ethyl acetate 1:2). Crystallisation from ether yields the title compound in the form of colourless crystals; m.p. 152°-153°. TLC (ethyl acetate): Rf=0.17.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[C:5]([N+:12]([O-])=O)[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].C(OCC)(=O)C>C1COCC1.CCCCCC.[Zn]>[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[C:5]([NH2:12])[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Concentrated HCl (20 mL) was added to a solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (I-3a: 8.0 g, 17 mmol) in THF (160 mL) and the resulting mixture was stirred for 5 minutes. This was followed by portion wise addition of zinc powder (6.8 g, 103 mmol) over a period of 30 minutes and stirring was continued for a further 30 min at room temperature. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was concentrated and the concentrate was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product was triturated with ether and filtered. The residue was dried to afford 6.3 g of the product (85% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([O-:22])=[O:21])=[CH:16][CH2:15]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:23][CH2:24]3)[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C([O-])C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Yield: 104.7 %

Procedure:
tButyl 4-[[4-(4-pyridyl)piperazin-1-yl]methylene]cinnamate (200 mg) was stirred in trifluoroacetic acid (5 ml) for 2 hours. The solvent was removed by evaporation and the resulting oil was titriated with anhydrous ether to give the title compound (210 mg) as a white solid: NMR (d6DMSO) δ3.05-3.25(m,4H), 3.7-4.1(bm,4H), 4.25(s,2H), 6.6(d,1H), 7.25(d,2H), 7.5(d,2H), 7.6(d,1H), 7.75(d,2H), 8.35(d,2H); m/e 324(M+H)+ ; calculated for C19H21N3O2.2CF3COOH.0.5H2O: C, 49.5; H, 4.25; N, 7.4. Found: C, 49.1; H, 4.2; N, 7.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
574 g. of this ester were dissolved in 1200 ml. of carbontetrachloride and, while boiling and exposing to a U.V. lamp, treated dropwise with a solution of 109 ml. of bromine in 400 ml. of carbontetrachloride. After all of the bromine had been dropped in, the mixture was heated for a further hour, concentrated in vacuo and the residue crystallized from low boiling petroleum ether, yielding as colorless fine crystals, 4-(bromo-methyl)benzoic acid methyl ester, which melted at 52°. For the reaction of this ester with 1-methyl-1,2-dicarbobenzoxy-hydrazine, the following procedure was followed:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37].[CH3:40][CH2:41][O:42][CH2:43]C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:43][O:42][CH2:41][CH2:40][Si:36]([CH3:38])([CH3:37])[CH3:35])[C:9]2[O:13][C:12]([C:14]([N:16]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:15])=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(Nc1ccc(N2CCOCC2)nc1)c1nnc(Nc2cccc(I)c2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(I)c2)o1)c1ccc(N2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
5-[(3-Iodophenyl)amino]-N-(6-morpholin-4-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Example 146) (610 mg, 1.24 mmol) was added portionwise to an ice-cooled suspension of sodium hydride (60% dispersion in oil) (119 mg, 2.97 mmol) in anhydrous DMF (5 mL) in dry glassware. The mixture was stirred at 0° C. for 10 minutes and ambient temperature for 30 minutes then recooled in an ice bath and [2-(chloromethoxy)ethyl](trimethyl)silane (0.482 mL, 2.73 mmol) was added dropwise. The mixture was allowed to warm up and stirred for 16 h. ether (60 mL) was added, and the mixture was washed with water (3×20 mL) and the aqueous extracts were re-extracted with ether (20 mL). The organic extracts were combined, dried and concentrated by evaporation and the residue was purified by chromatography, eluting with 0-20% ether/DCM to give the title compound (610 mg, 65%) as gum; 1H NMR δ 8.09 (1H, s), 7.94 (1H, s), 7.74 (1H, d), 7.59-7.40 (2H, m), 7.28 (1H, t), 6.86 (1H, d), 5.24-5.11 (1H, m), 3.80-3.48 (12H, m), 0.98-0.84 (4H, m), 0.10-0.05 (18H, m).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1CCCC1=O>>[C:12]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)#[N:13]
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CN1CCCC1=O
Product: Cn1ccc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
Cuprous cyanide (12.8 g, 143 mmol) was added to a stirred solution of 6-bromo-1-methylindole (10 g, 47 mmol) in N-methylpyrrolidinone (60 ml) under a nitrogen atmosphere. The reaction mixture was heated at 150° C. for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate (200 ml) and aqueous ammonia (200 ml of 0.88M). The organic layer was washed with brine (3×200 ml). dried (MgSO4) and concentrated. Flash column chromatography (elution with 70% hexane/30% ethyl acetate) gave the product as a crystalline white solid (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([CH3:21])[CH:4]=1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([C:8](=[O:20])[C:7]=2[CH:6]=1)=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19]
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C)cc1C2=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc2c1C(=O)c1c(OC)cc(CBr)cc1C2=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a hot solution of 1,8-dimethoxy-3-methyl-9,10-anthraquinone (4.5 g, 16 mM) and 1,3-dibromo-5,5-dimethylhydantoin (2.75 g, 19.2 mM) in carbon tetrachloride (500 mL) is added benzoyl peroxide (0.7 g), and the mixture is heated under reflux for 5 hours. The mixture is allowed to cool to room temperature. Insoluble hydantoin is removed by filtration, the filtrate is concentrated to dryness, and the residue recrystallized twice from ethyl acetate to give 3-bromomethyl-1,8-dimethoxy-9,10-anthraquinone (3.3 g, 57%), mp 176-178° C. 1H NMR (CDCl3) δ: 4.01 (3H, s, OMe), 4.03 (3H, s, OMe), 4.52 (2H, s, CH2Br), 7.26-7.84 (5H, m, aromatic H). Analyses (C17H13BrO4). Calculated: C, 56.53; H, 3.63; Br, 22.12. Found: C, 56.48; H, 3.67; Br, 21.93.
Reaction SMILES: CS(O[C:6]1[C:7](C)=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)(=O)=O.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:31](#N)C>>[C:19]1([C:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:6]3[CH:7]=[N:8][CH:9]=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:11]=3)[CH2:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ncc(-c2ccccc2)cc1OS(C)(=O)=O
Reactant: CC#N
Reactant: C1=C(c2ccccc2)CCNC1
Product: C1=C(c2ccccc2)CCN(Cc2cncc(-c3ccccc3)c2)C1

Procedure:
A solution of 26.3 g of 3-methylsulfonyloxy-methyl-5-phenyl-pyridine (obtainable by reduction of 5-phenyl- pyridine-3-carboxylic acid with LiAlH4 to give 3-hydroxy- methyl-5-phenyl-pyridine and mesylation) and 16 g of 4- phenyl-1,2,3,6-tetrahydropyridine in 100 ml of acetonitrile is stirred at 20° for 12 hours and worked up in the customary manner to give 3-(4-phenyl-1,2,3,6 -tetrahydropyridyl-methyl)-5-phenyl-pyridine ("P"), melting point: 80°-82°. Dihydrochloride, melting point: 218°-220°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1(C)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1cccc(Br)c1
Yield: 78.5 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 17.3 g (0.1 mole) of 3-bromophenol, 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 19.8 g (70%) of white solid, mp 90°-91.5° C. (benzene).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21]([O-])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][P:21](=[O:22])([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(COP(=O)(OCc3ccccc3)OCc3ccccc3)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of compound 57 (0.25 mmol) in anhydrous DMF was added dibenzyl phosphate (0.80 mmol) and triphenylphosphine (0.80 mmol). The reaction mixture was stirred while diisopropyl azodicarboxylate was added slowly. The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water and brine, then dried with MgSO4. The Solvents were removed to afford a yellow oil. The oil was re-crystallized in EtOAc/Hexanes to afford an off-white solid 60 in 40% yield. MS (ES+): 527; Mp: 223-225° C.; 1H-NMR (CDCl3, 400 MHz): 9.91 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.11 (dd, J=8.0 and 1.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.59 (dd, J=8.0 and 1.0 Hz, 1H), 7.45 (dd, J=8.5 and 1.0 Hz, 1H), 7.36-7.26 (m, 11H), 5.08 (m, 6H). Anal. Calcd. for C29H23N2O6P.(0.15 hydrazine): C, 65.56; H, 4.48; N, 6.06. Found: C, 65.55; H, 4.33; N, 6.09.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:22](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:22][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 3-bromo-2-methylaniline (5 g, 27 mmol) in chloroform (1 mL) was added acetic anhydride (5 g, 27 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. Potassium acetate (0.75 g, 7.8 mmol) and isoamyl nitrite (0.78 g, 58 mmol) were added and the reaction mixture was refluxed for 18 h. The volatiles were removed under reduced pressure and water (0.65 mL) was added. The mixture was concentrated, diluted with concentrated hydrochloride acid (1 mL) and heated at 50° C. for 2 h. After being cooled to room temperature, aqueous sodium hydroxide solution (50%) was added until pH=10. The aqueous mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and purified on silica gel column (3% ethyl acetate in petroleum ether) to give the desired product (2.69 g, 34% yield) as a solid. MS (ESI): m/z 197.0 [M+1]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:14]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1cccc(Oc2ccccc2)c1
Yield: 74.8 %

Procedure:
In a similar manner to Example 8, 500 mg (2.80 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 600 mg (2.80 mmol) of 3-phenoxybenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was subjected to crystallization from n-hexane/ethyl acetate to obtain 780 mg (yield: 69.9%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1.[C:10]([C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:11].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:13]2[N:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]=[C:7]3[NH:9][C:22]([CH3:23])=[C:12]2[C:10]#[N:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Reactant: COCc1n[nH]c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 3-(methoxymethyl)-1H-1,2,4-triazole-5-amine (244 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was acidified with 1 N hydrochloric acid and then purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). The product was obtained as a solid (38.2 mg, 80% pure, 7% of theory).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24]1)(C)C>O1CCCC1.C(OCC)(=O)C>[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:29][CH2:30][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:32][CH2:33]2)=[CH:24]1
Reactant: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2cc[nH]c2)CC1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Tetrabutylammonium fluoride (2.45 ml, 2.45 mmol) was added to a solution of methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (2.5 g, 4.89 mmol) [prepared as described in Step 2 above] in tetrahydrofuran (48 ml) at 0° C. After 30 min., the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 15-40% ethyl acetate/hexanes) to yield methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (31%) as a clear oil. This material was converted to 1-[4-(pyrrol-3-yl)-piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (93%) by proceeding as described in Example 11, Step 1, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1C=O.[CH3:11][O:12][CH:13](OC)[O:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:6]([CH:13]([O:14][CH3:15])[O:12][CH3:11])[C:7]([Cl:10])=[CH:8][N:9]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Cl)cnc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1cc(Br)ncc1Cl

Procedure:
A mixture of 2-bromo-5-chloronicotinaldehyde (3.00 g, 13.6 mmol), trimethylorthoformate (4.48 mL, 40.8 mmol) and p-toluenesulfonic acid monohydrate (129 mg, 0.680 mmol) in MeOH (55 mL) was refluxed for 16 hours. The mixture was diluted in CH2Cl2 and washed with 10% aqueous potassium carbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. LC/MS method 2: MS (ESI): 267 [M+H]+, rt=2.22 min. 1H-NMR (DMSO-d6): δ (ppm) 8.53 (s, 1H), 7.65 (S, 1H), 5.53 (s, 1H), 3.31 (2d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 87.4 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.24 g, 0.54 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.1 g, 0.82 mmol), the title compound (0.25 g, 88%) was obtained.
Reaction SMILES: [OH:1][C:2]([C:10](=[O:28])[NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2)([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]N.C([N:41](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33][N:11]([C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2)[C:10](=[O:28])[C:2]([OH:1])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([NH2:41])=[O:5]
Reactant: CC(C)CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CC(O)(C(N)=O)C(=O)N(Cc1cc(F)cc(F)c1)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 15.2 %

Procedure:
A solution of 50.0 mg (0.13 mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 37.4 mg (0.26 mmol) 3,5-difluorobenzylamine in 1.5 ml dimethylformamid were cooled to 0° C. and 20 μl (0.14 mmol) triethylamine and 54.5 mg (0.14 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 19:1 to 1:1) yielded 10.0 mg (15%) (R/S)-N-(3,5-difluoro-benzyl)-2-hydroxy-2-isobutyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamide, MS (m/e): 508.5 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)=[O:17].O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)(=[O:9])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
1.0 g of m-chloroperbenzoic acid (purity: 70%, 4.1 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.8 mmoles) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction. the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 75.0%) of 3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 64 to 65° C.).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:17]#[N:18]>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:22][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[OH:13])[CH3:10]
Reactant: N#Cc1ccc(N)c(O)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Yield: 53.5 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.2 mL, 8.12 mmol) and 3-hydroxy-4-aminobenzonitrile (1.25 g, 8.11 mmol) in ethanol was heated at 85° C. for overnight. A tan precipitates forms. The solid was filtered, and collected. 1.12 g (53%) of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione was obtained. LC/MS(H+) 259