Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:18]=[C:17](Cl)[N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:5].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:10]([NH:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:2]=3[Cl:1])[N:18]=2)[CH2:35][CH2:34]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc([N+](=O)[O-])cc1Cl
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3ccc([N+](=O)[O-])cc3Cl)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
295 mg of the product obtained in Stage 1 above and 362 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/ methanol/ammonium hydroxide 85/15/1.5) then taken up in an ethanolic solution of hydrochloric acid, followed by leaving to crystallize, separating, drying under reduced pressure and 105 mg of expected product is recovered.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl -4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Cl.[CH3:36][NH:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.ClCCCl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([N:37]([CH3:38])[CH3:36])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](N(C)C)CC4)c3C)cc12
Temperature: 60 °C

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), dimethylamine hydrochloride (20.34 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and triethylamine (0.06 mL, 0.4 mmol) in 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 3-7% (7N NH3 in MeOH)/DCM. The fractions containing the cis and trans products separately were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.42-1.65 (m, 2H), 1.82 (d, J=7.1 Hz, 3H), 1.95-2.19 (m, 6H), 2.24 (s, 3H), 2.36-2.42 (m, 6H), 2.44-2.53 (m, 1H), 3.66 (br. s., 3H), 4.13-4.26 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.91 (dd, J=9.0, 4.2 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.49 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=510.25/512.25 (100/50) [MH+]. HPLC: tR=1.18 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[O:12]1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To solution of 2-amino-4-methoxycarbonylphenol [Acta Chimica Academiae Scientiarum Hungaricae, 99 (1), 49-50 (1979)] (4.78 g) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) were added sodium hydrogen carbonate (3.6 g) and 2-bromoisobutyryl bromide (6.90 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (70 ml), to the solution was added potassium carbonate (4.35 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (5.4 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=1[F:13].N1C=CC=CC=1>ClCCl>[CH2:18]([S:15]([NH:14][C:9]1[CH:10]=[CH:11][C:12]([F:13])=[C:7]([CH:8]=1)[NH:6][C:2](=[O:3])[O:4][CH3:5])(=[O:17])=[O:16])[CH3:19]
Reactant: COC(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccc(F)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(F)c(NC(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
22.1 g (229 mmol) of methyl chloroformate was added dropwise to a mixture of 50.0 g (229 mmol) of N-(3-amino-4-fluorophenyl)ethanesulfonamide, 18.1 g (229 mmol) of pyridine and 500 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for 5 hours. After the dichloromethane layer was separated out by adding water to the resultant mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 61.0 g of the objective product (yield: 96%) in the form of light brown crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C(Cl)(Cl)[Cl:15].N1C=CC=CC=1.ClCl>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:15])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccsc1NC(C)=O
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)sc1NC(C)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4 parts of methyl 2-acetamidothiophene-3-carboxylate in a mixture of 80 parts by volume of chloroform and 12 parts by volume of pyridine, 20 parts by volume of a 10% (W/V) solution of chlorine in carbon tetrachloride is added dropwise. After stirring for further 30 minutes, the mixture is washed with an aqueous sodium bicarbonate solution and, then, with water. Evaporation of the solvent, and recrystallization of the residue from methanol gives methyl 2-acetamido-5-chlorothiophene3-carboxylate as crystals. Colorless needles, melting point: 110°-110.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1(Nc2cccc(OC)c2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(Nc2cccc(OC)c2)CCNCC1

Procedure:
A mixture of 60 parts of methyl 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 10% of methanol, previously saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-[N-(3-methoxyphenyl)amino]-4-piperidinecarboxylate as an oily residue.
Reaction SMILES: II.[CH2:3]([O:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][N:10]1[C:14]([NH2:15])=[C:13]([C:16](=[S:18])[NH2:17])[S:12][C:11]1=[S:19])[CH3:4].[O-]S([O-])(=S)=O.[Na+].[Na+].[CH2:28](O)[CH3:29]>>[CH2:3]([O:5][C:6](=[O:20])[CH:7]([CH2:28][CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2=[N:15][S:18][C:16]([NH2:17])=[C:13]2[S:12][C:11]1=[S:19])[CH3:4]
Reactant: CCOC(=O)CCCn1c(N)c(C(N)=S)sc1=S
Reactant: CCO
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCOC(=O)C(CC)CCn1c(=S)sc2c(N)snc21
Yield: 95 %

Procedure:
An excess of iodine (I2) in ethanol was added dropwise to a stirred solution of 4-(4-amino-5-thiocarbamoyl-2-thioxo-thiazol-3-yl)-butyric acid ethyl ester (360 mg, 1.18 mmol) in ethanol (25 ml), at 25° C., while monitoring the reaction progress by TLC. Once the reaction was completed, (upon stirring overnight at 25° C.), a solution of Na2S2O3 was added, so as to remove excess of I2, and the resulting solution was neutralized with a 5% solution of NaHCO3. A mixture of water and ethyl acetate was added thereafter, phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvents were evaporated under reduced pressure to give yellow oil. Precipitation in acetonitrile gave 342 mg of Compound 43 (95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH:21]=O)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.Cl([O-])(=O)(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:25]=[CH:24][CH:23]=[C:20]([CH2:21][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:19]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: C1CCNC1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C=O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(CN4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 3-[3-(2-Methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzaldehyde (23 mg, 0.050 mmol) and Pyrrolidine (5 ul, 0.082 mmol) in 1.5 ml dichloethane was added 3 ul of AcOH. The mixture was stirred at room temperature for 30 mins, and then to the mixture was added sodium trioxyacetylborohydride (22 mg, 0.10 mmol) in one portion. The reaction was continued at room temperature for another 2 hrs the mixture was then concentrated to yield the SEM product which was treated with a solution of 5% perchlorate in acetic acid (2 mL) at room temperature for 1 hr. Solvents were evaporated, the residue was neutralized with sodium bicarbonate powder and then purified by flash silica gel chromatography using ethyl acetate then a mixture of EtOAc/DCM/MeOH/NH4OH (4/4/1/0.05) to afford 3-(2-Methoxy-phenyl)-5-(3-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrazolo[3,4-b]pyridine (8.50 mg, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ 1.89 (d, J=3 Hz, 4H), 2.76 (d, J=1.5 Hz, 4H), 3.89 (s, 2H), 3.9 (s, 2H), 7.11 (t, J=1 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.42 (t, J=7 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.65 (t, J=6.75 Hz, 1H), 7.72 (s, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.83 (d, J=2 Hz, 1H). MS: m/z 385 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([S:7](=[O:10])(=[O:9])[NH2:8])[S:4][C:3]=1[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15].[C:17]1([O:23]C(Cl)=O)C=CC=CC=1.C(N(CC)CC)C.[Cl:34][C:35]1[N:40]=[C:39]([NH2:41])[CH:38]=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=1>C(#N)C>[C:14]([O:13][CH2:12][CH2:11][C:3]1[S:4][C:5]([S:7]([NH:8][C:17](=[O:23])[NH:41][C:39]2[CH:38]=[C:37]([C:42]([F:45])([F:43])[F:44])[CH:36]=[C:35]([Cl:34])[N:40]=2)(=[O:10])=[O:9])=[CH:6][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: Nc1cc(C(F)(F)F)cc(Cl)n1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1sc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)cc(Cl)n2)cc1C
Reaction time: 2 h

Procedure:
To a solution of 0.263 g acetic acid 2-(3-methyl-5-sulfamoyl-thiophen-2-yl)-ethyl ester in 5 ml acetonitrile was added 0.188 g phenylchloroformate and 0.252 g triethylamine at ° C. and the mixture was stirred at this temperature for 2 h. To the resulting suspension was added 0.196 g 6-chloro-4-trifluoromethyl-pyridin-2-ylamine and the mixture was heated to 60C for 18 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated. The residue was triturated with diethylether. The solid was collected by filtration to yield the title compound as white crystals. MS (ISN) M−H+=488.4
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[CH2:54]([O:56][C:57](=[O:64])[C@H:58]([CH3:63])[CH2:59][C@H:60](N)[CH3:61])[CH3:55].C(N(CC)CC)C>CN(C=O)C>[CH2:54]([O:56][C:57](=[O:64])[C@H:58]([CH3:63])[CH2:59][C@@H:60]([CH3:26])[CH2:61][C:9](=[O:10])[CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:25])[CH3:55]
Reactant: CCOC(=O)[C@H](C)C[C@@H](C)N
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](C)CC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester (100 mg, 0.29 mmol) in DMF (10 mL) is added HOBt (45 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4R)-4-amino-2-methyl-pentanoic acid ethyl ester trifluoroacetate (47 mg, 0.29 mmol) and triethylamine (89 mg, 0.87 mmol) is added and the mixture is stirred at room temperature for 5 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give (2R,4R)-7-biphenyl-4-ylmethyl-2,4-dimethyl-6-oxo-nonanedioic acid 9-tert-butyl ester 1-ethyl ester.
Reaction SMILES: [C:1]([C@H:4]([C@@H:16]([CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]([CH3:14])[C:7]1=[O:15])([OH:3])=O.[OH:31][N:32]1C=CC=CC1=O.O1CCN(CC[N+]#[C-])CC1.C([O-])(=O)C.O[NH3+]>C(Cl)Cl.C(N(CC)CC)C>[CH:26]1([CH2:25][C@H:16]([C@@H:4]([C:1](=[O:3])[NH:32][OH:31])[CH2:5][N:6]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]([CH3:14])[C:7]2=[O:15])[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=c1ccccn1O
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: CC(=O)[O-]
Agent: [C-]#[N+]CCN1CCOCC1
Agent: [NH3+]O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
30 g 1-[2(R)-[1(R)-carboxy-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-3-cyclopentylpropionyl]piperidine and 8.71 g N-hydroxy-pyridone were dissolved in 120 ml CH2Cl2 in a 250 ml round bottom flask. The mixture was treated at r.t. with 10.73 g morpholinoethylisocyanide. After 10-20 min the mixture turned clear and stirring was continued at r.t. overnight. The solution was slowly added to a stirred suspension of 9.94 g hydroxylammonium acetate and 7.2 g triethylamine in 180 ml CH2Cl2 and the mixture was stirred for an additional 4 h. The reaction mixture contains about 97% product and about 3% starting material. This mixture was extracted with 95 ml water. The aqueous layer was extracted with 60 ml CH2Cl2 and the combined organic layers extracted twice with 95 ml (total 190 ml) 5% NaHCO3 solution and once with 95 ml 2% H2SO4 solution. The organic layer was evaporated at 35-40°. The oily residue was treated with 300 ml wet tert butyl methyl ether and evaporated to a volume of 200 ml and stirred for 10 hrs. The solid was filtered off, washed twice with 20 ml tert butyl methyl ether and dried under reduced pressure at r.t. yielding 25.6 g (82%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine MS (EI): 436, m.p. 120° dec.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([CH:21](O)[CH2:22][CH:23]=[CH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:45][NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48]>C1COCC1.CCOCC.O>[CH3:45][N:46]([CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][CH:23]=[CH2:24])[S:47]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:48])=[O:49]
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: C=CCC(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(c1ccccc1)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.3 %

Procedure:
DIAD (9.0 mL, 45.9 mmol) was added dropwise over 10 min to a stirred solution of 1-phenyl-3-buten-1-ol (4.0 g, 27.0 mmol), PPh3 (10.6 g, 40.5 mmol) and N-methylphenylsulfonamide (6.0 g, 35.0 mmol) in THF (200 mL) under N2 and the resulting mixture was stirred at RT for 20 h. H2O (200 mL) and Et2O (200 mL) were added and separated. The organics were washed with brine (150 mL) and concentrated under reduced pressure while loading on to MgSO4. The mixture was then purified by column chromatography on silica eluting with 3% Et2O/iso-hexanes to yield the sulfonamide (6.45 g, 79%). 1H NMR (CDCl3, 360 MHz) δ 7.78 (2H, d, J=7.8 Hz), 7.53 (1H, t, J=7.8 Hz), 7.44 (2H, t, J=7.8 Hz), 7.30–7.18 (5H, m), 5.67–5.52 (1H, m), 5.20 (1H, t, J=7.8 Hz), 5.02 (1H, dd, J=17.1, 1.5 Hz), 4.93 (1H, dd, J=10.2, 1.3 Hz), 2.70 (1H, app. quintet, J=7.1 Hz), 2.65 (3H, s), 2.44 (1H, app. quintet, J=7.1 Hz).
Reaction SMILES: [Br:1]C1C=C(C=C(Br)C=1N)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].Br[CH2:17][C:18](OCC)=O.CN(C)C=[O:26]>>[Br-:1].[CH3:10][NH+:8]([CH3:9])[CH:7]([CH2:17][CH3:18])[C:6]([OH:5])=[O:26]
Reactant: CN(C)CCOc1cc(Br)c(N)c(Br)c1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CBr
Product: CCC(C(=O)O)[NH+](C)C
Product: [Br-]
Temperature: 27 °C
Reaction time: 1 h

Procedure:
3,5-Dibromo-β-dimethylamino-p-phenetidine (16.9 grams; 0.05 mole) is dissolved in 50 milliliters of dimethyl formamide at a temperature of about 25° C. To this solution is added dropwise with stirring ethyl bromoacetate (9.2 grams; 0.055 mole). During the addition the mixture warms spontaneously to a temperature of about 49° C., and the mixture is cooled to 27° C. prior to addition of the final 2 grams of ethyl bromoacetate. A precipate forms in the reaction mixture after the addition is complete, and 50 milliliters of additional dimethyl formamide is added. The mixture is stirred for one hour, then held over night at room temperature. The crystalline solid product is collected as a filter cake by suction filtration of the mixture and the filter cake is recrystallized from boiling ethanol. The 82-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl (ethyl carboxymethyl) ammonium bromide is obtained as a light tan crystalline solid, melting at 187°-188° C. The product is found by combustion analysis to have carbon, hydrogen and nitrogen contents of 33.5, 4.3 and 5.6 percent, respectively, as compared with the theoretical contents of 33.3, 4.2 and 5.6 percent, respectively, calculated for the named structure. The structure of the product is confirmed by infrared spectroscopy and nuclear magnetic resonance analysis.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[C:24]([F:25])([F:27])[F:26])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(C#N)cc2C(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of 4-hydroxy-N-methylpiperidine (133 mg, 1.15 mmol) and potassium tert-butoxide (150 mg, 1.27 mmol) in tetrahydrofuran (2.5 mL) was stirred under nitrogen for 10 min. 4-Fluoro-3-(trifluoromethyl)benzonitrile (218 mg, 1.15 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, and the residue was partitioned between a 1 M NaOH solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5) affording 0.18 g (54% yield) of the pure product as a colourless solid. MS (APCI) m/z 285 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.16 (s, 3 H), 2.26-2.31 (m, 2 H), 2.44-2.48 (m, 2 H), 4.78-4.82 (m, 1 H), 7.51 (d, J=8.8 Hz, 1 H), 8.08 (dd, J=8.8, 2.0 Hz, 1 H), 8.14 (d, J=2.0 Hz, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:33]1[C:32]2[C:36]3[C:19]4([C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][C:18]4=[O:37])[CH2:26][O:27][C:28]=3[CH:29]=[CH:30][C:31]=2[NH:35][O:34]1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)N(Cc1ccccn1)ON3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).