Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[CH2:21]([O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CI>C1COCC1>[CH2:21]([O:28][CH:29]1[CH2:30][CH2:31][C:32]([CH3:2])([C:35]([OH:37])=[O:36])[CH2:33][CH2:34]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1CCC(OCc2ccccc2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C(=O)O)CCC(OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of LDA (made by dropwise addition of nBuLi (2.38M, 13.45 ml, 32.01 mmol) to a −78° C. solution of diisopropyl amine (4.5 ml, 32.0 mmol), in THF (160 ml), in THF, at −78° C.), was added 4-benzyloxy-cyclohexanecarboxylic acid (3.75 g, 16.0 mmol) (Eur. Pat. Appl. (1984), 33 pp. EP 123238A2) dissolved in THF (24 ml). After complete addition, the reaction mixture was stirred at 50° C. for approximately 2 hours. The reaction mixture was cooled to room temperature and MeI (filtered through basic alumina) was added to the reaction mixture, dropwise. After stirring at room temperature for overnight, the reaction mixture was quenched with ice water containing ether, and the aqueous layers were collected. The organic layer was washed one time with water, and the aqueous layer was combined with previous aq. layers. The combined aqueous layers were acidified with 2N HCl (pH=1), and extracted four times with ether. The ether extracts were brined, dried over MgSO4, filtered, and concentrated giving 3.3 g (83%) of 4-benzyloxy-1-methyl-cyclohexanecarboxylic acid as an off white solid. M−H=247.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:11][C:12]2([OH:10])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 71.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.1 g, 21.0 mmol), tert-butyl 1-oxa-6-azaspiro[2,5]octane-6-carboxylate (4.4 g, 21.0 mmol) and sodium hydrogen-carbonate (1.94 g, 23.1 mmol) in ethanol (20 ml) were stirred under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(2-chloro-4-nitroimidazol-1-ylmethyl)-4-hydroxypiperidine-1-carboxylate (5.4 g, yield 72%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]4[CH:44]=[CH:43][N:42]=[N:41]4)[C@H:35]([NH:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (47 mg, 0.12 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (40 mg, 0.11 mmol), and HATU (100 mg, 0.27 mmol), in DMF (0.4 mL), DIPEA (0.056 mL, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under reduced pressure. After concentration, the residue was purified by flash chromatography on silica using a CombiFlash® apparatus (0-100% EtOAc in hexanes) to give the sub-title compound as a light yellow powder (109 mg). LCMS calc. for C36H39BrN9O5 (M+H)+: m/z=756.2. Found: 756.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCc1ccccc1)c1ccc(Cl)nn1
Product: O=C(NCCCc1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-phenylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (15% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.93, 7.74, 7.63, 7.56, 7.39, 7.29-7.13, 6.92, 4.12-3.29, 2.68, 2.02-1.83.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[OH:14])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[O:14][CH:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=1
Reactant: COc1ccc(O)c(NC(=O)C(Br)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)NC(=O)C(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound obtained in Step A (5 g; 14.87 mmol) is dissolved in 15 ml of dimethylformamide (1 ml/1 mmol), and then potassium carbonate (1.5 eq.; 22.31 mmol; 3.08 g) is added. The solution is stirred at ambient temperature for 2.5 hours, and then 60 ml of water are added and a precipitate is formed. After one night in a refrigerator, the solid is filtered through fritted glass, rinsed with water, and dried under a dynamic vacuum under P2O5 to yield the title product, which is used in the subsequent reaction without being further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)O)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:35])CCOC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[N:12][CH:11]=[C:10]([CH:16]([F:35])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1ncc(C(O)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ncc(C(F)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 70 mg, 0.18 mmol) in DCM (1 mL) was added Deoxo-Fluor® (79 mg, 0.36 mmol). The solution was stirred at room temperature for 1 h then concentrated under reduced pressure. Purification (FCC, SiO2, 0-10% EtOAc/hexanes) afforded the title compound (21 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.47-7.31 (m, 5H), 7.15 (t, J=8.8 Hz, 2H), 6.70-6.52 (m, 1H), 3.96 (s, 3H). [M+H]=346.17.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1Cl
Temperature: 80 °C
Yield: 61.5 %

Procedure:
A mixture of 0.68 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 g of 3-chloroisonicotinic acid, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Analogous to the general method described in J. Org. Chem. 2004, 69, 8115, and Chem. Pharm. Bull, 1997, 1145. To a 2-necked flask containing 1-methyl-1H-1,2,3-triazole (1.00 g, 12.0 mmol, Intermediate 42, step a) was added THF (75 mL) and the solution was cooled between −40 to −20° C. To this colorless homogeneous solution was added n-BuLi (2.5 M in hexanes, 5.0 mL, 11.4 mmol) dropwise which afforded a dark brown viscous mixture. After stirring at 0° C. for 1 hours, a THF (10 mL) solution of 4-chlorobenzaldehyde (1.60 g, 11.4 mmol) was introduced and the reaction mixture began to be stirred freely and remained brownish. After 3 hours the reaction mixture was quenched by pouring into a saturated solution of NH4Cl and the aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil which solidified upon standing. The crude material was triturated with Et2O to provide the title compound as a brown solid.
Reaction SMILES: BrCC1CC1(F)F.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[CH3:17][C:18]1[N:19]=[C:20]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:30]2[CH2:31][CH2:32][N:28]([C:20]3[S:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]([CH3:17])[N:19]=3)[C:29]2=[O:33])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 13, making variations to replace bromomethyl-2,2-difluorocyclopropane with 4-fluorobenzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 364.2 (M+1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:51]([NH2:53])=[O:52])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:51]([NH2:53])=[O:52])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(N)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O

Procedure:
The methanol solution of 1.00 equivalent of 2TPB.Z-Trp-Arg-Arg-Lys(Boc)-NH2 (Mw=878.11) were passed several times through a column containing 6.00 equivalents of a methanol washed resin IRA 958 (Mw=1000). After checking the exchange by HPLC, the resin was filtered and washed three times with methanol. The combined organic phases were partially concentrated in vacuo. The concentrated solution was diluted with water and Pd catalyst were added. The suspension was then hydrogenated for at least 3 hours at 35±5° C. The catalyst was filtered off and washed twice with methanol. The filtrate was evaporated in vacuo, the residue dissolved in DMA and further concentrated in order to eliminate the remaining water. After the water content was checked, the precipitate was dissolved in DMA and partially evaporated in vacuo in order to adapt the weight of the solution. The final solution was titrated by 0.1N HCl and further used without any purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Na+].[CH3:11][S:12]([O-:14])=[O:13]>CS(C)=O>[CH3:11][S:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
4-Chlorobenzaldehyde (5.0 g, 36 mmol) and methanesulfinic acid sodium salt (4.04 g, 40 mmol) are dissolved in dry DMSO under argon. The stirred reaction mixture is heated at 100° C. for 17 hours then poured onto water (50 ml). The white precipitate is removed by filtration and dried under vacuum to afford the title compound (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:12][C:13]#[N:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[S:22](Cl)(=[O:25])(=[O:24])[NH2:23].C(Cl)Cl.O>CC(N(C)C)=O>[C:13]([CH:12]=[C:11]([C:15]1[CH:16]=[C:17]([O:21][S:22](=[O:25])(=[O:24])[NH2:23])[CH:18]=[CH:19][CH:20]=1)[C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:14]
Reactant: NS(=O)(=O)Cl
Reactant: COc1cc(OC)cc(C(=CC#N)c2cccc(O)c2)c1
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OS(N)(=O)=O)c2)c1
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl) -acrylonitrile (280 mg, 1 mmol) in dimethylacetamide (4 mL) was added a solution of sulfamic chloride in methylene chloride (1 mL, 2.3 mmol/mL, 2.3 mmol) at room temperature. After 15 h, water (30 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave (E/Z) sulfamic acid 3-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-phenyl ester (320 mg, 89% yield): mp, 301-303° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 6H, 2CH3), [3.76 (s)], [6.41 (s)], 6.44 (s, 1H, CH), 6.49-6.51 (m, 2H, Ar), 6.63-6.67 (m, 1H, Ar), 7.22 (brs, 1H, Ar), 7.38-7.65 (m, 3H, Ar), 8.07 (brs, 2H, NH2); Anal. Calcd for C17H16N2O5S+0.1H2O: C, 56.38; H, 4.51; N, 7.73. Found: C, 56.23; H, 4.36; N, 7.55.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[OH:20])=[O:4].[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[O:20][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[O:4]
Reactant: C=CCOC(=O)c1ccc2c(O)c(C(=O)OC)sc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc2c(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)sc2c1
Yield: 84 %

Procedure:
To a solution of 3-hydroxy-benzo[b]thiophene-2,6-dicarboxylic acid 6-allyl ester 2-methyl ester (3.2 g, 10.95 mmol) in DCM (50 mL) was added TEA (1.83 mL, 13.14 mmol), Tf2O (2.2 mL, 13.14 mL) and DMAP (67 mg, 0.55 mmol) at 0° C. The temperature was allowed to rise to room temperature and the resultant mixture was stirred for 4 hours, washed with aq. NaHCO3 and dried over MgSO4. The crude product was purified on CombiFlash column eluted with hexanes/EtOAc to give desire product, 3-trifluoromethanesulfonyloxy-benzo[b]thiophene-2,6-dicarboxylic acid 6-allyl ester 2-methyl ester as a white solid (3.88g, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:17](=O)[NH2:18])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1([C:17]#[N:18])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(C(N)=O)CC12CCCCC2
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1(C#N)CC12CCCCC2
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
(1-carbamoyl-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester (13.1 g, 46.4 mmol) was suspended in DMF (400 mL) and cooled in an ice bath. Cyanuric chloride (11.8 g, 64.9 mmol) was added. After 20 minutes the solution was homogeneous and after 30 minutes a new precipitate began to form. After 1 hour, the mixture was poured over 0.5N NaOH (500 mL) with ice bath cooling and then transferred to a separatory funnel. The solution was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine (2×400 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with brine (3×300 mL), dried over sodium sulfate, filtered and evaporated to give 12.1 g (98%) of (1-cyano-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J=5.2 Hz, 1H), 1.07 (d, J=5.2 Hz, 1H), 1.46 (s, 9H), 1.4-1.7 (m, 10H), 3.40 (m, 2H), 4.95 (s, 1H); MS (APCI) m/z 263 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COc1ccc(N)c(CO)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-morpholine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and morpholine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:14]1[CH:15]=[C:16]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([OH:25])=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([O:24][C:23](=[O:25])[CH:22]([O:26][CH2:27][CH3:28])[CH2:21][C:16]1[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCc1ccccc1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Oxalyl chloride (0.364 g, 2.87 mmol) was added dropwise to a mixture of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid (0.345 g, 1.15 mmol) and a catalytic amount of DMF in dry DCM (2.0 mL). The mixture was stirred for 17 h at room temperature before the excess oxalyl chloride was evaporated in vacuo. The remaining carboxylic acid chloride was redissolved in dry DCM (3.0 mL) and benzyl alcohol (0.15 g, 1.38 mmol) was added under nitrogen atmosphere. After stirring for 24 h at room temperature the solvent was removed in vacuo and the resulting oil was purified by column chromatography using DCM/MeOH (96:4) as the eluent to afford the title compound as an oil (0.22 g, 36.8%). Mass Spectrum: M−H+ 388.94.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N1C[C@@H:30](O)[C@H:29]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])C1)(OC(C)(C)C)=O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:43]1([C:40]2[CH:41]=[CH:42][C:37]([S:34]([N:33]3[CH2:30][CH2:29]3)(=[O:36])=[O:35])=[CH:38][CH:39]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
To a stirred solution of Ph3P (242 mg, 0.92 mmol) and (±)-N-Boc-trans-3-(4-phenylbenzenesulfonamido)-4-hydroxypyrrolidine (350 mg, 0.84 mmol) in THF (20 mL) at 0° C. was added diethyl azodicarboxylate (DEAD) (160 μL, 1.0 mmol) dropwise. The reaction mixture was stirred at room temperature overnight, then it was evaporated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to give the N-(4-phenylbenzenesulfonyl)aziridine (317 mg, 95%): 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=8, 2H), 7.76 (d, J=8, 2H), 7.62 (d, J=7, 2H), 7.48 (m, 3H), 3.73 (dd, J=12, 2, 2H), 3.64 (dd, J=6, 2, 1H), 3.53 (dd, J=6, 2, 1H), 3.40 (m, 2H), 1.42 (s, 9H); HRMS (ESI) calculated for C21H24N2O4SNa+ 423.1355. found 423.1355.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:17]([NH:24][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCN
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCN1C(=O)CC(NCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, heptylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.