Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[C:12]([NH:19][CH3:20])=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.ClC([O:31][C:32](Cl)(Cl)Cl)=O>O1CCOCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][C:11]2[C:12](=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)[N:19]([CH3:20])[C:32]1=[O:31]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1c(C)cccc1C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(C)cccc1C)C2
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A mixture of 195 mg (0.68 mmol) 5-(2,6-dimethylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.19 ml (1.4 mmol) of triethylamine in 10 ml of dioxan was added dropwise to an ice-cooled solution of 0.085 ml (0.7 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. To the residue were added 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 15 ml of pyridine and heated at reflux for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of dichloromethane and 20 ml of 2M hydrochloric acid. The organic phase was washed with 20 ml of water, dried over magnesium sulfate and evaporated to give 100 mg (47%) of 3-(2,6-dimethylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:17](C=O)=[CH:16][C:15]=3[C:26]([F:29])([F:28])[F:27])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:30]([O:32][C:33]([CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:34])[CH3:31].[C:55]1(C)C=CC=CC=1>>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([C:26]([F:27])([F:29])[F:28])=[CH:16][C:17]([CH:55]=[CH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])=[CH:20][C:21]=3[C:22]([F:24])([F:25])[F:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccccc1
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=O)cc3C(F)(F)F)cc12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.0 g (2.41 mmol) of aldehyde derivative from Example V is dissolved in 10 ml of toluene and 0.92 g (2.65 mmol) of ethoxycarbonylmethylene-triphenylphosphorane is introduced in portions. After stirring at room temperature for 2 days, the reaction mixture is concentrated to a half of the volume and chromatographed on silica gel 60 by means of toluene.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([N:26](C(OCC(C)C)=O)[C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:8].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>C(COC)OC>[C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([NH:26][C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CCC(=O)O)cc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A 1M solution of acetic acid in dimethoxyethane (5.6 ml) was added dropwise over 3 hours to a mixture of 2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) and potassium azodicarboxylate (1.4 g) in dry dimethoxyethane (20 ml) at 45° C. The mixture was heated at 45° C. for 18 hours. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was eluted through a pad of silica gel with ethyl acetate/hexane (1:3 v/v) and the resulting solid (230 mg) was dissolved in a mixture of tetrahydrofuran (16 ml) and methanol (4 ml). A solution of lithium hydroxide (118 mg) in water (4 ml) was added and the solution was stirred for 18 hours. Volatile material was removed by evaporation and the residue was dissolved in water (15 ml). The solution was washed with ethyl acetate (2×15 ml) and acidified with 20% aqueous citric acid. The mixture was extracted with ethyl acetate (2×15 ml) and the extracts were washed with water (10 ml) and saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ether to give 2-[4-(2-carboxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (42 mg), m.p. 166°-168° C.; 1H NMR (CDCl3): 2.25 (s, 3 H), 2.6 (t, 2 H), 3.0 (t, 2 H), 3.8 (s, 3 H), 7.2-7.3 (m, 5 H), 7.45-7.55 (m, 1 H), 8.65 (d, 1 H), 8.8 (d, 1 H), 10.25-10.5 (br, 1 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH2:17]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:26]([C:31]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[CH:31]=[CH:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH3:30]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Reactant: OCC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C=CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
to a cooled solution of oxalyl chloride (11.1 μL, 105 mmol) in dichloromethane (250 mL) was added at −78° C. a solution of dimethylsulfoxide (14.6 mL, 206 mmol) in dichloromethane (250 mL). After 5 min at the same temperature cyclohexylmethanol (10.8 mL, 87.5 mmol) and after additional 5 min triethylamine (60.7 mL, 438 mmol) were added. The reaction remained at −78° C. for two hours and then let warm to room temperature. The solvent was removed in vacuo. The resulting aldehyde was used for the next step without further purification. The crude cyclohexanecarbaldehyde was dissolved in toluene (200 mL) and ethanol (150 mL). After 15 min of stirring at 70° C. carbethoxy-methylene triphenylphosphorane (33.6 g, 96.5 mmol) was added in one portion. Stirring was continued for additional 24 hours. The solvent was removed in vacuo. The product was obtained by flash chromatography in 78% yield (12.5 g). 1H NMR (300 MHz, [D6-DMSO]: δ=1.07-1.34 (m, 8H, CH3 and cyclohexyl-CH2), 1.60-1.80 (m, 5H, cyclohexyl-CH2), 2.04-2.18 (m, 1H, cyclohexyl-CH); 4.16 (q, J=7.1 Hz, 2H, EtCH2), 5.74 (dd, J=15.8 Hz and J=1.5 Hz, 1H, C═C—H), 6.89 (dd, J=15.8 Hz and J=6.8 Hz, 1H, C═C—H).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C=O)C.[Cl:15][C:16]1[C:17]([F:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([F:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
Cyanuric chloride (140 mg, 0.78 mmol) was added to DMF (0.059 mL, 0.77 mmol) at room temperature. After the formation of a white solid (10 min), methylene chloride (4 mL) was added, followed by tert-butyl 3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (197 mg, 0.547 mmol). After the addition, the mixture was stirred at room temperature overnight. Water was added, and the resulting mixture was then diluted with dichloromethane. The organic phase was separated, washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (110 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10].I[CH2:52][CH3:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH2:52]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:50])[CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])[CH3:53]
Reactant: CCI
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-methoxy-2-oxoethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.071 mmol), iodoethane (0.047 mL, 0.571 mmol) and potassium carbonate (19.72 mg, 0.143 mmol) in acetonitrile (2.0 mL) and dioxane (2.0 mL) was heated up for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude intermediate methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(ethyl(2-methoxy-2-oxoethyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate. To this intermediate in dioxane (1 mL) was added 1N sodium hydroxide (0.224 mL, 0.224 mmol). The reaction mixture was heated up at 78° C. for 3 hours until LCMS indicated the consumption of starting material. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound as a white solid (29 mg, 59%). LCMS: m/e 687.40 (M+H)+, 2.11 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 4.02 (s, 2H), 3.85-3.63 (m, 2H), 3.58-3.37 (m, 4H), 3.22-3.01 (m, 1H), 2.69-2.43 (m, 1H), 1.73 (s, 3H), 2.30-1.20 (m, 24H), 1.08 (s, 3H), 1.07 (s., 3H), 1.06 (s., 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [Na+].[C:2]1([NH:8][S:9](=[O:12])(=O)[O-:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14].C1(C(F)(F)F)C=CC=CC=1>>[C:2]1([NH:8][S:9]([Cl:14])(=[O:12])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])Nc1ccccc1
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Product: O=S(=O)(Cl)Nc1ccccc1
Temperature: 70 °C

Procedure:
Phenyl sulfamic acid sodium salt (1.0 g), prepared by the method of Audrieth L. F et al, J. Org. Chem. 1944, 9, 89-101, and PCl5, 1.16 g were combined in the absence of solvent. After the exotherm subsided the contents were heated for a further 16 h at 70° C. Benzotrifluoride (5 mL) was added and the contents heated for a further 2 h, cooled, filtered and concentrated to give 182 mg of phenylsulfamoyl chloride. Compound 5 (Y═H) as its hydrochloride salt (20 mg, 0.085 mmol) was dissolved in 1 mL of dry CH2Cl2, and phenylsulfamoyl chloride (34 mg) in 0.5 mL of CH2Cl2 was added in portions followed by triethylamine (50 μL, 36 mg) in 0.5 mL of CH2Cl2. After stirring at ambient temperature for 16 h the reaction was quenched with saturated NaHCO3, separated, washed with water and brine, dried and purified by flash column chromatography (2% EtOAc in CH2Cl2) to give 20 mg of the title compound. LC-MS RT=3.56 min. (M−H)− 395.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23].Cl[CH:26](Cl)[O:27]C.Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH:7]=1)[CH:17]=[O:20].[Br:13][C:14]1[C:15]([CH:22]([CH3:24])[CH3:23])=[CH:16][C:17]([O:20][CH3:21])=[C:18]([CH:19]=1)[CH:26]=[O:27]
Reactant: COc1cc(C(C)C)ccc1Br
Reactant: COc1ccc(Br)c(C(C)C)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCCl
Product: COc1cc(C(C)C)c(Br)cc1C=O
Product: COc1cc(C(C)C)c(C=O)cc1Br
Reaction time: 0.17 h

Procedure:
To a solution of 1-bromo-4-isopropyl-2-methoxy-benzene and 1-bromo-2-isopropyl-4-methoxy-benzene from step 2 (6.621 g, 28.9 mmol) in 100 mL 1,2 dichloroethane was added TiCl4 (6.3 mL, 57.8 mmol) at 0° C. After 10 minutes, dichloromethoxymethane (Cl2CHOMe) (2.6 mL, 28.9 mmol) was added and the mixture was warmed to reflux. After 3 hours the mixture was cooled poured over ice and acidified with 50 mL 2 M HCl. The resulting slurry was extracted with CH2Cl2, and washed with brine. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a dark-green oil. Purification via flash chromatography (96:4 hexane/ethyl acetate) afforded 5-bromo-2-isopropyl-4-methoxy-benzaldehyde and 5-bromo-4-isopropyl-2-methoxy-benzaldehyde (2.876 g, 39%, 6.621 g, 72%) as a 1:1 mixture of inseparable isomers in the form of an orange oil, which was used directly in step 4.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[OH-].[K+].IC[C:17]#[N:18]>O.C(O)(=O)C.C(O)C>[NH2:6][C:5]1[C:7]([F:12])=[CH:8][C:9]([F:11])=[CH:10][C:4]=1[S:3][CH2:2][C:17]#[N:18]
Reactant: N#CCI
Reactant: Nc1nc2c(F)cc(F)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#CCSc1cc(F)cc(F)c1N
Temperature: 2.5 °C

Procedure:
A suspension of 2-amino-4,6-difluoro-benzothiazole (7.00 g) was stirred for 6 h at 160° C. under nitrogen in a solution of potassium hydroxide (12.6 g) in water (20 ml). The resulting mixture was cooled to 0-5° C. and a solution of acetic acid (8.85 ml) in water (10 ml) and subsequently ethanol (40 ml) and iodoacetonitrile (2.75 ml) were added. After 30 min the mixture was neutralized with acetic acid (2.25 ml) and filtered. The filtrate was evaporated to approx. 30 ml and diluted with water (150 ml). A yellow precipitate was filtered off and dried. The crude product was purified by flash chromatography on silica gel eluted with ethyl acetate—heptane (3:7) yielding the title compound, Rf=0.26, as orange crystals, mp 66-67° C.; 1H-NMR (DMSO-d6), δ (ppm): 7.30-7.07 (m, 2H, Ar—H), 5.33 (br, 2H, NH2), 4.05 (s, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc([N+](=O)[O-])c1
Reaction time: 40 h
Yield: 29.8 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (45 g, 229 mmol, 1 equiv) in CH2Cl2 (450 ml) was added pyridine (18.5 ml, 229 mmol, 1 equiv), DMAP (100 mg, 0.8 mmol, catalytic) and 3-chloropropanesulfonyl chloride (28 ml, 230 mmol, 1 equiv). The resulting mixture was stirred for 40 h then diluted with AcOEt. The organic phase was diluted with 2N aqueous HCl solution. The resulting solid was filtered to give 3-(3-chloro-propane-1-sulfonylamino)-5-nitro-benzoic acid methyl ester (23 g, 32%). The filtrate was separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt and isohexane to give a further 50 g (65%) of 3-(3-chloro-propane-1-sulfonylamino)-5-nitro-benzoic acid methyl ester (D14) as a pale brown solid. [M−H]−=334.9, RT=3.11 min
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:9]([C:19](=[O:34])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C:28]3=[O:33])=[CH:23][CH:22]=2)[CH2:8]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:1][S:2]([O:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:9]([C:19](=[O:34])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C:28]3=[O:33])=[CH:23][CH:22]=2)[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
9.1 1.3 ml (16.65 mmol) of methanesulfonyl chloride are added dropwise with ice cooling to a solution of 4.5 g (11.1 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 20 ml of pyridine, and the reaction solution is stirred at room temperature for 12 hours. The pyridine is subsequently stripped off under reduced pressure, 10 ml of saturated citric acid solution are added to the residue, and the acidic solution is extracted twice with 10 ml of methylene chloride each time. The combined organic phases are then washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. Removal of the drying agent by filtration and stripping-off of the solvent gives 5.4 g (100%) of tert-butyl (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a yellow oil, ESI 484.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=[O:9])[CH2:7][CH3:8].C(Cl)Cl.B(Br)(Br)[Br:30].C(Cl)Cl>CO>[BrH:30].[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccc(OC)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccc(O)cc1

Procedure:
Into a 100 ml flask equipped for stirring, under a nitrogen atmosphere are placed 0.55g of 6-dimethylamino-4-(4-methoxyphenyl)-4-phenyl-heptane-3-one, 40 ml of methylene chloride and 12.1 ml of a solution of boron tribromide/methylene chloride (10% solution obtained commercially). The mixture was allowed to stir at room temperature overnight. Thereafter, 30 ml. of methanol was added with cooling. The residual oil, obtained upon removing the solvent at reduced pressure, was treated with 7 ml of water, whereupon the crude product crystallized. After filtration and washing with water, the solid was recrystallized from water to give 0.137 g of the above captioned product m.p. 246°-247.5° C. Concentration of the aqueous filtrate yielded a small second crop of 20 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]2[Se:39][C:38]([CH3:40])=[N:37][C:36]=2[CH:41]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]2[Se:39][C:38]([CH3:40])=[N+:37]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[C:36]=2[CH:41]=1
Reactant: COc1cc2nc(C)[se]c2cc1OC
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Product: CCCCCCCCCCCCCCCCCC[n+]1c(C)[se]c2cc(OC)c(OC)cc21
Product: O=S(=O)([O-])c1ccc(Cl)cc1
Temperature: 130 °C
Yield: 65.1 %

Procedure:
Octadecyl parachlorobenzenesulfonate (11.2 g) was added to 5.84 g of 5,6-dimethoxy-2-methylbenzoselenazole, and the mixture was heated at 130° C. for 6 hours. The crystals yielded by the reaction were washed with ether and then recrystallized from a solvent mixture composed of hexane and benzene. The subsequent drying gave 10.4 g of 5,6-dimethoxy-2-methyl-3-octadecylbenzoselenazolium parachlorobenzenesulfonate (yield 65%).
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH2:7].[O:12]1[CH2:17][CH2:16][O:15][CH2:14]C1.[C:18]([O-:21])(O)=O.[Na+]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH:7][C:18](=[O:21])/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:17]([OH:12])=[C:16]([O:15][CH3:14])[CH:6]=1
Reactant: C1COCCO1
Reactant: NCc1ccc(O)c(O)c1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Product: COc1cc(/C=C/C(=O)NCc2ccc(O)c(O)c2)ccc1O
Temperature: 70 °C
Reaction time: 2.75 h

Procedure:
N-succinimidyl ferulate (503 mg, 1.73 mmol) and 3,4-dihydroxybenzylamine hydrobromide (402 mg, 1.83 mmol) were dissolved in water (10 ml) and 1,4-dioxane (10 ml) under nitrogen. After NaHCO3 (160 mg, 1.90 mmol) had been added, the solution was stirred for 2.5-3 h at about 70° C. and left to cool. The mixture was extracted with ethyl acetate, the combined organic phases were washed with hydrochloric acid (10%), water and saturated aqueous NaCl solution, dried over Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel. Yield: 540 mg (99%); 1H-NMR (400MHz, CDCl3): δ=7.55 (1H, d, 15.5 Hz), 7.02 (1H, dd, 8.2 Hz, 1.9 Hz), 6.93 (1H, s, 1.9 Hz), 6.89 (1H, d, 8.3 Hz), 6.88 (1H, d, 2Hz), 6.82 (1H, d, 8.1 Hz), 8.72 (1H, dd, 8.1 Hz, 2.0 Hz), 6.51 (1H, s), 6.21 (1H, d, 15.5 Hz), 5.82 (1H, t, 5.8 Hz) 5.79 (1H, s), 5.45 (1H, s), 4.45 (2H, d, 5.8 Hz), 3.90 (3H, s) ppm; 13C-NMR (100 MHz, CDCl3): δ=165.1, 148.2, 147.8, 145.1, 144.1, 139.0, 130.3, 126.4, 121.4, 119.0, 118.3, 115.6, 115.3, 115.0, 110.8, 55.5, 41.9 ppm, MS (EI): m/z=315.1 (100%), 178.1 (66%), 177.1 (84%), 150.1 (36%), 147.0 (22%), 145.1 (46%), 138.1 (83%), 117.1 (24%), 89.0 (24%), 77.1 (22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH:12]([C:23]2([C:28]([OH:30])=O)[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC#[N:33].C(O)(C(F)(F)F)=O.[OH2:41]>>[OH:41][NH:33][C:28]([C:23]1([CH:12]([S:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:30]
Reactant: CC#N
Reactant: O
Reactant: COc1ccc(SC(CCCCc2ccccc2)C2(C(=O)O)CCCC2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(SC(CCCCc2ccccc2)C2(C(=O)NO)CCCC2)cc1OC
Yield: 29 %

Procedure:
The procedure Example 38, Step E is used. From 1-[1-(3,4-Dimethoxyphenylsulfanyl)-5-phenylpentyl]cyclopentane carboxylic acid (0.5 g, 1.2 mmol) the impure product is purified by reverse-phase HPLC (50 to 100% CH3CN in 0.1% TFA/H2O, 30 minutes) to yield 1-[1-(3,4-Dimethoxyphenylsulfanyl)-5-phenylpentyl]cyclopentane carboxylic acid hydroxyamide (0.15 g, 29%): 1H NMR (300 MHz, CDCl3) δ 9.03 (bs, 1H), 7.70 (bs, 1H), 7.29-7.24 (m, 2H), 7.20-7.13 (m, 3H), 6.99 (dd, J=8.2, 2.0 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.04 (d, J=11.0 Hz, 1H), 2.63-2.57 (m, 2H), 2.38-2.30 (m, 1H), 1.97-1.93 (m, 1H), 1.81-1.38 (m, 12H); MS (EI) m/e 443 (M+).