Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8](=[O:22])(=[O:21])[N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:23]C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:23][C:3]1[CH:4]=[CH:5][C:6]([S:8]([N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])(=[O:22])=[O:21])=[CH:7][C:2]=1[Br:1]
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(Br)c1)N1CC(C)(C)C=N1
Yield: 1 %

Procedure:
7.0 g (1 mol equiv.) N-(2-Bromo-4-{[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-2,2,2-trifluoro-acetamide was dissolved in 225 mL methanol; 10.3 g (5 mol equiv.) potassium carbonate and 30 mL water were added and the reaction mixture was refluxed for 2.5 hours. Volatiles were evaporated under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and concentrated on silica gel. Purification by flash chromatography on silica gel (Et2O) afforded 4.1 g (73%) 4-amino-3-bromo-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7.3 Hz, 3H), 1.21 (s, 6H), 3.43-3.52 (m, 2H), 3.74 (br.s., 2H), 4.45 (br.s., 2H), 6.73 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.83-6.92 (br.s., 1H), 7.65 (dd, J=8.4, 2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH:15]=O)[CH:12]=2)=[CH:5][S:4][N:3]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH2:15][N:29]3[CH2:30][C@H:31]4[C@:27]([C:24]5[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=5)([CH2:32]4)[CH2:28]3)[CH:12]=2)=[CH:5][S:4][N:3]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1nscc1-c1cn(CCC=O)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nscc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.5 %

Procedure:
3-[5-(3-methyl-4-isothiazolyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep 0.126 mmol) was dissolved in 1,2-Dichloroethane (DCE) (1 ml). (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P4, 28.6 mg, 0.126 mmol) and ACETIC ACID (0.022 ml, 0.378 mmol) were added and the mixture was stirred at rt for 15 minutes. Then it was cooled at 0° C. and SODIUM TRIACETOXYBOROHYDRIDE (29.4 mg, 0.139 mmol) was added. The mixture was stirred at 0° C. for 3 hours. The mixture was treated with NaHCO3 aqueous saturated solution (5 mL) and extracted with DCM (3×5 mL). The organic were filtered on a separatory cartridge, combined and dried to afford a crude that was submitted to LC preparative purification. Fraction collected was dried (rotary) to afford the title compound as a white solid (8.7 mg, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][CH:12]=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:12]1[S:11]/[C:10](=[CH:9]\[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:22][CH3:23])=[O:21])/[N:14]([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19]2)[C:13]=1[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Cl)cc1C(=O)/C=C1\SC=C(C)N1CC1CCC1
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(=O)/C=C1\SC(Br)=C(C)N1CC1CCC1
Reaction time: 16 h

Procedure:
In a 20 mL vial, a solution of Example 169B (620 mg, 1.772 mmol) was dissolved in acetonitrile (4 ml). N-bromosuccinimide (268 mg, 1.506 mmol) was added and the reaction was stirred for 16 hrs. The reaction was concentrated and purified by chromatography over silica gel (hex-EtOAc 4:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.82-1.93 (m, 4 H) 1.95-2.06 (m, 2 H) 2.29 (s, 3 H) 2.71-2.84 (m, 1 H) 3.88 (s, 3 H) 4.06 (d, J=7.12 Hz, 2 H) 6.82 (s, 1 H) 7.14 (d, J=8.82 Hz, 1 H) 7.44 (dd, J=8.82, 2.71 Hz, 1 H) 7.66 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 428 (M+H)+. Anal calcd for C19H22ClF2NO3S: C, 54.61; H, 5.31; N, 3.35. Found: C, 54.51; H, 5.26; N, 3.35.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16](=O)[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24](=[O:26])[NH2:25])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[Na]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[NH:25][C:24](=[O:26])[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=2)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccccc1C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CO[Na]
Solvent: CO
Product: CC(c1nc2ccccc2c(=O)[nH]1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 5 %

Procedure:
A solution of 4-[1-(2-carbamoyl-phenylcarbamoyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (20 g, 0.05 mmol, crude from the last step) and MeONa (10 g, 0.19 mol) in MeOH (500 mL) was heated to reflux for 6 hr and the solvent was removed in vacuo. The residue was diluted with water and extracted with EtOAc (300 mL×3), the organic layer was dried with Na2SO4, concentrated and purified by column chromatography to afford the product (2 g, 5%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:19][O:18][CH:17]([O:20][CH3:21])[CH2:16][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccc(S)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CSc1ccc(O)cc1)OC
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a solution of 4-mercaptophenol (3.81 g) in DMF (80 ml) is added potassium carbonate (8.3 g) and 1-bromo-2,2-dimethoxyethane (3.55 g). The mixture is stirred at 70° under nitrogen for 2 hr, then cooled and poured into 0.1N citric acid (600 ml). The product is extracted with ether, and the ether extracts are concentrated and distilled in vacuo (140°-145°, 0.01 torr), to provide 4-((2,2-dimethoxyethyl)thio)phenol as a pale yellow viscous oil (5.21 g, 81%).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1>CO>[NH2:14][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1)[C@H:3]([OH:22])[CH2:2][Cl:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Solvent: CO
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl

Procedure:
tert-butyl (1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 3, 1.0 gm, 2.98 mmol) and Dowex50WX2-400 resin (4.6 gm 23.8 mmol) and methanol (25 mL) are mixed. The mixture is then placed over a J-Kim shaker with heating at 50° for 2 hr. ESMS analysis indicates no starting material left in the mixture. The reaction contents are filtered through a sintered funnel and the resin washed with methanol (25 mL) and methanol/methylene chloride (1/1, 25 mL). The resulting mixture is eluted with ammonia in methanol (2N, 2×25 mL). The eluate is concentrated under reduced pressure to give the title compound, ESMS=236.1.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the title compound of Example 13 (1.0 g) in pyridine (15 mL) under nitrogen at approximately 5° C. (ice water bath) was added dropwise via syringe methanesulfonyl chloride (0.28 mL). The ice bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The reaction was then evaporated under vacuum, and the residue was treated with 1M HCl. The insoluble product was collected by filtration, washed twice with 1M HCl, and then with water. The solid was suspended in methanol, heated to reflux on a steam bath, cooled to room temperature, and the product was collected by filtration. Recrystallization from acetonitrile yielded the title compound as a pinkish solid. Mp: 211°-212° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:26][C:27]([Cl:31])([Cl:30])[CH2:28]O>ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:28][C:27]([Cl:31])([Cl:30])[Cl:26])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Cc1ccc(CBr)cc1)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
4-Bromomethylphenylacetic acid (12) (10.3 g, 44.8 mmol) was suspended in dichloromethane (30 ml). Trifluoroacetic anhydride (9.28 ml, 67.2 mmol) was added at 0° C., and the resulting mixture was stirred for 30 min. Then, 2,2,2-trichloroethanol (6.47 ml, 67.2 mmol) was added dropwise, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a colorless oil. The oil was left standing overnight to give 2,2,2-trichloroethyl 4-bromomethylphenylacetate (13) as white crystals (15.9 g, yield 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (0.75 mL) was added powdered potassium hydroxide (0.281 g, 5.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.151 g, 1.2 mmol) was added and stirred for further 2 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 31% yield). 2,8-Dimethyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.156 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.000119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.03 g, 47% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=1Br.[CH3:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=1[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: N#Cc1cc(Br)c(Br)s1
Reactant: Cc1ccc(B(O)O)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cc1ccc(-c2sc(C#N)cc2Br)c2ccccc12
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A round-bottomed flask was charged with 4,5-dibromothiophene-2-carbonitrile (536 mg, 2.00 mmol), 4-methylnaphthalen-1-ylboronic acid (409 mg, 2.20 mmol), Pd2(dba)3 (18.3 mg, 0.020 mmol) and KF (383 mg, 6.60). After degassed, dioxane (5 mL) and P(Bu-t)3 (0.24 mL, 0.2M, 0.048 mmol) was added. The reaction mixture was stirred at rt until complete. 30 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:CH2Cl2=3:1). 0.58 g (88%) of product was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[NH:14][C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.[CH2:32]([O:34][CH2:35]Cl)[CH3:33].Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>Cl[Si](C)(C)C>[CH3:8][C:6]1[CH:5]=[C:4]([N:9]([C:13]2[N:14]([CH2:35][O:34][CH2:32][CH3:33])[C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[C:10](=[O:12])[CH3:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CCOCCl
Reactant: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
A mixture of N-(3,5-dimethyl-phenyl)-N-(5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (109) (301 mg, 1 mmol), hexamethyldisilazane (5 mL), and chlorotrimethylsilane (5 drops) was refluxed for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in acetonitrile (5 mL). Chloromethyl ethyl ether (110 μL, 1.2 mmol) and SnCl4 (1 M in dichloromethane, 100 μL, 0.1 mmol) were added. The mixture was stirred at room temperature for 16 hrs. Excess sodium bicarbonate was then added and the mixture was stirred for 1 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 162 mg (45%) of a white solid. m.p. 182-183° C.; HRMS (EI) Calcd. 359.184507. Found 359.183174.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:20])[CH3:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:18]([CH3:20])[CH3:19])[CH:5]=[O:6]
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), then 2-bromopropane (3.5 mL, 37.3 mmol) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to 0° C., and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water and a saturated saline solution, and the resultant was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, dichloromethane was added to the residue, the precipitate was separated by filtration, and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-13:7) and then the target fraction was concentrated under vacuum to obtain the title compound (1.84 g, 28%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]=[C:6]1[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:3].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]=[C:6]1[C:13]1[CH:14]=[C:15]([O:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC1C(c2cccc(OC(=O)C(C)(C)C)c2)=CC2CCC1C2
Yield: 87.3 %

Procedure:
Stir a mixture of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (200 mg, 0.778 mmol), 2,2-dimethyl-propionyl chloride (111 mg, 0.927 mmol) and triethyl amine (234 mg, 2.316 mmol) in CH2Cl2 (40 mL) at ambient temperature for 12 hours. Concentrate the mixture under vacuum, and purify the residue by Preparative TLC to give 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester as white solid (232 mg, Yield: 87.5%). MS (m/z): 342 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.32 (t, J=15.6 Hz, 1H), 7.06-7.08 (d, J=7.6, 1H), 6.88-6.90 (d, J1=8.0, J2=1.6, 1H), 6.84-6.85 (t, J=3.6, 1H), 6.05-6.07 (d, J=6.8, 1H), 3.22-3.32 (m, 1H), 2.52-2.60 (m, 1H), 2.62-2.63 (m, 1H), 2.37-2.41 (m, 1H), 2.17 (s, 6H), 2.07-2.14 (m, 1H), 1.71-1.85 (m, 6H), 1.37 (s, 9H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH3:18].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([O:16][CH3:17])=[C:14]([C:5](=[O:7])[CH3:6])[CH:15]=1
Reactant: COc1ccc(Cl)c(C)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Cl)cc1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A suspension of 2.12 g of AlCl3 in 20 ml of CCl4 is cooled to 0° C. under a nitrogen atmosphere, and a solution of 1.25 g of acetyl chloride in 10 ml of CCl4 is added dropwise. A solution of 2.5 g of 2-chloro-5-methoxytoluene in 10 ml of CCl4 is then added dropwise, and the mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. The mixture is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (70:30; v/v) mixture. 0.68 g of the expected product, m.p.=83° C., is obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]>CO>[OH:31][NH:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=3)=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH:22]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)c1
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)cc2)c1
Reaction time: 48 h
Yield: 41.1 %

Procedure:
A mixture of 0.334 g (E)-3-[1-(3′-methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 11.0 ml methanol and 18.0 ml 1M aqueous HCL is stirred for 48 h. The suspension is evaporated and the solid is isolated and washed with water and diisopropylether. The crude product is purified by PLC plates chromatography. By this method 0.116 g of a red solid are obtained. Melting point: 137-148° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C.[CH2:23]([O:25][C:26](=[O:78])[CH2:27][CH2:28][CH2:29][C:30](=[O:77])[CH2:31][C@H:32]([OH:76])/[CH:33]=[CH:34]\[C@H:35]([CH3:75])[C@H:36]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[C@@H:37]([CH3:66])/[CH:38]=[C:39](/[CH3:65])\[CH2:40][C@H:41]([CH3:64])[C@@H:42]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[C@H:43]([CH3:55])[C@@H:44]([O:51][C:52]([NH2:54])=[O:53])[C@@H:45]([CH3:50])/[CH:46]=[CH:47]\[CH:48]=[CH2:49])[CH3:24]>C(#N)C>[CH2:23]([O:25][C:26](=[O:78])[CH2:27][CH2:28][CH2:29][C@@H:30]([OH:77])[CH2:31][C@H:32]([OH:76])/[CH:33]=[CH:34]\[C@H:35]([CH3:75])[C@H:36]([O:67][Si:68]([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:69])[CH3:70])[C@@H:37]([CH3:66])/[CH:38]=[C:39](/[CH3:65])\[CH2:40][C@H:41]([CH3:64])[C@@H:42]([O:56][Si:57]([C:60]([CH3:61])([CH3:62])[CH3:63])([CH3:58])[CH3:59])[C@H:43]([CH3:55])[C@@H:44]([O:51][C:52]([NH2:54])=[O:53])[C@@H:45]([CH3:50])/[CH:46]=[CH:47]\[CH:48]=[CH2:49])[CH3:24]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@@H](O)CC(=O)CCCC(=O)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC#N
Solvent: CC(=O)O
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@@H](O)C[C@H](O)CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To a solution of 250 mg (0.95 mmol) of tetramethylammonium triacetoxyborohydride in 0.52 mL of anhydrous acetonitrile is added 0.52 mL of anhydrous acetic acid and the mixture is stirred at ambient temperature for 30 minutes. The mixture is cooled to −29° C., and a solution of 50 mg (0.453 mmol) of (7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-11,17-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-10,12,14,16,18,20-hexamethyl-5-oxo-8,13,21,23-tetracosatetraenoic acid ethyl ester in 0.5 mL anhydrous acetonitrile is added. The mixture is stirred at −29° C. for 18 hours. The reaction is quenched with 1 mL of 0.5N aqueous sodium potassium tartrate and the mixture is allowed to warm slowly to ambient temperature. The mixture is diluted with CH2Cl2 and washed with aqueous saturated NaHCO3. The aqueous layer is back extracted with CH2Cl2 four times. The combined organic layers are washed with brine, dried with Na2SO4 and concentrated in vacuo to give the crude product as a white solid (50 mg, 99%). m/z (ESI+) 846 (100 (M+Na+)).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]C)=[O:7])=[CH:4][CH:3]=1.[C:13]1([CH:19]2[CH2:24][C:23](=[O:25])[O:22][C:20]2=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC#N>CC(O)C>[CH3:9][O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH:1][C:20](=[O:21])[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][C:23]([OH:25])=[O:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Solvent: CC(C)O
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)C(CC(=O)O)c2ccccc2)cc1

Procedure:
Ethyl 4-aminobenzoate (910 mg, 5.50 mmol) and phenyl succinic anhydride (1070 mg, 6.00 mmol) were dissolved in 40 mL abs. CH3CN and stirred overnight at r.t. The solid precipitate was isolated and digirated with 2-propanol, dried in vacuum, dissolved in DCM and washed with citric acid. 4-{[4-(methoxycarbonyl)-phenyl]amino}-4-oxo-3-phenylbutanoic acid was isolated as a crystalline solid (980 mg, 2.88 mmol). M.p. 212° C.; TLC (cyclohexane/EtOAc 7/3) Rf 0.17; 1H NMR (400 MHz, D6-DMSO) δ 1.39 (t, J=7.2 Hz, 3H); 2.75 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 3.42 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 4.09 (dd, J=3.7 Hz, J=17.2 Hz, 1H); 4.35 (q, J=7.2 Hz, 2H); 7.33–7.41 (m, 5H), 7.75 (mc, 2H), 7.94 (mc, 2H). The regiochemistry was determined using NOESY NMR spectroscopy.