Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](Cl)=[O:50])[CH3:47]>>[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](=[O:50])[NH:36][CH2:35][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:38])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12)[CH3:47]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Agent: O=C([O-])C(F)(F)F
Product: CCN(CC)C(=O)NCCC[Si](C)(C)CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@@]3(CC)OC(C)=O

Procedure:
The required product was prepared according to Procedure E, above, using Compound 21 and diethylcarbamyl chloride. The required product was obtained in 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25](SC)[N:24]=2)=[CH:4][CH:3]=1.CO.O[O:34][S:35]([O-:37])=O.[K+].[CH3:39]C(C)=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:35]([CH3:39])(=[O:37])=[O:34])[N:24]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C(O)CN(C)C)ccn23)n1
Reactant: CC(C)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CC(O)c1ccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 100 mL round bottom flask containing sulfide 42 (720 mg, 1.70 mmol) was charged with methanol (20 mL), then a solution of Oxone (3.14 g, 5.10 mmol) in water (20 mL), then acetone (20 mL). After stirring at room temperature for 12 hours, the reaction was cooled to below −20° C. in a dry ice/isopropanol bath, then SO2 was bubbled in for 5 minutes. The reaction was then concentrated under reduced pressure to remove organic solvent, and the resulting aqueous mixture was neutralized with an aqueous potassium carbonate solution. The resulting aqueous solution was extracted exhaustively into ethyl acetate, and the organic fractions were pooled, dried over MgSO4, filtered, and concentrated under reduced pressure, and the sulfone product was not purified further. Yield of 43: 470 mg (61%). 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 6H), 2.49 (m, 2H), 3.47 (s, 3H), 4.85 (m, 1H), 5.60 (m, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.37 (d, J=5.6 Hz, 1H), 7.71 (m, 3H), 8.80 (d, J=5.6 Hz, 1H), 9.51 (d, J=7.4 Hz, 1H). MS (ESI+) 456.2.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[I:36]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([I:36])=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. acetonitrile and N-iodosuccinimide (2.0 eq), followed by ceric ammonium nitrate (0.05 eq) were added, and the solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting gum was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with 9:1 hexane:ethyl acetate, to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide as an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=C)=[CH:14][N:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:21].[Na+].C1COCC1.O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[O:21])=[CH:14][N:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
2-[(1-cyclobutylpiperidin-4-yl)oxy]-5-vinylpyridine (2.59 g, 10 mmol) and sodium periodate (10.7 g, 50 mmol) were stirred in a mixed solvent of THF (10 mL) and water (10 mL) at room temperature. Osmium tetroxide (0.2 M in t-BuOH, 1 mL) was dropwise added to the reaction solution, and stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with aqueous 1 N sodium hydroxide solution, aqueous saturated sodium thiosulfate solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (1.04 g, 40%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:9](=[O:29])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)N(Cc1cccc(F)c1)C(=O)C(C(=O)OC(C)(C)C)CC2
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1Br)CCC(C(=O)OC(C)(C)C)C(=O)N2Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
A suspension of 3-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (1.00 g, 2.503 mmol) and NBS (0.49 g, 2.754 mmol) in acetic acid (0.8 mL) and chloroform (8 mL) was heated at reflux for 4 hrs. The reaction mixture was allowed to cool to room temperature, diluted with DCM (30 mL), washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4. Filtration and evaporation of the organic layer gave a solid residue, which was purified by flash chromatography on silica column eluted with ethyl acetate/n-hexane (25% of ethyl acetate in n-hexane). The title compound was obtained as a white powder (0.400 g, 33%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1.O>C1COCC1>[N:7]1([C:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)C=C(n1ccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a suspension of LiAlH4 (202 mg) in dry THF (2.4 ml) a solution of 1,2-dihydro-3-(1-imidazolyl)-6-ethoxycarbonyl-naphthalene (2.8 g) in dry THF (22 ml) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was refluxed for 1 day and then stirred overnight at room temperature. H2O (40 ml) was added and the precipitate formed filtered off. The filtrate was concentrated, extracted with CHCl3, dried (Na2SO4) and evaporated under vacuum to give 1,2-dihydro-3-(1-imidazolyl)-6-hydroxymethyl-naphthalene (2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40]>C(Cl)Cl.O>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:40])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(N)c2)cc1)NC(=O)CCC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(NC(C)=O)c2)cc1)NC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 65 h
Yield: 92 %

Procedure:
A solution of (R)-ethyl 4-(3′-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (70.5 mg, 0.171 mmol), Et3N (0.027 ml, 0.205 mmol) and Ac2O (0.019 ml, 0.205 mmol) in DCM (1.7 ml) is allowed to stir at room temperature for 65 hours. The reaction mixture is diluted with water. The products are extracted with DCM in a phase separator and concentrated to give crude (98 mg). The crude is purified by silica gel flash column chromatography (eluent: DCM/MeOH=10:1) to give (R)-ethyl 4-(3′-acetamidobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (71.5 mg); HPLC retention time=1.45 minutes (condition D); MS (m+1)=455.4; 1H NMR (400 MHz, CD3CN, mixture of rotamers, data for major rotamer) δ ppm 1.21 (t, J=7.1 Hz, 3H) 2.07 (s, 3H) 2.31-2.34 (m, 2H) 2.40-2.51 (m, 4H) 2.82-2.84 (m, 2H) 3.58 (s, 3H) 4.07 (q, J=7.1 Hz, 2H) 4.34-4.43 (m, 1H) 6.46 (br d, J=8.9 Hz, 1H) 7.28-7.39 (m, 4H) 7.52-7.54 (m, 3H) 7.80 (s, 1H) 8.37 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:15][CH2:14][N:13](C([O-])=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:33]>ClCCCl.CO.O>[ClH:33].[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCN(C(=O)[O-])CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CO
Product: Fc1cccc(NC2CCNCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Fluoroaniline (28.38 ml, 0.296 mol) was added to a solution of 4-oxo-1-piperidine carboxylate (60 g, 0.302 mol) in 1,2-DCE (600 ml) and the mixture stirred for 15 minutes. Sodium tri(acetoxy)borohydride (83 g, 0.392 mol) was added gradually over 5 minutes and the mixture stirred for 5.5 h, then poured into a mixture of 2M HCl (100 ml), water (200 ml) and ice (1 l). The phases were separated and the aqueous phase extracted with DCM (200 ml). The combined organic phases were dried over MgSO4 and concentrated to give a pale yellow solid which was dissolved in MeOH (400 ml) and treated with 2M HCl (100 ml). The resulting solution was stirred at 60° C. overnight. 5M HCl (100 ml) was added and heating continued for a further 7 h. The reaction mixture was concentrated in vacuo to give a yellow oily solid. This was re-crystallized from MeOH/EtOAc to give two batches of the title compound (42.6 g & 17.0 g). These batches were then re-crystallized from IMS/EtOAc and the resulting batches were dried in vacuo at 50° C. to give the title compound (49.0 g total). δH (CD3OD, 250 MHz) 7.54 (1H, q), 7.24 (2H, m), 7.15 (1H, t), 3.89 (1H, m), 3.54 (2H, d), 3.11 (2H, t), 2.24 (2H, d), 2.01 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][N:7]=1.[BrH:11].BrBr>>[BrH:11].[BrH:11].[Br:11][CH2:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: CC(=O)c1nccnc1C
Agent: Br
Agent: BrBr
Product: Cc1nccnc1C(=O)CBr
Yield: 55 %

Procedure:
The title compound was synthesised according to Example 4 from 1-(3-Methyl-pyrazin-2-yl)-ethanone and HBr/bromine in 55% yield as grey solid. MS (m/e): 215.0 (M+H, 100%).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[OH-].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][Cl:22])([O-:15])=[O:14]>O.C(O)C>[ClH:22].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][N:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)([O-:15])=[O:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=CCN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.4 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5.68 grams of isoindoline hydrochloride and 2.86 grams of sodium hydroxide in 15 milliliters of water is added to a solution of 6.8 grams of m-nitrocinnamyl chloride in 160 milliliters of ethanol, and the mixture is stirred for 10 hours at room temperature. After completion of the reaction, the reaction product is concentrated, and the residue is extracted with chloroform. The extract is then purified by silica gel column chromatography, following which the resulting oily product is converted to a hydrochloride in a customary manner and recrystallized from ethanol to obtain 5.6 grams (yield 52%) of N-(m-nitrocinnamyl)-isoindoline hydrochloride as crystals having a melting point of 208°-210° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:20]([F:19])[CH:21]=1)=[O:14]
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1cc(F)cc(C(F)(F)F)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)benzyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.37 mmol of 3-fluoro-5-trifluoromethyl-benzylamine. LC/MS [6.51 min; 534 (M+1)]
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:48])([OH:47])[CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([OH:47])([CH3:48])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)/C=C/CBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](SC/C=C/C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.2 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (33.5 mg, 0.0577 mmol), (E)-5-bromo-2-methyl-3-penten-2-ol (41.2 mg, 0.230 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate=5:1, developed twice) to give 26.2 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from (E)-5-bromo-2-methyl-3-penten-2-ol.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:22]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[N:28]=[CH:27][C:23]=2[N:24]=[CH:25][N:26]=1>>[ClH:20].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:21]4[C:22]5[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[N:28]=[CH:27][C:23]=5[N:24]=[CH:25][N:26]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Product: CN(C)c1cc2c(Nc3ccc4c(ccn4S(=O)(=O)c4ccccc4)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 1benzenesulphonyl-1H-indol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.64 (1H,s), 8.90(1H,s), 8.60(4H,m), 7.90(1H,d), 7.65(5H,m), 6.92(1H,d) 3.20(6H,s); m/z (M+) 445.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC.CSC>C(Cl)Cl>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)N1C(=O)C(Nc2ccc(OCc3ccccc3)cc2)=C(c2ccccc2)S1(=O)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Solvent: CCOCC
Product: CC(C)(C)N1C(=O)C(Nc2ccc(O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 41 h
Yield: 42 %

Procedure:
4-{[4-(Benzyloxy)phenyl]amino}-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.330 g, 0.71 mmol) was dissolved in dry DCM (40 ml). Boron trifluoride diethyl etherate (1.01 g, 7.13 mmol) and dimethyl sulfide (0.443 g, 7.13 mmol) were added and the reaction mixture was stirred at rt for 41 h. The solvent was evaporated and the residue was dissolved in EtOAc (150 ml) The mixture was washed with water (200 ml), dried (MgSO4), filtered and evaporated. The residue was purified by silica gel column chromatography using a heptane and EtOAc (70:30) as eluant to give the title compound (0.111 g, 42%). 1H NMR (500 MHz, CD3OD): δ 7.21-7.16 (m, 1H), 7.13-7.05 (m 4H), 6.63-6.59 (m, 2H), 6.40-6.36 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz, CD3OD): δ 161.2, 155.9, 133.9, 130.7, 130.2, 129.5, 128.8, 126.8, 125.5, 115.7, 62.3, 27.9; Mass Spectrum: M+H+ 373.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:37])=O>>[Cl:37][C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (240 mg) and thionyl chloride (1 mL) was stirred at room temperature for 12 h and the excess thionyl chloride was removed under reduced pressure to give desired 1-[4-(chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl{aminomethyl]piperidine. The acid chloride was used without further purification.
Reaction SMILES: O=[C:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH3:34])=[C:28]([O:35][CH3:36])[C:27]=1[OH:37])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.S1(CCCC1)(=O)=O>C1CCCCC1>[OH:37][C:27]1[C:28]([O:35][CH3:36])=[C:29]([O:33][CH3:34])[CH:30]=[C:31]([CH3:32])[C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)CCCCCCCCCCCC(=O)O)c(O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=S1(=O)CCCC1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Yield: 58.6 %

Procedure:
13-oxo-22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (5.21 g) is reduced in the presence of p-toluenesulfonic acid (250 mg) and p-toluenesulfonyl hydrazide (2.33 g) in a solvent mixture of dimethylformamide (25 ml)-sulfolane (25 ml)-cyclohexane (25 ml) as in the corresponding step of Reference Example 5. The resultant crude product is recrystallized from methanol to obtain 2.97 g of 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid, m.p. 67° C.-68° C. The physico-chemical constants of this product are all in agreement with those of the crystals obtained in Reference Example 4.
Reaction SMILES: [C@H]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:42].Cl.Cl.NC1CCN([CH2:52][C@@H:53]([N:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]2)C)CC1>>[ClH:42].[ClH:42].[OH:61][CH:58]1[CH2:59][CH2:60][N:55]([C@@H:53]([CH3:52])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][CH2:57]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(F)cc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113, see example 60) and amine 50 analogously to the method described in example 1.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>C(O)C>[CH:31]1([NH:34][C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: NC1CC1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(NC3CC3)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 385 mg (6.74 mmol) of cyclopropylamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 385 mg (6.74 mmol) of cyclopropylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. This was followed by stirring in the microwave at 90° C. for 1 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 95.3 mg (61% of theory)