Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([Br:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2ccc(Br)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-bromoanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: C(OC(N[C@@H](CC1C=CC=CC=1)C([O-])=O)=O)(C)(C)C.[OH:20][C@@H:21]1[C@H:25]2[O:26][C:27]([CH3:30])([CH3:29])[O:28][C@H:24]2[C@H:23]([NH3+:31])[CH2:22]1.Cl.C(=O)([O-])[O-].[K+].[K+].Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>O.CC(CC(C)=O)C.C(OCC)(=O)C>[OH:20][C@@H:21]1[C@H:25]2[O:26][C:27]([CH3:29])([CH3:30])[O:28][C@H:24]2[C@H:23]([NH:31][C:40](=[O:41])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:22]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2[NH3+]
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(=O)OCc1ccccc1
Temperature: 30 °C
Reaction time: 1.33 h

Procedure:
To (3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-aminium (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate (10.06 g, 22.32 mmol) was added 30 mL ethyl acetate. The resulting thick slurry was put on ice-bath and stirred for 80 min. HCl (1 M, 24.5 mL, 24.5 mmol) was slowly added during 25 min while the temperature was kept below 5° C. (pH aqueous phase: 1-2). The phases were separated and the organic phase was washed with 10 mL of water after which the aqueous phases were combined. Potassium carbonate (10.3 g, 73.78 mmol) was dissolved in 25 mL of water. MIBK (30 mL) and benzyl chloroformate (4.17 g, 23.22 mmol) were added at 20° C. The combined aqueous phases were added slowly over 15 min and the mixture was warmed at 30° C. for 25 min without stirring. The phases were separated and the organic phase washed with 10 mL water. The organic phase was evaporated until about 11 g was remaining. Water (40 mL) was added and evaporation was continued until about 25 g was remaining. The mixture was filtered and the isolated product was washed with iso-octane and then dried at 40° C. in vacuum oven overnight. After drying, the title product was isolated (6.54 g), HPLC-purity: 97.7% (area), 1H-NMR assay: 100%.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][C:9]=1[N:10]=[CH:11]N(C)C)=[O:4].[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1>C(O)(C)C>[Si:17]([O:16][CH2:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][N:35]([CH3:46])[CH3:34])=[CH:44][CH:43]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)([C:30]([CH3:32])([CH3:33])[CH3:31])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N=CN(C)C
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: CC(C)O
Product: CN(C)CCOc1ccc(-n2cnc3cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)sc3c2=O)cc1

Procedure:
5-(tert-Butyldiphenylsilanyloxymethyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(2-dimethylaminoethoxy)phenylamine by method A with addition of isopropanol in addition. The product with the molecular weight of 583.83 (C33H37N3OSSi) was obtained in this way; MS (ESI): 584 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:29]1[C:34]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1[C@@]21COCC(N)=N1
Temperature: 90 °C
Yield: 87.4 %

Procedure:
A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL). Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added. The vial was placed in a 100° C. oil bath for 5 min. the reaction mixture was cooled to room temperature and (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (86 mg, 0.226 mmol) was added in one portion. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added, and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid. Step 2: A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (51 mg, 0.118 mmol), 2-fluoropyridin-3-ylboronic acid (33.2 mg, 0.236 mmol), potassium phosphate (75 mg, 0.354 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4.18 mg, 5.90 μmol). The vial was flushed with Ar (g), then dioxane (442 μL) and water (147 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (46.23 mg) as an off-white solid. MS m/z=449.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([C:13]1[N:17]=[C:16]([CH:18]2[CH2:20][CH2:19]2)[O:15][N:14]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.O1CCOCC1.[ClH:28]>>[ClH:28].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[N:17]=[C:16]([CH:18]2[CH2:20][CH2:19]2)[O:15][N:14]=1)[OH:12]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1noc(C2CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(N)[C@H](O)c1noc(C2CC2)n1

Procedure:
A solution of {(S)-1-[(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (3.41 g, 0.011 mmol) in 4N HCl in dioxane (43 mL, 0.172 mmol) is stirred at room temperature for 2 h. Solvent evaporated under reduced pressure. Residue triturated with a mixture of ethyl acetate and ether. It is then filtered to give (S)-2-Amino-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-butan-1-ol HCl salt as a solid (2.47 g).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[C:22]3[C:27]([CH:28]=[CH:29][C:19]=2[N:18]=1)=[CH:26][C:25]1[C:30]2[C:35]([CH2:36][O:37][C:24]=1[CH:23]=3)=[CH:34][C:33]([C:38]1[NH:42][C:41]([C@@H:43]3[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]3[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=1)=[CH:32][CH:31]=2)=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.[Pd]>[CH3:50][O:49][CH2:48][C@@H:46]1[CH2:45][N:44]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[C@H:43]([C:41]2[NH:42][C:38]([C:33]3[CH:34]=[C:35]4[CH2:36][O:37][C:24]5[CH:23]=[C:22]6[C:27]([CH:28]=[CH:29][C:19]7[N:18]=[C:17]([C@@H:12]8[CH2:13][CH2:14][C@H:15]([CH3:16])[NH:11]8)[NH:21][C:20]=76)=[CH:26][C:25]=5[C:30]4=[CH:31][CH:32]=3)=[CH:39][N:40]=2)[CH2:47]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)OCc7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
A mixture of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[(benzyloxy)carbonyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (830 mg, 1.08 mmol) and 100 mg 10% Pd/C in 20 mL ethanol was hydrogenated at 1 atm overnight. Additional 10% Pd/C (300 mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 722 mg. Purification by reverse phase HPLC gave 100 mg purified product.
Reaction SMILES: [Br:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:15]=[C:14]([O:16][CH:17]([F:19])[F:18])[C:12]([NH2:13])=[CH:11][CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5].[Br:22]N1C(=O)CCC1=O.O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][C:11]1[CH:10]=[C:9]([C:3]([F:8])([C:4]([F:7])([F:6])[F:5])[C:2]([Br:1])([F:20])[F:21])[CH:15]=[C:14]([O:16][CH:17]([F:18])[F:19])[C:12]=1[NH2:13]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
4-(1-Bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)aniline (810 mg) was dissolved in acetic acid, added with N-bromosuccinimide (390 mg), and stirred at 70° C. for 3 hours. Water was added to the reaction solution and extraction was carried out twice using ethyl acetate. The organic phases were combined and neutralized with sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoroprop-2-yl)-6-(difluoromethoxy)aniline (730 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]=1[CH2:23]Cl)=[CH:20][CH:19]=[CH:18][CH:17]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]=1[CH2:23][O:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: ClCc1c(Cl)ncc2ccccc12
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2c(Cl)ncc3ccccc23)cn1
Temperature: 60 °C
Yield: 14 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (73 mg, 0.48 mmol, 1 eq.), 3-chloro-4-(chloromethyl)isoquinoline (crude above, 0.48 mmol), and K2CO3 (265 mg, 1.92 mmol, 4 eq.) in DMF (2.0 mL) was heated at 60° C. for 1 h. The mixture was cooled, filtered, concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes to give 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (22 mg, 14%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ=10.19 (s, 1H), 9.05 (s, 1H), 8.23 (s, 1H) 8.06 (d, 1H), 7.98 (d, 1H), 7.76 (t, 1H), 7.63 (t, 1H), 7.01 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H). LRMS (M+H+) m/z 329.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[N:7][CH:8]=1.Cl[Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CN=C1>CN(C=O)C>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][CH2:21][CH2:20][NH:19][C:4]2[C:3]([CH2:2][O:1][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)[N:5]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCCCNc1nc(Nc2cccc([N+](=O)[O-])c2)ncc1CO)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1NCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
A DMF solution (5 ml) of phenylmethyl [3-[[5-(hydroxymethyl)-2-[(3-nitrophenyl)amino]pyrimidin-4-yl]amino]propyl]carbamate (250 mg), chloro(1,1-dimethylethyl)dimethylsilane (190 mg) and 1H-imidazole (170 mg) was stirred at room temperature (48 h). After addition of ice water the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue with diethyl ether yielded the title compound (300 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:4].[OH-].[K+].O>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:18]([N:21]=[C:22]=[S:23])([CH3:20])[CH3:19]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[S:7]([NH:10][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[S:23])(=[O:8])=[O:9]
Reactant: CC(C)N=C=S
Reactant: Cc1csc(N)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc(N)c1S(=O)(=O)NC(=S)NC(C)C
Temperature: 52.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 2-amino-4-methyl-thiophene-3-sulfonamide (0.30 g), potassium carbonate (0.32 g), and isopropyl isothiocyanate (272 μl) in dry acetone (5 ml) under nitrogen was heated at 50-55° C. overnight. Then the solvent was evaporated and the residue was dissolved in water (15 ml); pH was adjusted to 2 by addition of 4 M hydrochloric acid, and the mixture was stirred for 30 min. The precipitated crystals were filtered off, rinsed with a small amount of water and dried to give 0.24 g (yield 54%) of the title compound; m.p. 118-120° C.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([CH2:59][CH2:60]CCCCC=C)[C:54]([O:56]CC)=[O:55]>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:60][CH2:59][CH:53]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:71])[C:67]([F:70])([F:69])[F:68])[C:54]([OH:56])=[O:55])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35](OC)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1.O>CCOCC>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35]([C:5]5[S:4][C:3]([Si:2]([CH3:9])([CH3:8])[CH3:1])=[N:7][CH:6]=5)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cnc([Si](C)(C)C)s2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
2-(Trimethylsilyl)thiazole (285 μl, 1.784 mmol) in dry ether (2 mL) was added to butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (6 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (88 mg) as a yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H=481.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[N:10]([S:13]([C:16]1[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][S:19][C:20]=1[CH3:21])(=[O:15])=[O:14])=[C:11]=[O:12]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]([CH3:9])[C:5](=[O:8])[N:6]([C:11]([NH:10][S:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][S:19][C:20]=2[CH3:21])(=[O:14])=[O:15])=[O:12])[N:7]=1
Reactant: COc1n[nH]c(=O)n1C
Reactant: COC(=O)c1csc(C)c1S(=O)(=O)N=C=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(C)c1S(=O)(=O)NC(=O)n1nc(OC)n(C)c1=O
Temperature: 70 °C
Reaction time: 5.8 h
Yield: 93.2 %

Procedure:
12.9 g of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (3) (100 mmol) were initially charged in 200 ml of xylene and heated to 70° C. At this temperature, 119 g of a 22% solution of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate (2) (100 mmol) in dry xylene were metered in. The mixture was stirred at 70° C. for a further 5.8 h. Subsequently, workup was effected at room temperature by filtering the precipitated product. After washing with 50 ml of xylene and subsequently drying, 36.4 g of methyl 4-({[(3-methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)carbonyl]amino}-sulfonyl)-5-methylthiophene-3-carboxylate (4) (91% of theory, content relative to standard: 97.5%) of melting point 201° C. were obtained.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2-n2cnc(Br)c2[C@@H]2CCCN12

Procedure:
2.5 g (10.4 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of dimethylformamide are stirred at room temperature for 30 minutes with 1.86 g (10.4 mmol) of N-bromosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. After two-fold recrystallization from ethyl acetate, there is obtained (S)-1-bromo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 225°-226°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)C1C=CC=CC=1.[C:26]1([O:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[O:32]([C:33]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:9]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)Oc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine (5 g.) in dichloromethane (50 ml.), phenylchloroformate (2 ml.) is added and the mixture is stirred at ambient temperature (ca 20°C) for 24 hours. The solvent is evaporated and the residual oil is recrystallised from ethanol to give 4-phenoxycarbonyl-2-toluene-p-sulphonyloxymethylmorpholine, m.p. 101°-103°C.