Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.Br[CH:11]=[C:12]([CH3:14])[CH3:13]>>[CH3:13][C:12]([CH3:14])=[CH:11][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: CC(C)=CBr
Reactant: COC(=O)c1cc[nH]n1
Product: COC(=O)c1ccn(C=C(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 17(a) starting from methyl 1H-pyrazole-3-carboxylate (8 g, 63.4 mmol) and 1-bromo-2-methyl propene (12.7 g, 95.2 mmol). The product was purified with flash chromatography. Yield 2.4 g. 1H-NMR (400 MHz; CDCl3): δ 1.81 (d, 3H), 1.87 (d, 3H), 3.93 (s, 3H), 6.70 (d, 1H), 6.87 (d, 1H), 7.47 (d, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].S(Cl)(Cl)=O.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:12][O:11][C:9]([C:2]1[S:1][C:5]([C:6](=[O:8])[NH:25][C@H:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=2)[CH3:24])=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)c1ccc(C(=O)[O-])s1
Reactant: Cc1ccc([C@H](C)N)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N[C@@H](C)c2ccc(C)cc2)s1
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 1.4 g (7.5 mmol) of methyl thiophen-2,5-dicarboxylate in CH2Cl2 (5 ml) is treated with 1.5 ml (18 mmol) thionylchloride and one drop of DMF and subsequently heated at 80° C. for 1 hour. The solvent and excess of thionylchloride are evaporated under reduced pressure, and the residue is dissolved in CH2Cl2 (10 ml) and treated slowly with (S)-1-(p-tolyl)ethylamine (1.0 g, 7.4 mmol) in CH2Cl2 (10 ml) and triethylamin (2 ml, 14.2 mmol). Stirring at rt is continued for 1 additional hour. The product is isolated after acidic work-up and recrystallisation as yellow solid (mp=165° C.) in 71% yield (1.6 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:8]([CH3:15])[N:7]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:15][N:8]1[CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(F)(F)F)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
1-Methyl-4-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester (20 g, 90 mmol) was dissolved in methanol (100 ml). Sodium hydroxide in methanol (1M) (95 ml, 95 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, stored at room temperature for 16 hours and concentrated. The residue was dissolved in aqueous hydrochloric acid (2M) (55 ml) and isopropyl acetate (300 ml). The two phases were separated and the aqueous phase was extracted with more isopropyl acetate (100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated. This gave the product as a white solid (17.5 g, 100% yield). M.p. 174-175° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>[Pd].C(OCC)(=O)C>[CH2:19]([NH:20][CH2:6][C:2]1[NH:3][CH:4]=[CH:5][N:1]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCN
Reactant: O=Cc1ncc[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
In a 500-ml autoclave were placed 2-imidazolecarboxaldehyde (6.9 g (70 mmol), product of Aldrich), n-laurylamine (12.8 g (69 mmol)), 5% Pd-C (2 g), and ethyl acetate (200 ml). The contents of the flask were stirred for 24 hours at room temperature under hydrogen (20 kg/cm2). The catalyst was removed, and the solvent was concentrated. Purification via silica gel column chromatography (n-hexane:ethyl acetate=2:1) afforded 11.0 g of N-lauryl-2-imidazole methyl amine as white crystals (yield: 60%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[CH2:31][CH3:32].CN(C1C=CC=CN=1)C.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.O>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][C:36]2[CH:37]=[CH:38][C:33]([CH2:30][CH2:31][CH3:32])=[CH:34][CH:35]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CCCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(OC(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
10.0 g of dicyclohexylcarbodiimide in 20 ml of toluene are added with water cooling to a mixture of 9.1 g of 4-trifluoromethoxybenzoic acid, 6.0 g of 4-propylphenol, 2.7 g of dimethylaminopyridine and 30 ml of toluene. The mixture is stirred for 2 hours, 1 g of oxalic acid is added, and the mixture is stirred for a further hour and filtered with suction. The filtrate is washed by shaking with 1M HCl, the phases are separated, and the organic phase is washed by shaking with 1M NaOH and worked up. After purification by chromatography and/or crystallization, 4-propylphenyl 4-(trifluoromethoxy)-benzoate having C 59° I is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH3:2][CH2:1][O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O
Temperature: 62.5 °C
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-amino carbonylmethyl]-benzoate (4.5 g, 0.0093 mol) was dissolved in methanol (45 ml), followed by the addition of sodium hydroxide solution (0.75 g of sodium hydroxide dissolved in 6 ml water). The reaction mixture was heated at 60-65° C. for 3-4 hours. Methanol (80-85%) was removed from the reaction mixture under vacuum. The remaining reaction mixture was diluted with water (45 ml) and pH was adjusted to 6.5-7.0 with 1N HCl. The precipitated solid was stirred for 2-3 hours followed by filtration and washing with water (45 ml). The product was further dried at 50-55° C. under vacuum for 6-8 hours to produce Repaglinide (Yield=83.2%; HPLC Purity: 99.89%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22](O)=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (50 mg, 0.10 mmol) obtained in Example 55 was dissolved in DMF (2 mL), and the mixture was cooled to 0° C. N,N′-carbonyldiimidazole (36 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To this mixture were added methanesulfonamide (21 mg, 0.22 mmol) and DBU (21 mg, 0.22 mmol), and the mixture was stirred at 60° C. for 5 hr. 5% Aqueous citric acid solution was added to the mixture, and the precipitate was collected by filtration, and washed with water to give the title compound (compound 57) (31 mg, 55%).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>>[C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Nc1nccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1nccc2c1CCCC2
Yield: 59.1 %

Procedure:
Reaction of N-(isoquinol-1-yl)acetamide (159 mg, 0.854 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroisoquinolin-1-yl)acetamide (96 mg, 59%): 1H NMR δ 1.74-1.76 (m, 4H), 2.16-2.19 (m, 3H), 2.60-2.70 (m, 2H), 2.70-2.76 (m, 2H), 6.86 (d, 1H, J=5 Hz), 8.03 (d, 1H, J=5 Hz); 13C NMR δ 22.3, 22.8, 23.8, 25.1, 29.6, 122.9, 144.4 (2C), 149.5, 150.2, 170.6; MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide also was isolated (16 mg, 11%): 1H NMR δ 2.28 (m, 3H), 2.96-3.01 (m, 2H), 3.56-3.61 (m, 2H), 7.20 (d, 1H, J=8 Hz), 7.33-7.38 (m, 1H), 7.44-7.49 (m, 1H), 8.27 (d, 1H, J=8 Hz); 13C NMR δ27.2, 28.7, 29.7, 39.3, 127.3, 127.5, 128.0, 132.6, 137.9, 162.8, 188.0; MS m/z: 191 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:36]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccc4Cl)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 2-chlorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL) and then washed with H2O (40 mL), 1N HCl (40 mL), brine (40 mL), and dried over MgSO4. The organic layer was concentrated in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min):) to afford 2-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.55 g, 60%): mp, 209-211° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.87-2.93 (m, 1H), 4.92 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 7.39-7.57 (m, 4H), 7.82-7.89 (m, 3H), 9.12 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.91, 38.10, 48.86, 121.95, 127.15, 128.97, 129.62, 129.83, 130.94, 131.54, 133.10, 134.80, 136.49, 138.74, 166.77, 166.93, 167.48, 169.80, 172.74. Anal Calcd for C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87; Cl, 8.33. Found: C, 59.24; H, 3.45; N, 9.71; Cl, 8.32.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.C([Li])CCC.[C:41]1([C:47]2[CH:48]=[CH:49][C:50](=[C:52]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.O>[C:41]1([C:47]2[CH:48]=[CH:49][CH:50]([C:52]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:20]3[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]4[CH:10]=[C:9]5[C:14](=[CH:13][C:12]=4[C:19]3([CH3:26])[CH3:25])[CH2:15][C:16]3[CH:17]=[C:18]4[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]4=[CH:7][C:8]5=3)[CH:51]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC(c3ccccc3)=C1)C2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of 1.0 g (2.59 mmol) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene in 30 ml of THF, 1.75 ml (2.85 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 hours. Then, a solution of 0.92 g (3.11 mmol) of 3,6,6-triphenylfulvene in 10 ml of THF was slowly added at room temperature, followed by stirring for 15 hours. To the reaction solution, 20 ml of water was added to terminate the reaction. The resulting solution was subjected to extraction with diethyl ether, then dried over anhydrous magnesium sulfate and vacuum evaporated to dryness to obtain a yellow solid. The solid was washed twice with a small amount of methanol and dried under reduced pressure to obtain 1.24 g of an opaque white solid (yield: 69.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Sc2cccc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Sc2cccc(Cl)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 30c (320 mg, 1.15 mmol), LiOH (110 mg, 4.59 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% aqueous citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, filtered, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue (compound 30d, 290 mg) was dried under reduced pressure for 18 h and was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH:8]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[CH2:9][NH:10][C:11](=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:14]1.O.CO>N1C=CC=CC=1.CS(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:15]2[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:22])[F:23])[C:17](=[O:18])[N:13]([CH2:12][C:11]([NH:10][CH2:9][CH:8]([NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=3)=[O:33])[N:14]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 μl (56 μmol) of methanesulphonyl chloride were added to a solution of 30 mg (51 μmol) of the compound of Example 58A in 0.5 ml of pyridine, and the mixture was stirred at RT overnight. Since HPLC analysis showed a lot of remaining starting material, further equivalents of methane-sulphonyl chloride (3.1 eq. in total) were added a little at a time until complete conversion had been achieved. 100 μl each of water and methanol were then added. After 5 min of stirring, the reaction mixture was diluted with about 3 ml of DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 22 mg (68% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:10][C:11]([C:13]#[C:14][C:15](OCCC)=[O:16])=[O:12])[CH2:8][CH3:9]>C(O)C>[CH2:7]([O:10][C:11]([C:13]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:15](=[O:16])[CH:14]=1)=[O:12])[CH2:8][CH3:9]
Reactant: CCCOC(=O)C#CC(=O)OCCC
Reactant: Nc1nccs1
Solvent: CCO
Product: CCCOC(=O)c1cc(=O)nc2sccn12
Reaction time: 8 h

Procedure:
10 g of 2-aminothiazole are dissolved in 150 ml of absolute ethanol and 19.8 g of acetylene dicarboxylic acid di-n-propyl ester are added to the resulting solution. The mixture is heated to 50° to 60° C. for 10 minutes. After standing overnight at room temperature the precipitate is filtered off, washed with ether and dried in vacuo. 7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid n-propyl ester melting at 154°-156° C. with decomposition is thus obtained in a yield of 14.5 g (61% of the theoretical).
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH:5]([CH3:11])[S:4]1(=[O:13])=[O:12]>CO>[NH2:1][C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH:5]([CH3:11])[S:4]([NH:3][CH3:2])(=[O:13])=[O:12]
Reactant: N
Reactant: CC1=CC(=O)C(C)S(=O)(=O)N1C
Solvent: CO
Product: CNS(=O)(=O)C(C)C(=O)C=C(C)N
Reaction time: 8 h

Procedure:
A moderately rapid stream of dry ammonia was introduced at 20°-25° during 3 hours into a solution of 2.5 g of 2,3,6-trimethyl-2H-1,2-thiazin-5(6H)-one 1,1-dioxide in 25 ml of methanol and the mixture was thereupon left to stand overnight. The dark yellow solution obtained was concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from ethanol. There were obtained 2.3 g of 4-amino-N,1-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 140°-143°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:33]=[CH:32][C:25]2[CH:26]=[C:27]([C:29](O)=[O:30])[O:28][C:24]=2[CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[O:28][C:24]2[CH:23]=[C:22]([O:21][CH3:20])[CH:33]=[CH:32][C:25]=2[CH:26]=1)=[O:30]
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: COc1ccc2cc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)oc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:31]([OH:32])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A stirred solution of diisopropylamine (9.75 mL) in dry tetrahydrofuran (200 mL) at -70° C. is treated dropwise with a solution of butyl lithium in hexane (27.2 mL; 2.5M) and the solution is stirred for 30 minutes. It is then treated with a solution of 3,5-dichloro-4-methylpyridine (10.25 g) in dry tetrahydrofuran (60 mL) during 30 minutes, while keeping the temperature below -75° C., and the solution is then stirred for a further 30 minutes. It is then treated with 3-cyclopentyloxy-4-methoxybenzaldehyde (13.92 g) in dry tetrahydrofuran (60 mL) during 15 minutes, and stirred for a further 1 hour 30 minutes at -75° C. The solution is treated with aqueous ammonium chloride solution and extracted with ethyl acetate (3×100 mL). The organic layers are combined, washed with brine, dried and concentrated to low volume. The resulting precipitate is filtered off, to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol (20.5 g), m.p. 124°-125° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([S:9][CH3:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=1[C:12](=[O:19])[CH2:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15].[C:20]([O:23][C:24](=O)C)(=O)[CH3:21]>C(O)(=O)C>[CH3:1][S:2][C:3]1[C:8]([S:9][CH3:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=1[C:12](=[O:19])[C:13](=[CH:24][O:23][CH2:20][CH3:21])[C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15]
Reactant: CSc1c(Cl)ccc(C(=O)CC(=O)C2CC2)c1SC
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC=C(C(=O)c1ccc(Cl)c(SC)c1SC)C(=O)C1CC1
Yield: 100.9 %

Procedure:
A mixture of 1-[2,3-bis(methylsulphenyl)-4-chlorophenyl]-3-cyclopropylpropan-1,3-dione (3.45 g) and acetic anhydride (3.37 g) in acetic acid was stirred and heated at reflux for 3 hours. It was cooled and evaporated to dryness. The residue was dissolved in toluene and re-evaporated to give 1-[2,3-bis(methylsulphenyl)4-chlorophenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (4.1g) as a brown oil which was not further purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: Fc1ccc(OCc2ccccc2)cn1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)cn2)cc1

Procedure:
5-Benzyloxy-2-fluoropyridine (980 mg, 4.82 mmol) was reacted with N-[3-(4-hydroxy-phenyl)-1-methylpropyl]acetamide in analogy to example 1b.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(S(=O)[O-])c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(C#N)c4)ccc31)C1CCC(C2)N1
Yield: 35 %

Procedure:
Intermediate 5 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7.5:2.5 hexane/ethyl acetate) to give tert-butyl 2-(3-cyanophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (106 mg, 35%) as a yellow solid: 1H NMR (CDCl3, 300 MHz): δ 8.13-8.24 (m, 3H), 7.76 (td, J=7.8, 1.2 Hz, 1H), 7.66 (dd, J=8.7, 1.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 5.20-5.37 (m, 1H), 4.58-4.82 (m, 1H), 3.62 (s, 3H), 3.25-3.50 (m, 1H), 2.52 (d, J=16.2 Hz, 1H), 2.13-2.42 (m, 2H), 1.88-2.00 (m, 1H), 1.55-1.68 (m, 1H), 1.38 (s, 9H).