Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5]Br.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1
Reactant: CC(CF)(CF)C(=O)CBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)COc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 70.9 %

Procedure:
215 g (1 mole) of 3,3-bisfluoromethyl-1-bromobutan-2-one were added dropwise to a stirred mixture of 162 g (1 mole) of 3-trifluoromethylphenol and 180 g (1.3 moles) of powdered potassium carbonate in 1,200 ml of acetone at 20° to 30° C. The mixture was stirred at 50° C. for 6 hours the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 210 g of 3,3-bisfluoromethyl-1-(3-trifluoromethylphenoxy)-butan-2-one of boiling point 114°-18° C./0.6 mm Hg were obtained. ##STR10##
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:13][C:5]2[NH:6][C:7]([C:9]([O:11]C)=[O:10])=[CH:8][C:4]=2[CH:3]1[O:14][CH3:15]>CCOC(C)=O>[F:16][C:2]1([F:1])[CH2:13][C:5]2[NH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]1[O:14][CH3:15]
Reactant: COC(=O)c1cc2c([nH]1)CC(F)(F)C2OC
Solvent: CCOC(C)=O
Product: COC1c2cc(C(=O)O)[nH]c2CC1(F)F
Temperature: 34.5 °C

Procedure:
A magnetically-stirred solution/suspension of methyl 5,5-difluoro-4-methoxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, (17.40 mg, 0.075 mmol) in pH=7 buffer solution, was treated with pig-liver esterase (PLE) (64.44 mg, 100 U/mg), and warmed at 32-37° C. for a period of 18 h after conversion to product appeared to stop. The suspension was diluted with EtOAc (20 mL) and dried onto Celite. The crude was then purified by silica gel chromatography (twice). 7.9 mg. 1H NMR (400 MHz, ACETONE-d6) δ ppm 3.17-3.41 (m, 2H), 3.43 (s, 3H), 4.60 (d, J=13.28 Hz, 1H), 6.81 (s, 1H), 10.93 (br. s., 1H); 19F NMR (400 MHz, ACETONE-d6) δ ppm −105.48 (d, J=0.63 Hz, 1F), −93.65 (d, J=0.65 Hz, 1F); LCMS-MS (ESI−) 216.2 (M-1).
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH3:12][C:13]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:14]=1[O:15][CH2:16][C:17](O)=O.[CH2:25]([NH:28][CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[O:39][CH3:40])[CH2:30]1)[CH2:26][CH3:27]>>[CH3:40][O:39][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[CH2:37][CH2:38][CH:29]([N:28]([CH2:17][CH2:16][O:15][C:14]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:13]=1[CH3:12])[CH2:25][CH2:26][CH3:27])[CH2:30]2
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: Cc1ccc(C)c(OCC(=O)O)c1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1cc(C)ccc1C)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced by 2,5-dimethylphenoxyacetic acid and (-)-2-(N-n-propylamino)-5-methoxytetralin was replaced by (+)-2-(N-n-propylamino)-5-methoxytetralin. The crude mixture was subjected to flash chromatography (Silica: 9:1 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.1-6.6(m, 6H), 4.0(t, 2H), 3.8(s, 3H), 2.3(s, 3H), 2.15(s, 3H), 0.9(t,3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][NH:17][CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][N:17]([CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:25])([CH3:26])[CH2:19]2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(NCc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)CC(C)(C)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CC(N(Cc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)S(C)(=O)=O)CC(C)(C)C1

Procedure:
This compound is obtained as an oil by reacting 6-chloro-N-dimethylaminomethylene-3-[(3,3,5-trimethylcyclohexylamino)methyl]benzenesulfonamide with methanesulfonyl chloride in methylene chloride in the presence of pyridine as auxiliary base and by purification by column chromatography (silica gel, methylene chloride:methanol=95:5).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[F:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: Fc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(F)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-fluoro-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([CH2:15][OH:16])[CH2:5]1)(=[O:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl>[C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([CH2:15][O:16][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of (2S)-4-acetyl-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (2.14 g) and imidazole (770 mg) in dichloromethane (20 ml) was added dropwise a solution of tert-butyldimethylsilyl chloride (1.7 g) in dichloromethane (5 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S)-4-acetyl-1-allyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methylpyrrolidine (2.725 g).
Reaction SMILES: [H-].[Na+].Cl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1.F[C:20]1[C:25]([C:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C=O.CCOC(C)=O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:15][C@H:16]([O:18][C:20]2[C:25]([C:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:17]1
Reactant: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC=C(c2cccnc2O[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.13 g, 3.18 mmol) was added to a solution of cis-3-(benzo[d]thiazol-2-ylamino)cyclobutanol hydrochloride (0.20 g, 0.795 mmol) in N,N-dimethylformamide (2.7 mL) under argon and the mixture was stirred for 30 min at RT. 1-(4-(2-Fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.17 g, 0.79 mmol) was next added, and the resulting mixture was heated at 100° C. for 2 h. The cooled reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as an off-white amorphous solid. [M+1]=421.0.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]cc(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(F)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) was dissolved in DMF (37.5 mL) and cooled to 0° C. Sodium hydride (1.5 g, 37.2 mmol) was added and the reaction mixture was stirred for 10 minutes and then treated with tosyl chloride (6.6 g, 34.9 mmol). The mixture was stirred for 30 minutes at 0° C. and then at room temperature for another 90 minutes. The reaction mixture was poured into water (100 mL) and the resulting solid was collected, washed with water and hexanes three times and dried in vacuo to afford 8.26 g of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.92 (dd, J=8.4, 2.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[CH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)piperidine from Step A (0.95 g, 2.7 mmol) was hydrogenated using 5% Pd/C (10 mg) in 95% ethanol (20 mL) at atmospheric pressure. After 3.5 h, the mixture was filtered and the catalyst was washed with 95% ethanol. Evaporation of the filtrate gave 0.95 g of 1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine as a colorless syrup.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14](=[O:28])[C:13]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>ClCCl>[F:7][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14](=[O:28])[C:13]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)N1COC(CO)=C(c2ccccc2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)N1COC(CF)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulphur trifluoride (1.27 ml) was added to a stirred solution of tert butyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (3.5 g) in dichloromethane at -78° C. After 0.5 hour the solution was allowed to warm to room temperature and stirred for 16 hours. The mixture was poured into saturated ammonium chloride solution and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica get, eluting with dichloromethane/hexane (1:1) to give tert butyl 2-(6-fluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.31 g) as a white solid, m.p. 80.5-82.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N+:21]([C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:33][CH:32]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylforrnamide (10 mL) under argon was treated with 55% sodium hydride (0. 175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-nitrophenoxy)ethanol (1.56 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 9:1) and crystallized from dichloromethane-hexane to provide 0.75 g of 4-[[2-(4-nitrophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a 4:1 molar hydrate, mp 122°-123° C.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]3[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:31]=4[CH:32]=[CH:33][CH:34]=3)(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[C:25]([S:22]([N:18]3[CH2:19][CH2:20][CH2:21][CH:16]([C:14]4[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:45])=[O:3])[CH:11]=[C:12]([C:35]5[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=5)[CH:13]=4)[CH2:17]3)(=[O:24])=[O:23])[C:26]=2[CH:27]=[CH:28][N:29]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc4cnccc34)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc4cnccc34)C2)c1
Temperature: 78 °C
Yield: 63.5 %

Procedure:
To a solution of compound 41a, 2-{5-[1-(Isoquinoline-5-sulfonyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester (59.0 mg, 0.092 mmol) in EtOH (4.6 ml) was added 2M KOH (0.46 ml, 0.92 mmol). The reaction was heated to 78° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, gave the product (35.7 mg, 63% ) 1H NMR (300 MHz, MeOD) δ ppm 0.79-0.86 (m, 6 H) 1.33-1.46 (m, J=13.21, 6.78, 6.65, 6.65, 6.65 Hz, 1 H) 1.49-1.64 (m, 3 H) 1.76-1.92 (m, 3 H) 2.64-2.72 (m, 1 H) 2.74-2.81 (m, 2 H) 3.62 (t, J=7.91 Hz, 1 H) 3.86 (d, J=10.55 Hz, 2 H) 7.13 (s, 1 H) 7.31 (s, 1 H) 7.40 (s, 1 H) 7.61-7.69 (m, 4 H) 8.00 (t, J=7.72 Hz, 1 H) 8.57-8.66 (m, 3 H) 8.99 (d, J=5.65 Hz, 1 H) 9.73 (s, 1 H) Calcd for C33H33F3N204S (M+H) 610.69, Found 611.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28][CH3:29])[CH:17]=2)=[CH:3]1.ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:40])[CH:17]=2)=[CH:3]1
Reactant: CSCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCS(C)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
116 mg of the product of Example 96 in 5 ml of dichloromethane were treated at 0° C. with 60 mg of 85% metachloroperbenzoic acid in 5 ml of dichloromethane. The solution was allowed to warm to room temperature and was then stirred for 1 hour. The solution was washed with aqueous sodium bicarbonate and dried. The solution was concentrated and the residue was crystallized from ethyl acetate/hexane to give 84 mg of rac-3-(1-methyl-3-indolyl)-4-[1-(3-methylsulphinylpropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 140° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].S([O-])(O[CH3:26])(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N(C)c2cccc([N+](=O)[O-])c2N)cc1

Procedure:
0.093 mol (28.5 g) of 2-amino-3-nitro-N-tosylaniline is dissolved in 112 ml of normal sodium hydroxide solution at 30° C. 0.122 mol (15.45 g) of methyl sulphate is added gradually, in the course of 1 hour 30 minutes, whilst stirring. The temperature remains between 35° and 40° C. Towards the end of the addition of the methyl sulphate, 3 ml of 10N sodium hydroxide solution are gradually added simultaneously in order to keep the pH alkaline.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]([CH2:45][CH3:46])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:40]=[C:41]([F:44])[C:42]=2[CH3:43])[C:37](O)=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:19]=2[N:20]=1)[CH3:9].CN(C(O[N:55]1N=N[C:57]2C=CC=[CH:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[CH2:8]([N:10]([CH2:45][CH3:46])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:40]=[C:41]([F:44])[C:42]=2[CH3:43])[C:37]([NH:55][CH:56]([CH3:61])[CH3:57])=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[C:19]=2[N:20]=1)[CH3:9]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid trifluoroacetate (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isopropylamine (7.03 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (19.3 mg, 60%). LC-MS m/z 581 (M+H)+.
Reaction SMILES: C[Si](Br)(C)C.C(OC([NH:13][C@H:14]([CH:18]=[C:19]([CH3:27])[CH2:20][P:21]([O:25]C)([O:23]C)=[O:22])[C:15]([OH:17])=[O:16])=O)(C)(C)C.O>ClCCl>[NH2:13][C@H:14]([CH:18]=[C:19]([CH3:27])[CH2:20][P:21]([OH:25])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]
Reactant: COP(=O)(CC(C)=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: CC(=C[C@@H](N)C(=O)O)CP(=O)(O)O
Reaction time: 4 h
Yield: 81.3 %

Procedure:
0.71 ml of trimethylsilyl bromide is added at 0° to a solution of 123 mg of 9 in 3 ml of dichloromethane. After stirring at 0° for 4 hours, 20 ml of water are added. After 30 minutes, the dichloromethane phase is separated off and washed three times with 15 ml of water each time. The aqueous phases are extracted three times with 20 ml of dichloromethane each time and concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of 5N hydrochloric acid and is then stirred for 48 hours, diluted with 20 ml of water and extracted three times with 20 ml of dichloromethane each time. The aqueous phase is concentrated by evaporation in vacuo, and the residue is dried under a high vacuum and dissolved in 3 ml of etharol, and then approximately 1 ml of propylene oxide is added dropwise thereto. The suspension is filtered. Washing of the filtration residue with ethanol and drying under a high vacuum at roomtemperature yields 62 mg of 10, m.p. 165° C. (decomposition).
Reaction SMILES: C([N+:8]1[CH:17]=[CH:16][C:15]2[C:14]3[N:18]([CH3:33])[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=3[CH2:12][CH2:11][C:10]=2[CH:9]=1)C1C=CC=CC=1.[Br-].CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[CH2:24]([O:23][C:21]([C:20]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:9]=[N:8][CH:17]=[CH:16][C:15]=3[C:14]=2[N:18]([CH3:33])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:22])[CH3:25]
Reactant: CCOC(=O)c1c2c(n(C)c1-c1ccccc1C)-c1cc[n+](Cc3ccccc3)cc1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(n(C)c1-c1ccccc1C)-c1ccncc1CC2

Procedure:
To a solution of 7-benzyl-3-ethoxycarbonyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-7-ium; bromide XXIIIA (1.64 mmol) in dry DMSO (1 mL), 1M potassium tert-butoxide (11.5 mmol) in THF was added. The solution was bubbled with dry air overnight. Volatiles were removed, the residue was suspended in DCM, washed with water, dried (Na2SO4), filtered and the solvent evaporated. Chromatography on silica gel (eluant: DCM/MeOH 20:1) afforded the title compound. ESI (+) MS: m/z 347 (MH+). 1H NMR: 1.1 (t, J=7.1, 3H), 2.15 (s, 3H), 2.9 (m, 2H), 3.02 (m, 2H), 4.05 (q, J=7.1, 2H), 4.2 (s, 3H), 7.2-7.4 (m, 4H), 7.48 (d, J=5.1, 1H), 8.36 (d, J=5.1, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2>>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:16]/[C:13]1[NH:12][C:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=3[C:14]=1[CH3:15])/[C:31](=[O:37])[NH:32]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 25.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 were used as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 42 (25 mg, yield 25.2%) as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccccc2)C[C@H](C)N3C(C)=O)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 54) (104 mg, 0.206 mmol) in dichloromethane (DCM) (3 mL) at room temperature under nitrogen was treated with trifluoroacetic acid (TFA) (0.5 mL, 6.49 mmol) and the resulting mixture was stirred at this temperature for 1 h then concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine trifluoroacetate (99 mg, 0.191 mmol, 93% yield) as a brown solid.