Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>C(Cl)Cl>[F:24][C:25]([F:32])([F:31])[C:26]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:27]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(F)(F)F)CC1
Reaction time: 20 h

Procedure:
To a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (48.7 g, 0.243 mol) and DIPEA (130 mL, 0.749 mol) in DCM (250 mL) was added ethyl trifluoroacetate (35.6 mL, 0.300 mol) dropwise while stirring. After 20 hours, the solution was washed with citric acid solution (200 mL×3, 10% w/v aq) and sodium bicarbonate solution (200 mL×3, conc aq), dried (MgSO4), and filtered through silica (24 g). The silica was washed with DCM and the combined eluant was partially concentrated (100 mL), and used directly in the next step. APCI/MS calcd. for C12H19F3N2O3 296.1. found m/z=294.9 (M−1).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C1(S)C=CC=CC=1.[CH3:38][Si:39]([CH2:42][SH:43])([CH3:41])[CH3:40]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: C[Si](C)(C)CS
Agent: Sc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC[Si](C)(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by a procedure similar to the one described in Example 300, Step A, replacing benzenethiol with the appropriate amount of (trimethylsilyl)methanethiol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]Br>O>[C:12]1([CH3:19])[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[C:4](=[O:21])[N:3]([CH3:22])[C:2]([NH:1][CH2:33][CH2:32][O:31][CH3:30])=[N:7][C:6]=2[N:8]([CH3:20])[CH:9]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (55 mg, 0.18 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-methoxyethylbromide (232 mg, 0.60 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 2 hours and heating under reflux for 2 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (9:1) to give 15 mg (23%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:21][CH:20]=[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:18]=[CH:17]2)[N:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C=CC(O)=CC=1)O>O1CCOCC1>[F:27][C:2]([F:1])([F:26])[C:3]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[N:4]=1
Reactant: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c3ccc4ccccc4c32)cc1
Yield: 89.9 %

Procedure:
4,5-Dihydro-4-[3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide from Step 2 (393 mg, 1.0 mmol) was dissolved in 1,4-dioxane (50 ml), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (227 mg, 1.0 mmol) was added. The reaction was heated to reflux for 16 hours at which time a second equivalent of DDQ (227 mg, 1.0 mmol) was added and the reaction was heated to reflux for an additional 24 hours. At three successive 24 hour intervals, 1.0 mmol additional DDQ was added and heating continued until no starting material was left. The reaction was cooled to room temperature at which time most of the hydroquinone by-product precipitated. The reaction was filtered and concentrated. The residue was chromatographed on silica gel eluting with 50% ethyl acetate in hexane to yield 4-[3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide (352 mg, 90%): 1H NMR (acetone d6) δ=6.89 (broad s, 2H), 7.5 (m, 1H), 7.7 (m, 2H), 7.89 (s, 2H), 8.0 (d, 2H, j=8.7 Hz), 8.15 (d, 1H, j=8.3 Hz), 8.3 (d, 2H, j=8.7 Hz); 19F NMR (acetone d6) δ-61.7 ppm (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.[CH3:25][O-:26].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:26][CH3:25])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.1 %

Procedure:
0.35 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one, 0.96 g of sodium methoxide (28%-methanol solution) and 6 ml of methanol were mixed and stirred for 14 hours under reflux with heating. Next, to the reaction mixture was added 0.96 g of sodium methoxide (28% methanol solution), and stirred for 9 hours under reflux with heating. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: hexane+tert-butyl methyl ether), to obtain 0.25 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one.
Reaction SMILES: O[C:2]1[C:7]2[C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4](C(C(C)CCCCC)C)[CH:3]=1.[ClH:28].O1CCN(CCCC(O)=O)CC1>>[ClH:28].[CH3:17][C:15]1([CH3:18])[CH2:14][C:9]2[C:10]([CH3:13])([CH3:12])[O:11][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=3[C:8]=2[CH2:16]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)(C)C1
Agent: Cl
Agent: O=C(O)CCCN1CCOCC1
Product: CC1(C)CC2=C(C1)C(C)(C)Oc1ccccc12

Procedure:
9-Hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran from Example 28 is reacted with γ-morpholinobutyric acid hydrochloride following the procedure of Example 4 to produce 7-(3-methyl-2-octyl)-9-[4-morpholino)-butyryloxy]-2,2,4,4-tetramethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran hydrochloride.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](Cl)=[O:29]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[CH3:25])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Product: CC(C)=CC(=O)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 105.4 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (1 g, 2.82 mmol) and 3,3 dimethyl acryloyl chloride (0.33 mL, 2.97 mmol) and following the procedure as outlined in Example 1, 1.25 g of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated as a white foam in 93% purity @ 214 nm; LCMS (APCI): 421 [M+H]+; mp 52° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=2[F:21])=[C:5]([F:22])[C:4]=1[F:23].[F:24][C:25]([F:30])([F:29])[S:26]([O-:28])=[O:27].[Na+].O.C(OCC)(=O)C>C(#N)CC>[F:17][C:16]1[C:11]([C:6]2[C:7]([F:10])=[C:8]([F:9])[C:3]([CH2:2][S:26]([C:25]([F:30])([F:29])[F:24])(=[O:28])=[O:27])=[C:4]([F:23])[C:5]=2[F:22])=[C:12]([F:21])[C:13]([F:20])=[C:14]([F:19])[C:15]=1[F:18]
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Reactant: O=S([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC#N
Solvent: O
Product: O=S(=O)(Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)C(F)(F)F
Temperature: 25 °C
Yield: 94 %

Procedure:
4-bromomethylperfluorobiphenyl (3.68 g, 9 mmol) and sodium trifluoromethane sulfinate (1.69 g, 10.8 mmol) were dissolved in propionitrile (30 mL), and the resultant solution was subjected to heating under reflux for 12 hours. After the reaction, the solution was cooled to room temperature, and water was added for extraction with ethyl acetate. The organic phase was dried with magnesium sulfate, filtrated, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (hexane-ethyl acetate=20:1 to 8:1 to 1:1), and the aimed {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}(triflyl)methane (3.91 g, 8.46 mmol, 94% yield) was isolated. 1H NMR (CDCl3, 300 MHz) δ 4.75 (s, 2H, CH2Tf); 19F NMR (CDCl3, 282 MHz) δ−78.24 (s, 3F, CF3), −136.82 to −136.62 (m, 1F), −137.72 (dd, J=10.7, 18.3 Hz, 2F), −138.84 (dd, J=10.7, 18.3 Hz, 2F), −149.69 (t, J=21.3 Hz, 1F), −160.63 (dt, J=6.1, 21.3 Hz, 2F).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Cl:1][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
A solution of N-chlorosuccinimide (0.015 g, 0.11 mmol) in DMF (0.1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (35 mg, 0.099 mmol) in N,N-dimethylformamide (0.5 mL, 6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The mixture was then diluted with water and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc in hexane) to give the desired product (36 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:30]([F:29])([F:38])[F:39])[CH:32]=3)=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)c3c(c21)CC(C)(C)O3
Yield: 38.3 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.237 mmol), 3-(trifluoromethyl) aniline (0.057 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.49 (s, 2H), 3.59 (s, 3H), 7.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.31 (s, 1H), 8.47 (s, 2H), 9.90 (s, 1H), 10.91 (s, 1H); MS [M]+: 550.11.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
14.1 g. (85 mMol) of the above-obtained p-nitrophenethylamine and 34 ml. (340 mMol) triethylamine are dissolved in 170 ml. methylene chloride and 17.9 g. (85 mMol) p-chlorobenzenesulphonic acid chloride in 170 ml. methylene chloride added dropwise thereto at 0° to 5° C. within the course of 1 hour. After stirring for a further hour at 0° C., the reaction mixture is allowed to warm up to ambient temperature. It is then poured on to ice, mixed with 2N hydrochloric acid and shaken out with methylene chloride. The organic phase is washed neutral, dried over anhydrous magnesium sulphate and evaporated to dryness. The oily residue is chromatographed over silica gel with ligroin/ethyl acetate/glacial acetic acid (1.5:1.0:0.006 v/v/v) as elution agent. There are obtained 10.2 g. (35% of theory) of the desired compound in the form of a colourless oil. 1H-NMR (60 MHz, d6 -DMSO, ppm): δ=2.7-3.1 (m, 5H, CH2, NH); 7.35 and 8.10 (AB system 2d, J=9.5 Hz, 4H); 7.55 and 7.75 (AB system, 2d, J=10 Hz, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(F)cc1
Yield: 65 %

Procedure:
In accordance with the same procedures as in Preparation 7, except for using 2,6-dichloro-3-nitropyridine and 4-fluorobenzylamine, the titled compound was obtained as yellow solid. (Yield: 65%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C:57]3([NH2:60])[CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C:57]3([NH:60][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[C:2]([CH3:1])[CH:3]=4)[CH2:58][CH2:59]3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC1(c2nc3cc(Cl)ccc3[nH]2)CC1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC2(c3nc4cc(Cl)ccc4[nH]3)CC2)ccc1C(=O)N1CCCC1
Yield: 44 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)cyclopropylamine in tetrahydrofuran. Yield: 44%; Rf value: 0.37 (silica gel; ethyl acetate/ethanol=9:1); C23H23ClN4O2 (422.91); mass spectrum: (M+H)+=423/425 (chlorine isotope).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:70])([F:69])[C:25]1[CH:26]=[C:27]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[CH2:28][N:29]([CH2:36][C:37]1[C:38]([N:49]2[CH2:53][CH2:52][CH2:51][C@@H:50]2[C@H:54]2[CH2:59][CH2:58][C@H:57]([CH2:60][OH:61])[CH2:56][CH2:55]2)=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][C:43]([F:47])=[C:42]([F:48])[CH:41]=2)[C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1>C(Cl)Cl>[F:67][C:65]([F:66])([F:68])[C:63]1[CH:62]=[C:27]([CH:26]=[C:25]([C:24]([F:23])([F:69])[F:70])[CH:64]=1)[CH2:28][N:29]([CH2:36][C:37]1[C:38]([N:49]2[CH2:53][CH2:52][CH2:51][C@@H:50]2[C@H:54]2[CH2:55][CH2:56][C@H:57]([CH:60]=[O:61])[CH2:58][CH2:59]2)=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][C:43]([F:47])=[C:42]([F:48])[CH:41]=2)[C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CO)CC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](C=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dess-Martin periodinate (4.07 g, 9.6 mmol) is added to a suspension of trans-(4-{(R)-1-[3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-yl]pyrrolidin-2-yl}cyclohexyl)methanol (6.25 g, 9.1 mmol) in CH2Cl2 (75 mL) at 0° C., and the resulting mixture is stirred at room temperature for 20 min. The reaction mixture is quenched by addition of sat. NaHCO3 aq. and extracted with CH2Cl2. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give trans-4-{(R)-1-[3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-yl]pyrrolidin-2-yl}cyclohexanecarbardehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:13][C:14]1[C:23]2[C:18](=[C:19](Br)[C:20]([CH3:25])=[CH:21][C:22]=2[F:24])[N:17]=[N:16][C:15]=1[C:27]([NH2:29])=[O:28]>>[NH2:13][C:14]1[C:23]2[C:18](=[C:19]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[C:20]([CH3:25])=[CH:21][C:22]=2[F:24])[N:17]=[N:16][C:15]=1[C:27]([NH2:29])=[O:28]
Reactant: OB(O)c1ccc2[nH]ncc2c1
Reactant: Cc1cc(F)c2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1cc(F)c2c(N)c(C(N)=O)nnc2c1-c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using (1H-indazol-5-yl)boronic acid and 4-amino-8-bromo-5-fluoro-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.28 (s, 3 H), 7.19-7.30 (m, 1 H), 7.35 (d, J=16 Hz, 1H), 7.59-7.70 (m, 2 H), 8.07 (s, 1 H); ESI-MS m/z [M+H]+ 337.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)nc(N3CCCC3)c2)cc1
Yield: 32.6 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 142 mg (0.55 mmole) 3,5-bis(trifluormethyl)phenylboronic acid, 25 mg sodium carbonate and 20 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 48 hours in 10 ml 1,2-dimethoxyethane and 1 ml water. The solvent is removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1 ) of the residue yields 84 mg (32%) pure 4-[2-(3,5-bis-trifluoromethyl-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a pale yellow solid mp.: 184-186° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.Cl.C([N:35]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:31][O:30][CH2:29][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:35])=[O:16])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 106.1 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (1.02 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (868 mg), 1-hydroxybenzotriazole (612 mg) and N,N-dimethylformamide (20 mL) was stirred at 50° C. for 25 min. The mixture was cooled to room temperature, and 10% ammonium hydroxide solution (3 mL) was added to the mixture. After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.08 g, 100%) as an orange oil. MS 450 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)([OH:2])=[O:4]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of 4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one (8.00 g, 29.0 mmol) in N,N-dimethylformamide (80 mL) were added potassium carbonate (8.02 g, 58.0 mmol) and isobutyl bromide (4.76 g, 34.8 mmol), and the mixture was stirred at 80° C. for 2 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and a saturated aqueous solution of sodium hydrogencarbonate was added. The mixture was then extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off. Following the procedure of the residue was reacted to yield the title compound as a yellow solid [yield: 65.1% (2 steps)].