Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:16])=[O:4].[Na+].[NH2:19][CH2:20][C:21]([O-:23])=[O:22]>COCCO>[Cl:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][C:6](=[O:17])[C:5]([C:3]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])=[C:14]2[OH:15]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cccc(Cl)c2oc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccc(Cl)c2oc1=O
Yield: 76.9 %

Procedure:
A mixture of 8-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (150 mg, 0.59 mmol) and glycine sodium salt (286 mg, 2.95 mmol) in 2-methoxyethanol (6 mL) was heated to reflux overnight. Reaction mixture was concentrated and dissolved in water (25 mL). The solution was acidified by 1 N aq HCl to pH=2-3 and extracted with EtOAc. Organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give the title compound (135 mg). MS ESI(−) m/e: 296 (M−1).
Reaction SMILES: O[CH:2]([C:4]1[CH:21]=[CH:20][C:7]2/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)[CH3:3].B(Br)(Br)Br.[CH2:26]([C:29]1[NH:30][C:31]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:26]([C:29]1[N:33]([CH:2]([C:4]2[CH:21]=[CH:20][C:7]3/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[CH2:11][CH2:12][C:6]=3[CH:5]=2)[CH3:3])[C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=2[N:30]=1)[CH2:27][CH3:28]
Reactant: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCCc1nc2cccc(C)c2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCc1nc2c(C)cccc2n1C(C)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
[step 1] (E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (67 mg, 0.24 mmol) obtained in Example 83, step 2 was dissolved in dichloromethane (1 mL), boron tribromide (1.0 mol/L dichloromethane solution; 0.73 mL, 0.73 mmol) was added at 0° C., and the mixture was stirred for 20 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in DMA (0.5 mL), 2-propyl-4-methylbenzimidazole (63 mg, 0.36 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added, and the mixture was stirred at 70° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give (E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (46 mg, 45%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=1.C1(C)C=CC=CC=1>C(O)C>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Cc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 92.1 %

Procedure:
To a vigorously stirred solution of 4.27 g (16.6 mmol) of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step D), 32 mmol (26 mL of a 1.25N aqueous solution) of NaOH in 40 mL of ethanol was added 1.89 g (10 mmol, 1.27 mL) of 4-bromo-2-fluorotoluene, 60 mL of toluene, and 289 mg (0.25 mmol) of tetrakis(tfiphenylphosphine)palladium. The mixture was stirred at 90° C. for 4.5 h, cooled to room temperature, and the volatiles were removed in vacuo. The residue was extracted with ethyl acetate (3×) and the combined organic layers were washed with water, brine, and dried (Na2SO4). The crude product obtained after filtration and removal of solvents was flash chromatographed over silica gel (elution with hexane-EtOAc) to afford 2.96 g (92%) of the desired product cleanly (TLC in 4:1 hexane-EtOAc) as an off-white foam; mass spectrum (FAB) m/e 322 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=4[N:35]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-butyl-6-(1H-benzimidazol-2-yl)-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)#[N:2].O.[NH2:32][NH2:33].O>CO>[F:23][C:18]1[CH:17]=[C:16]([N:5]([CH2:6][CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:4]2[NH:3][C:1]([NH2:2])=[N:33][N:32]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: NN
Reactant: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Solvent: CO
Solvent: O
Product: Nc1nnc(N(CCCOC2CCCCO2)c2ccc(F)c(F)c2)[nH]1
Temperature: 25 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)-N-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)carbamimidate (73 mg, 176 μmol) in methanol (0.5 mL) was added hydrazine hydrate 25% in water (35.2 mg, 34.8 μl, 176 μmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using methylene chloride/methanol 19:1 (v/v) as eluent. The title compound was obtained as a light yellow viscous oil (46 mg, 74%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC(N)=O
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Sc2ccccc21

Procedure:
The title compound, white solid, m.p.=151-154° C., MS: m/e=342.2 (M+H+) was prepared in accordance with the general method of example 6 from 9H-thioxanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:51][C@H:52]([CH:57]([CH3:59])[CH3:58])[C:53]([O:55][CH3:56])=[O:54]>CN(C=O)C>[CH3:56][O:55][C:53](=[O:54])[CH:52]([NH:51][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][CH:20]=1)[CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)NC(COc1ccc(Br)cc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of the compound obtained in step e above (22e) (816 mg, 2.27 mmol), NMM (0.55 mL, 4.922 mmol) and HOBt (521 mg, 3.864 mmol) in DMF (10 mL) was stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCI (478 mg, 2.497 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, (R)-methyl 2-amino-3-methylbutanoate hydrochloride (417 mg, 2.497 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography to give the title compound as colourless oil (900 mg, 84%).
Reaction SMILES: Br[CH:2]([CH2:12]Br)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].[CH2:14]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][CH:2]1[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A solution of 48.5 g (154 mmoles) of n-hexyl 2,3-dibromopropionate (II, Z=O(CH2)5CH3) in 100 ml of dry benzene stirred at 40° C. is added dropwise to a warm solution (80° C.) of 37 g (154 mmoles) of N,N'-dibenzylethylenediamine and 55 ml of triethylamine in 100 ml benzene. The mixture was stirred for 3 hours at 80° C. After cooling and filtration of the triethylammonium chloride, the solution was evaporated off and the crude residue treated with diethyl ether and washed with water. The organic layer was dried (MgSO4), evaporated and chromatographed on a silica gel column using diethyl ether/petroleum ether (10:90, in vol.) as eluent, yielding 52.5 g (86.5%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 33.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 3,4,5-trichloropyridine (141 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (51 mg), a white solid, in 33% yield.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH3:9]>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:8](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:9]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-(−)-2-methyl-2-propanesulfinamide (1.0 g, 8.25 mmol) and acetaldehyde (2.0 mL, 35.61 mmol) in dichloromethane (20 mL) at ambient temperature under nitrogen atmosphere was added CuSO4 (2.9 g, 18.15 mmol). The mixture was stirred at ambient temperature for 18 h. The reaction was filtered through celite and the filtrate solvent was removed under reduced pressure. N-ethylidene-2-methyl-2-propanesulfinamide was obtained as a clear colorless oil (1.18 g; 1H NMR, 400 MHz, CDCl3, 8.8 ppm (q, 11H), 2.24 ppm (d, 3H), 1.2 ppm (s, 9H)).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([OH:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]([CH2:22]P(OC)(OC)=O)=[O:21]>O>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[C:1]([OH:3])=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 17 h

Procedure:
3-Carboxybenzaldehyde (25 g, 0.167 mol) and K2CO3 (69 g, 0.499 mol) were added to water (250 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (32.3 mL, 0.2 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was warmed and stirred at RT for 17 h. The mixture was acidified to pH ˜1, filtered and dried in vacuo to afford the product as an off-white solid (37.25 g, >100%—slightly wet). 1H NMR (300 MHz, CD3OD) δ: 8.23 (1H, s), 8.06 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=7.5 Hz), 7.75 (1H, d, J=15.9 Hz), 6.61 (1H, d, J=16.2 Hz), 7.54 (1H, t), 3.81 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N(C)S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)S(C)(=O)=O

Procedure:
A mixture 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg crude) in 4 M HCl in dioxane (12 mL) and water (4 mL) were heated at 100° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and subsequently neutralized aqueous NaHCO3 to pH to 5-6. The aqueous layer was extracted with EtOAc, the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (20→80% gradient of MeCN-water) to provide 4-chloro-N{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a solid. MS m/z: 582.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(S(=O)(=O)Nc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Yield: 0.1 %

Procedure:
A solution of diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl) sulfonamido)benzoyl)-L-glutamate (0.22 g, 0.37 mol) in ethanol (3 ml) and 0.25N NaOH (12 ml) was stirred at room temperature for 3 hours. The solution was slowly acidified to pH 3 with 1N HCl and the resulting precipitate filtered, washed with water, and dried under high vacuum to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl) sulfonamido)benzoyl)-L-glutamic acid as a white solid (0.20 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.73-2.15 (m, 2H, glu CH2), 2.27 (t, J=7 Hz, 2H, glu CH2), 2.43 (s, 3H, CH3), 4.22-4.36 (m, 1H, glu CH), 7.20 (d, J=9 Hz, 2M, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 7.76 (d, J=9 Hz, 1H, Ar), 7.90 (dd, J=9,2 Hz, 1H, Ar), 8.18 (d, J=9 Hz, 1H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.39 (d, J=8 Hz, 1H, glu NH), 10.44 (d, J=2 Hz, 1H, Ar), 10.86 (br s, 1H, SO2NH), 12.32 (br s, 2H, CO2H's), 12.75 (br s, 1H, N2H). Anal. Calculated for C25H22N4O8S.4/5H2O): C, 54.30; H, 4.30; N, 10.13; S, 5.80. Found: C, 54.29; H, 4.25; N, 10.13; S, 5.72.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(Cl)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>C(#N)C>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:18]2[NH:17][CH:21]=[CH:20][N:19]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: N#CC(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: N#CC(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
5.9 g diphenyl-chloroacetonitrile (prepared from diphenyl-chloroacetamide, Ber. 41, 3593 by heating in phosphorus oxychloride; b.p. 130°C./0.4 mm Hg) are heated with 5 g imidazole in 50 ml acetonitrile at boiling temperature for 18 hours. After treating with 20 ml of water, the mixture is extracted with methylene chloride. The solvent is distilled off after drying in a vacuum. The solid residue is recrystallized from ethyl acetate/petroleum ether. Diphenyl-imidazolyl-acetonitrile i.e. diphenyl-imidazolyl-acetic acid nitrile of m.p. 98°C. is thus obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:5][C:6]1[S:7][C:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[C:9]([CH3:18])[C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([O:21][C:19]([C:8]1[S:7][C:6]([NH:5][C:3]([C:2]([F:1])([F:29])[F:30])=[O:4])=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[CH3:18])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)C(F)(F)F)c1C(=O)O
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound prepared in Example 5 (155 mg, 0.34 mmol) was dissolved in DCM (2.5 ml) and TFA (3 ml) was added dropwise. After 18 h, the reaction was concentrated. The crude solid was partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer was extracted with CHCl3 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield 130 mg of a white solid (99%). 1H-NMR (CDCl3) 2.83 (s, 3H), 5.34 (s, 2H), 7.40 (m, 5H); 13C-NMR (CDCl3)); mp-179-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:24][CH:25]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Product: Cc1ccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)nc1
Yield: 32.5 %

Procedure:
4-(5-(2-Amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1 and the 2-chloromethyl-5-methyl-pyridine (32 mg, 0.23 mmol) described in Manufacturing Example 42-1-2 were used to obtain the title compound (23 mg, 33%) according to the methods similar to those of Example 10.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH-].[K+]>C(COC)OC>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 89 %

Procedure:
1-(p-toluenesulphonyl)indole was prepared according to the procedure described in Y. Kikugawa Synthesis 1981, 460-461, by reaction of indole with p-toluenesulphonyl chloride in the presence of potassium hydroxide in dimethoxyethane at ambient temperature for 30 minutes. Yield: 89%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Product: Nc1ncc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.230 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 28%). MS (ISP) 434.1 [(M+H)+]; mp 242-245° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97 %

Procedure:
To an ice-cooled solution of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate and imidazole (2 eq.) in DMF (0.4 M), chloro(triisopropyl)silane (2 eq.) was added dropwise. The mixture was stirred at RT for 7 h, diluted with EtOAc, washed with sat. aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 6:1). After evaporation of the solvents the product was obtained as colourless oil (97%). MS (ES−): 519.7 (M−H+).