Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:13][C:12]=2[C:11]([CH2:30][CH2:31][CH3:32])=[N:10]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:14]3[NH:15][C:16](=[O:18])[C:17]4[N:9]([CH3:8])[N:10]=[C:11]([CH2:30][CH2:31][CH3:32])[C:12]=4[N:13]=3)=[CH:21][CH:22]=2)(=[O:27])=[O:28])[CH2:4][CH2:3]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)Cl)cc3)nc12
Reactant: CN1CCNCC1
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-methyl piperazine (1.28 ml, 0.0115 mol) was added to a solution of 4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]-1-benzenesulfonyl chloride (1.35 g, 0.0035 mol) in ethanol (20 ml) and the reaction stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was extracted with further dichloromethane (50 ml), the combined organic extracts dried (MgSO4), filtered, and evaporated under reduced pressure.
Reaction SMILES: [OH-].[Li+].[NH:3]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:14]([O:16]C)=[O:15])=[O:11])[N:5]=[CH:4]1>C1COCC1>[NH:3]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:14]([OH:16])=[O:15])=[O:11])[N:5]=[CH:4]1
Reactant: COC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)CCc1c[nH]cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)O)cc1
Reaction time: 16 h
Yield: 79 %

Procedure:
40 ml of a 1N aqueous solution of lithium hydroxide are added to a solution containing 11.0 g (33.3 mmol) of methyl (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoate in 100 ml of THF. After stirring for 16 hours, the reaction medium is concentrated. The residue is purified by silica gel chromatography (eluent 70/30/1 dichloromethane/methanol/triethylamine). 8.4 g in the form of a white powder are obtained with a yield of 79%.
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:17]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:4]([C:1](=[O:3])[CH3:2])[C:5]=2[CH:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c3ccccc3n(C(C)=O)c2c1
Temperature: -78 °C
Yield: 55.5 %

Procedure:
9-Acetyl-carbazole (41.85 g, 0.2 mol) was dissolved in 1 L methylene chloride and 28.5 mL acetylchloride (0.4 mol) and 120 g aluminum chloride (0.9 mol) were added and the solution refluxed for 1.5 h. The solution was cooled to −78° C. and 6N HCl was added slowly while stirring and allowed to warm to room temperature. Methylene chloride was added to dissolve the precipitate and the solution was extracted, and the organics dried over Na2SO4, decolorized with charcoal, filtered and concentrated. Recrystallization from benzene/hexane gave 27.9 g 2,9-diacetylcarbazole.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:25]=[CH:24][N:23]=[C:22]3[C:13]=2[CH:14]=[CH:15][C:16]2[C:21]3=[N:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1>CO.C(Cl)Cl>[C:1]([C:19]1[CH:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21](=[C:22]3[C:13](=[CH:14][CH:15]=2)[C:12]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)=[CH:25][CH:24]=[N:23]3)[N:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)ccnc3c2n1
Yield: 70 %

Procedure:
This yellow compound was prepared in a process analogous to the synthesis of PBP in which 2 equivalents of t-butyllithium were used for each equivalent of bathophenanthroline. The clean product was obtained after running chromatography in a silica/mixture of methanol/CH2Cl2 (1:1) column with a yield of 70 percent. 1H NMR (500 MHz, CDCl3) ppm: 9.28 (m, 1H), 7.81-7.74 (m, 2H), 7.68 (s, 1H), 7.57-7.35 (m, 11H), 1.62 (s, 9H). Analysis for mono-t-BBP. Found: C, 86.19, H, 6.18, N, 7.19. Calculated: C, 86.56, H, 6.25, N, 7.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([O:21]C)=[O:20])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1.[OH-].[Na+].C1COCC1.Cl>CO>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([C:19]([OH:21])=[O:20])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cccc3cccnc23)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn(-c2cccc3cccnc23)nc(C(=O)O)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a suspension of methyl 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylate (5.00 g, 16.1 mmol) in MeOH (64 mL) were added 1 M NaOH aqueous solution (64 mL) and THF (64 mL) at 0° C. The mixture was heated to 80° C. The homogeneous mixture was cooled to 0° C. To the mixture was added 1 M HCl aqueous solution (64 mL) at 0° C. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (3.59 g, 75% yield) as a fresh-colored solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 7.73 (1H, dd, J=8.4, 4.3 Hz), 7.81-7.89 (1H, m), 8.12 (1H, dd, J=7.4, 1.4 Hz), 8.30 (1H, dd, J=8.4, 1.2 Hz), 8.61 (1H, dd, J=8.5, 1.6 Hz), 8.96-9.05 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13](C)C)=[O:11])[CH:3]=1>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: COC(=O)c1cc(N)c(F)c(Cl)n1
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
Isopropyl 4-amino-6-chloro-5-fluoropicolinate (1.35 g, 5.80 mmol) was dissolved in anhydrous CH3OH (50 mL), treated with titanium(IV) isopropoxide (300 mg, 2.2 mmol), and heated at reflux for 4 h. After cooling, the volatiles were removed under vacuum, and the residue was taken up in EtOAc (30 mL). This solution was stirred with H2O (1 mL) for 20 min and then filtered through diatomaceous earth. The filtrate was washed with satd aq NaCl (10 mL), dried (Na2SO4), and evaporated to give the title compound (1.2 g, 97%): mp 180-183° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J=6.0 Hz, 1H), 6.93 (s, 2H), 3.83 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −131.36, −131.42, −135.47, −135.53; EIMS m/z 204.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[C:10]([C:17]([OH:19])=O)=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=3)[C:17](=[O:19])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C(C)C)nc2C(=O)O)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C(=O)c3nn(C(C)C)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Step 41.5). tR: 4.05 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 397 [M+H]+ (LC-MS 2); Rf=0.60 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.47 (m, 6H) 1.90 (s, 3H) 3.34 (s, 3H) 4.54-4.65 (m, 1H) 6.12 (s, 1H) 7.17-7.24 (m, 2H) 7.30-7.39 (m, 3H) 7.69 (d, J=2.7 Hz, 1H) 7.85 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[CH:16]=[CH2:17].[Cl-].[NH4+]>CN(C)C=O.C(OCC)C>[CH2:17]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH:16]=[CH2:15]
Reactant: O=C(O)c1ccc[nH]1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc[nH]1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid (1.5 g, 14 mmol) in N,N-dimethylformamide (50 mL) at 25° C. was added cesium carbonate (4.8 g, 14.7 mmol) and allyl bromide (1.34 mL, 15.4 mmol) and stirred for 16 h. The reaction mixture was treated with saturated aqueous ammonium chloride solution and diethyl ether (20 mL). The layers were separated and the aqueous layers were extracted with diethyl ether (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1H-pyrrole-2-carboxylic acid allyl ester (1.6 g, 10.6 mmol, 76% yield) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.77 (1H, m), 5.35 (1H, dd, J1=10.4 Hz, J2=1.2 Hz), 5.39 (1H, dd, J1=16.8 Hz, J2=1.6 Hz), 6.26 (1H, m), 5.96 (1H, m), 6.94 (2H, m), 9.2 (1H, bs).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Reaction time: 16 h
Yield: 56 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (150 mg, 0.34 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) were taken up in dimethylformamide (3 ml). HATU (195.2 mg, 0.51 mmol) and N,N-diisopropylethylamine (110.4 mg, 0.86 mmol) were added at room temperature and the reaction mixture was stirred for 16 h (monitored by LC-MS). To the reaction, water was added (10 ml) and the mixture was stirred for 5 min. Thereafter, the aqueous mixture was extracted with ethyl acetate (2×15 ml) and the combined extracts were washed with water (3×10 ml), dried and concentrated under reduced pressure. The obtained crude product was purified by normal silica gel column chromatography (100-200 mesh) using 30% ethyl acetate in hexane as mobile phase to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (333) (130 mg, 56%) as a yellow sticky solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16]N1C=NN=C1.CS(C)=O.CC(C)([O-])C.[Li+]>C(O)(=O)C>[NH2:16][C:8]1[C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 4-methyl-3,5-dinitrobenzonitrile (4) (10.5 kg), 4-amino-1,2,4-triazole (17.0 kg) and dimethyl sulfoxide (68.6 kg) is dosed into a mixture of lithium t-butoxide (12.2 kg) and dimethyl sulfoxide (106.6 kg) over about 50 minutes, while maintaining the temperature of each solution at about 20-25° C. After aging at about 20-25° C. for about 2 hours, acetic acid (8.9 kg) is dosed into the reaction mixture at about 20° C. over about 10 minutes. The product is crystallized by dosing water (158 L) into the reaction mixture over about 1.5 hours at about 20° C. The product slurry is cooled to about 10-15° C. and held at this temperature for about 45 minutes. The resultant slurry is filtered, and washed with water (106 L). The wet cake obtained is dried in a vacuum tray dryer at about 50° C. and 30 torr until drying is complete to provide 2-amino-4-methyl-3,5-dinitrobenzonitrile (5) (9.8 kg, 87% Yield) as an orange-brown solid.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[O:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47](O)=[O:48].Cl.CON(OC)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:47]([CH:43]3[CH2:44][CH2:45][CH2:46][O:42]3)=[O:48])[CH2:33][CH2:34]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: O=C(O)C1CCCO1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCNCC1
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)C2CCCO2)CC1
Temperature: 4 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.0 g, 1.90 mmol) and triethylamine (1.35 mL, 9.50 mmol) in chloroform (80 mL) was cooled to 4° C. 2-Tetrahydrofuroic acid (0.243 g, 2.09 mmol) and 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.401 g, 2.09 mmol) were sequentially added, and the reaction was stirred for two hours. The reaction was incomplete as determined by thin layer chromatography (TLC) analysis. The reaction was cooled to 4° C., and 1-hydroxybenzotriazole (0.283 g, 2.09 mmol) was added. The reaction was allowed to warm to ambient temperature, stirred for 16 hours, and then diluted with chloroform (100 mL). The resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×100 mL), water (200 mL), and brine (150 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified by HPFC followed by recrystallization from ethyl acetate to provide 0.68 g of 2-ethoxymethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 191–192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:16])[CH2:14][NH:13][C:12](=[O:15])[NH:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:13]2[CH2:14][C:10]([CH3:16])([CH3:9])[NH:11][C:12]2=[O:15])=[CH:6][CH:7]=1
Reactant: CC1(C)CNC(=O)N1
Reactant: Brc1ccc(I)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CN(c2ccc(Br)nc2)C(=O)N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a suspension of 2-bromo-5-iodopyridine (1.0 g, 3.52 mmol), 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6) (400 mg, 3.52 mmol, 1.0 equiv.), cesium carbonate (1.72 g, 5.28 mmol, 1.5 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (82 mg, 0.141 mmol, 0.04 equiv.) in 10 ml of toluene was added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (Pd2 (dba)3*CHCl3) (73 mg, 0.07 mmol, 0.02 equiv.). The mixture was stirred for 1 hour at 100° C. The mixture was directly loaded on a 50 g silicagel column and was eluted with an heptan:ethyl acetate gradient 100:0 to 0:100 and an ethyl acetate:methanol gradient 100:0 to 80:20. The desired 1-(6-bromo-pyridin-3-yl)-4,4-dimethyl-imidazolidin-2-one (810 mg, 85% yield) was obtained as a light yellow solid, MS: m/e=207.1/272.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:23]1[C:24]([CH3:31])=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][CH2:40][CH2:41][OH:42]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:39][CH2:40][CH2:41][OH:42])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:10])=[O:11])=[CH:4][C:3]=1[C:23]1[C:24]([CH3:31])=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1
Reactant: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCCO)cc1Cl
Temperature: 45 °C
Yield: 60.5 %

Procedure:
To 5-[2-chloro-4-hydroxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile (90 mg, 0.2 mmol) in dry acetonitrile (1.5 mL), was added Cs2CO3 (130 mg, 0.4 mmol), followed by an addition of 3-bromo-1-propanol (36 mg, 0.26 mmol). The mixture was heated at 45° C. for 24 hrs and partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, washed with brine (2×5 mL) and dried over MgSO4. After filtration, the mixture was concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/1) to give 5-[2-chloro-4-(3-hydroxy-propoxy)-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 9-1 as a white solid (62 mg). MS: 511.9 (M+H)+; tR=8.07 min (method 2). NMR (CDCl3), δ, 8.344 (1H, s), 7.634 (1H, s), 7.597 (1H, s), 7.235 (1H, s), 7.164-7.184 (2H, m), 7.008-7.060 (1H, m), 6.871 (1H, d, J=7.8 Hz), 4.287 (2H, t), 3.769-3.805 (4H, m), 2.775-2.786 (2H, m), 2.064 (3H, s), 1.850-1.905 (2H, m), 1.959-1.995 (2H, m), 1.653 (2H, s).
Reaction SMILES: [NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([CH:53]([C:58]([CH:69]([O:74][SiH](C)C)C(C)(C)C)([CH:60]([O:65][SiH](C)C)C(C)(C)C)[NH-:59])[O:54][SiH](C)C)(C)(C)C>C(O)(=O)C.O>[NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:54][CH2:53][C:58]([CH2:69][OH:74])([CH2:60][OH:65])[NH-:59]
Reactant: C[SiH](C)OC(C(C)(C)C)C([NH-])(C(O[SiH](C)C)C(C)(C)C)C(O[SiH](C)C)C(C)(C)C
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Solvent: CC(=O)O
Solvent: O
Product: [NH-]C(CO)(CO)CO

Procedure:
39 mg of Z-Phe-Phe-Leu-Val-tris(tert.-butyldimethylsilyloxymethyl)-methyl amide (Example 62) are stirred for 3 hours in 3 ml of acetic acid/H2O 2:1. After evaporating off the sovent and medium-pressure chromatography (LOBAR® prefabricated column, size B, 40-60 μm, system B8), the title compound is obtained in the form of a colourless powder. Rf (B8)=0.36.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:9]([O:11]N1C(=O)CCC1=O)=O)[CH:2]=[CH2:3].Cl.[CH3:27][NH:28][OH:29]>ClCCl>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:8]([C:9](=[O:11])[N:28]([OH:29])[CH3:27])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Reactant: CNO
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
Starting material (8(c)) was prepared as follows. A mixture of 7(b) (2.00 g; see Example 7), N-methylhydroxylamine hydrochloride (1.06 g) triethylamine (1.72 ml) and dichloromethane (60 ml.) was stirred at 5° or 30 minutes. It was then allowed to warm to ambient temperature and stirred for a further 16 hours. The reaction mixture was then poured directly onto a flash column eluting with ethyl acetate/hexane (50:50) to give 3-(N-methyl-hydroxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(a)) as a cream solid (1.43 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[S:34][N:33]=[CH:32][N:31]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCC[C@@H]2c2ccccc2)cc1F
Yield: 0.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (220 mg, 374 mmol) prepared in Example 6a, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (155 mg, 95%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]O)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH2:34]([NH:38][CH3:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][N:38]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH3:39])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: CNCC(C)C
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CN(C)CC(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as a light brown solid (141 mg, 61%).