Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[N:16][N:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>CN(C)C=O.O>[CH3:18][C:17]1[N:13]([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH2:2][O:19][CH2:20][C:21]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]=[N:15][N:16]=1
Reactant: Cc1nnnn1-c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole (30.0 mg, 0.09 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (29.0 mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (2.4 mg, 0.1 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (40% ethyl acetate/hexanes) gave 40 mg (81%). LC/MS (HPLC method 3): tR=3.14 min, 532.24 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>>[OH-:18].[CH3:1][C:2]1[C:15]2[C:10]([N+:9]([CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])=[C:8]3[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=S1(=O)CCCO1
Reactant: Cc1c2ccccc2nc2ccccc12
Product: Cc1c2ccccc2[n+](CCCS(=O)(=O)O)c2ccccc12
Product: [OH-]
Temperature: 125 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
This compound was prepared using a method reported in Adamczyk, M.; Chen, Y. Y.; Mattingly, P. G.; Pan, Y.; Rege, S. J. Org. Chem. 1998, 63, 5636. A mixture of 9-methylacridine (270 mg, 1.4 mmol) and 1,3-propane sultone (1.8 g, 14.8 mmol) was stirred in a pressure vessel for 4 h at 125° C. After cooling down, the mixture was purified by column chromatography (SiO2, solvent gradient from 5:95 MeOH/CH2Cl2 to 15:85 MeOH/CH2Cl2) to obtain a mixture of yellow strongly fluorescent fractions. This mixture was concentrated and heated with 37 mL 1N HCl to reflux for 4.5 h. Upon cooling down overnight, the water was evaporated off and the oily residue was purified by column chromatography (SiO2, gradient from CH2Cl2 to 1:9 CH2Cl2/MeOH) to furnish 9-methyl-10-(3-sulfopropyl)acridinium hydroxide inner salt as a yellow solid (202 mg, 46%). 1H NMR (400 MHz, CD3OD): δ 2.60 (m, 2 H), 3.23 (t, J=6.2 Hz, 2 H), 3.56 (s, 3 H), 5.63 (t, J=8.8 Hz, 2 H), 8.01 (m, 2 H), 8.44 (m, 2 step function. This is in vast contrast to di-4-ANEQPTMA and di-4-ANHTQPTMA, where the exponential time constant exceeds 30 ms, making them unusable for electrophysiological applications.
Reaction SMILES: F[C:2](F)(F)[S:3]([O-])(=O)=O.[Li+].CO[C:12]([O:27][CH3:28])([C:21]1C=CC=CC=1)[C:13](C1C=CC=CC=1)=[O:14].[C:29]1(=O)OC(C)CO1>>[CH2:29]1[O:14][C:13]2[C:12](=[CH:21][S:3][CH:2]=2)[O:27][CH2:28]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC1COC(=O)O1
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: [Li+]
Product: c1scc2c1OCCO2

Procedure:
Polymer Electrolyte: Five grams (g) of propylene carbonate, 5 g of poly(ethylene glycol)diacrylate (Mn=700), 1 g of lithium trifluoromethanesulfonate (“Litrif”), and 17.5 milligrams (mg) of dimethoxyphenylacetophenone (“DMPAP”) were added together and sonicated for 15 minutes until dissolved. The electrolyte is a colorless to light yellow liquid before UV exposure and a transparent gel afterwards. All chemicals were purchased from Sigma-Aldrich and used as received.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH3:45][C:46]1[CH:47]=[C:48]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C:49](=[O:52])[NH:50][N:51]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:56]2[CH2:57][CH2:58][CH:53]([C:48]3[C:49](=[O:52])[NH:50][N:51]=[C:46]([CH3:45])[CH:47]=3)[CH2:54][CH2:55]2)=[O:34])[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CCNCC2)c(=O)[nH]n1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)cnc43)CC2)c(=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Triethylamine (33.0 μL, 0.24 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (33.0 mg, 0.079 mmol) and 4-nitrophenyl chloroformate (16.0 mg, 0.079 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, a solution of 6-methyl-4-piperidin-4-ylpyridazin-3(2H)-one (15.0 mg, 0.079 mmol) in dichloromethane (1 mL) and triethylamine (22 μL, 0.16 mmol) were added and the mixture allowed to warm to ambient temperature. After 4 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (22 mg). MS 565.2306 (M+1).
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C1Nc2ccccc2N2CCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NC[C@@H]1CCCN21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.7 %

Procedure:
A solution of 1.04 g of (3aS)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxalin-4-one prepared in Reference Example 9 in 30 ml of anhydrous tetrahydrofuran was dropwise added, with ice-cooling, to a suspension of 0.53 g of lithium aluminum hydride in 30 ml of anhydrous tetrahydrofuran over 30 minutes. After the dropwise addition, the mixture was refluxed with heating for 2 hours. The reaction solution was ice-cooled, then 100 ml of ethyl acetate was gradually added thereto and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction liquid and the separated insolubles were filtered off through a Celite layer. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography treatment and eluted with chloroform/ethyl acetate (99/1) to give 0.95 g (yield 98.1%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=O)[CH2:5][CH2:4]1.[C:11](O)(=O)C.[NH2:15][C:16](=[NH:38])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=2)=[N:21][CH:22]=1>>[CH3:35][C:29]([CH3:34])([CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[NH:15][C:6]([C:3]4([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]4)=[CH:11][N:38]=3)=[CH:22][N:21]=2)=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Reactant: CC(=O)O
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C4(C(F)(F)F)CC4)[nH]3)cn2)cc1
Yield: 81.7 %

Procedure:
By using 1-(trifluoromethyl)-1-cyclopropanecarboxylic acid (300 mg), and methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate acetate (453 mg), the procedure was carried out in the same manner as in Example 2-1) to obtain methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate (439 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21][I:22]>CC(C)=O>[I-:22].[CH3:1][S+:2]([CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCCCSC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC[S+](C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
In a flask equipped with a stirrer was charged 3.0 g of the crude methyloctadecylsulfide, 2.1 g of methyl iodide and 50 ml of acetone, and the mixture was stirred at room temperature for 24 hours. Precipitated crystals were collected by filtration under reduced pressure and recrystallized from acetone to obtain 3.4 g of the title compound. Melting point: 82.5° C.
Reaction SMILES: [OH-].[Na+].C(N[CH2:7][C:8]1[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)(=O)C.[C:17]([O:21][C:22]([N:24]=[N+]=[N-])=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([NH:24][CH2:7][C:8]1[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: CC(=O)NCc1ccc(CC(=O)O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.3 ml of a 2 N aqueous sodium hydroxide solution is added to a solution of 0.6 g of 2-(5-acetylaminomethyl-2-thienyl)-acetic acid in 5 ml of dioxane. The mixture is stirred for 12 hours at 55°-60° C. and cooled to 25° C., 0.2 ml of tert.-butoxycarbonyl azide is added, the mixture is stirred for 16 hours at room temperature and 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid is isolated in accordance with the process described above.
Reaction SMILES: CC([O:5][C:6]([CH2:8][CH:9]([OH:35])[CH2:10][CH:11]([OH:34])[CH:12]=[CH:13][C:14]1[C:23]([CH:24]2[CH2:26][CH2:25]2)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:7])(C)C.[OH-].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[N:22]=[C:23]([CH:24]3[CH2:26][CH2:25]3)[C:14](/[CH:13]=[CH:12]/[C@@H:11]([OH:34])[CH2:10][C@@H:9]([OH:35])[CH2:8][C:6]([OH:7])=[O:5])=[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:16]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
From pitavastatin tertiary butyl ester: 50 g of pitavastatin tert-butyl ester was taken in 250 ml of methanol and stirred for 10 minutes at 25° C. 6 g of sodium hydroxide is dissolved in 60 ml of water and slowly added to the reaction mixture. Stirred the reaction mixture to 2 hrs at 25°. Distilled off the solvent completely under reduced pressure. To the obtained solid added 50 ml of dichloro methane and stirred for 10 minutes. Cooled the reaction mixture to 0° C. and adjusted the pH to 3.0 with 20% aqueous HCl solution. 60 g of sodium chloride is added to the reaction mixture and stirred for 15 minutes. Raised the temperature to 25° C. and stirred for 30 minutes. Filtered the solid precipitated. Water was added to the solid and stirred for 10 minutes. Filtered the solid and washed with water. Dried the obtained solid to get the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)C[C@H](F)[C@@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D −32.75° (c=0.800, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitrarily.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:22](I)([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[N:18][N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3nn[nH]n3)cc2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
5-(4-Benzyloxyphenyl)-2H-tetrazole (500 mg) was added to a suspension of sodium hydride (96 mg) in dimethylformamide (5 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hour. After addition of isopropyl iodide (405 mg) thereto, the mixture was stirred at 60° C. for 2 hours under heating. The reaction mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (571 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15](=O)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[BH3-][C:21]#[N:22].[Na+]>[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:22][CH3:21])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [BH3-]C#N
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: [Ti+4]
Agent: CN
Agent: [Na+]
Product: CNC(C)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 4.4 %

Procedure:
A mixture of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (247 mg, 0.91 mmol) and methyl amine (455 μL, 2.0 M in THF, 0.91 mmol) was stirred at RT for 2 min. Titanium (IV) isoproxide (336 μL, 1.14 mmol) was then added. The viscous green/yellow solution was stirred at RT for 3 h. NaBH3CN solution (640 μL, 1.0 M in MeOH, 0.64 mmol) was added and the cloudy solution was stirred at RT for 16 h. The solution was quenched with saturated NaCl solution (3 mL), filtered, and washed with MeOH (50 mL). 6M HCl (20 mL) was added and the aqueous phase was washed with Et2O (2×20 mL). The pH of the aqueous phase was adjusted to pH=12 with 3M NaOH and washed with EtOAc (3×30 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated. To a solution of the crude amine in Et2O (3 mL) was added HCl (3 mL, 2.0 M in Et2O). The crude HCl salt was recrystallized from CH3CN (6 mL) at 110° c to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (8 mg) as white crystals. HPLC Rt=8.90 min; 1H NMR (400 mHz, CD3OD) 7.57-7.53 (m, 2H), 7.33-7.31 (m, 1H), 3.15-3.13 (m, 2H), 2.61 (s, 3H), 2.45 (broad d, J=11.73 Hz, 1H), 2.30 (broad d, J=12.46, 1H), 1.59-1.51 (m, 5H), 1.31-1.08 (m, 6H); LC-MS 7.87 min, (M+1) 286 @ 8.10 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(O)CN
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(C)O)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (2RS)-1-amino-2-propanol, the title compound was obtained in 75% purity by HPLC. MS(ESI+): m/z=432.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:37]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[N:37]1([C:42]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][C:10]([C:13]4[CH:18]=[N:17][N:16]5[C:19]([C:22]6[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=6)=[CH:20][N:21]=[C:15]5[CH:14]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCN(C(=O)N6CCCC6)CC5)nc4)cnn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, 1-pyrrolidinecarbonyl chloride (6.84 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at r.t. for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CS(C)=O>O>[CH2:14]([N:21]1[C:7](=[O:9])[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: O=C(O)CNCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(Cc2ccccc2)C(=O)c2cc(Br)ccc2N1
Temperature: 200 °C
Yield: 98.2 %

Procedure:
A mixture of 5-bromoisatoic anhydride (1 g, 4.13 mmol), N-benzylglycine (0.628 g, 4.13 mmol) and DMSO (3 mL) was heated in the microwave at 200° C. for one hour. After cooling, the mixture was diluted with water and the precipitate was filtered off, washed with water and dried, giving 4-benzyl-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.4 g, 98%) as an off-white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([N+:25]([O-])=O)=[CH:7][C:8]([F:24])=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:10]=2)[CH2:3][CH2:2]1.[H][H].Cl.C(O[C:34](=N)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])C>CO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]2[C:8]([F:24])=[CH:7][C:6]3[N:25]=[C:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:4]([CH:1]4[CH2:2][CH2:3]4)[C:5]=3[CH:10]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)c([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Reactant: CCOC(=N)CC(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Yield: 76.8 %

Procedure:
tert-Butyl 4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]-1-piperazinecarboxylate (17.21 g, 45.2 mmol) is dissolved in methanol (500 ml) and hydrogenated with 5 percent Pd/C (500 mg) under hydrogen at normal pressure. The hydrogen uptake amounts to 3.04 l. The palladium/carbon is filtered off under an inert gas and the methanol is distilled off under reduced pressure. The residue is dried in a high vacuum, then dissolved in DMF (150 ml) and treated with ethyl 3-ethoxy-3-iminopropanoate hydrochloride (17.3 g, 88.4 mmol). The solution obtained is heated to 50° for 2 hours. The DMF is distilled off, the residue is dissolved in water and the pH is adjusted to 8.0 with saturated sodium bicarbonate solution. The solution is extracted with ethyl acetate and the organic phase is washed in succession with water, 10 percent sodium chloride solution and then dried over magnesium sulfate. The solution is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent:ethyl acetate). The product is then recrystallized from ethyl acetate/hexane. There are obtained 15.5 g (78%) of ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate with a m.p. of 152°-153°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH3:12].[H][H]>CO.[Ni]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: [H][H]
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: [Ni]
Solvent: CO
Product: CC(N)Cc1ccc(O)cc1

Procedure:
A mixture of 7.00 g (46.6 mmol) 4-hydroxyphenylacetone and 200 mL 7N ammonia in MeOH is charged with 0.70 g Raney nickel. The mixture is stirred in an hydrogen atmosphere (50 psi) at r.t. over night. After complete reaction, the mixture is filtrated, the solvent is removed in vacuo and the crude product is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(F)c(Br)c1Cl
Reaction time: 0.13 h

Procedure:
To a mixture of anhydrous cupric chloride (3.1 g) and 2 -bromo-3,4-difluoro-6-nitroaniline (4.6 g) in anhydrous acetonitrile (30 ml) was added t-butylnitrite (2.8 g) dropwise at 51° to 56° C. during 5 minutes. After stirring for 8 minutes at the same temperature, the reaction mixture was poured into chilled 10% diluted hydrochloric acid (30 ml) and extracted with benzene. The organic layer was washed with diluted hydrochloric acid and with water successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:5) to give the title compound (4.0 g).