Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19](Cl)=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CCC(=O)N2C
Yield: 64.6 %

Procedure:
A mixture of 0.06 g (0.0002 mole) of 9-benzyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-22), 0.04 g (0.00024 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.056 g of 4-(9-benzyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-22a) as an off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.CC(C)([O-])C.[K+].C([Li])CCC.[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][CH:25]=[C:26]([CH3:27])[C:22]=2[CH:21]=1.[C:30](=[O:32])=[O:31]>CCOCC>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([C:30]([OH:32])=[O:31])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: O=C=O
Reactant: Cc1csc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2ccc(Br)cc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A mixture of diisopropylamine (4.44 g.) and potassium t-butoxide (5.02 g.) in dry ether was cooled to -78° C. under an atmosphere of dry nitrogen and n-butyl lithium (28.4 ml. of 1.55M solution in hexane) was added with stirring over 5 minutes. The mixture was stirred at -78° for 30 minutes and then a solution of 5-bromo-3-methylbenzo[b]thiophene (9.10 g.) in dry ether (25 ml.) was added over 5 minutes. The resulting mixture was stirred at -78° C. for 30 minutes and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water and the ether layer was separated. The aqueous layer was acidified with acetic acid and the solid was filtered off, washed with water and crystallized from acetic acid to give 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid (7.30 g.), m.p. >300°.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>C(OCC)(=O)C.CN(C=O)C>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: O=C1C=CC(=O)N1
Reactant: BrCCCCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C=C(CCCCCBr)C(=O)N1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
12 g (0.124 mole) maleimide were dissolved in 60 ml ethyl acetate and 22.4 g (0.33 mole) distilled furane were added over 10 minutes, whereupon the mixture became slightly warm, and the batch was stirred for 25 hours at room temperature. The precipitate was subsequently filtered off under suction and was dried under vacuum at room temperature. Yield: 10.5 g=51.3% theoretical. The substance was pure as determined by GC and its IR, NMR and mass spectra corresponded to the desired 7-oxabicycloheptene-1,2-dicarboxylic acid imide. 10 g (0.06 mole) of this imide were is dissolved in 300 ml distilled DMF, an amount of KI which covered the tip of a spatula was added, and 8.1 g (0.072 mole) K-tert-butylate were added under N2. After 2 hours 69.6 g (0.303 g) 1,5-dibromopentane in 100 ml DMF were added drop-wise over 7 hours with stirring and at room temperature. The batch was subsequently stirred for 50 hours at room temperature. The DMF solution was filtered from the precipitated KBr and the DMF was substantially removed by distillation in a rotary evaporator under vacuum. The liquid residue was distilled in a microdistillation apparatus under a vacuum of 1×10−3 mbar, whereupon at a boiling temperature of 50-55° C. it was solely the excess 1,5-dibromopentane which distilled over. The temperature of the oil bath was then slowly raised to 140° C. After a preliminary flow of 2.3 g, 5.5 g product distilled over at a boiling temperature of 113° C./3×103 mbar. This product was pure as determined by G C, and its IR, NMR and mass spectra corresponded to the desired 5-bromopentylmaleimide. Yield: 5.5 g=37.4%.
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[NH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][NH:14][C:2]([NH:1][CH:4]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[S:3]
Reactant: NCCO
Reactant: Cc1cccc2c1CCC2N=C=S
Solvent: C1CCOC1
Product: Cc1cccc2c1CCC2NC(=S)NCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
680 mg (3.59 mmol) 1-isothiocyanato-4-methyl-indane is dissolved in 13 ml THF at room temperature under argon. Then 0.21 ml (3.59 mmol) 2-amino-ethanol is added slowly. The reaction mixture is stirred at room temperature overnight. After completion of the reaction as indicated by TLC the solvent is removed under reduced pressure to give the crude product. Subsequent purification by column chromatography on silica gel (CH2Cl2/MeOH 15:1) and stirring in Et2O affords the title compound 1-(2-hydroxy-ethyl)-3-(4-methyl-indan-1-yl)-thiourea as a white powder (Mp 90-93° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=[O:24].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4])=[O:24]
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1Cl)N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-chloro-cinnamic acid (0.1 mmol), EDC·HCl (0.2 mmol), DMAP (0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography with 5% methnol in ethyl acetate to provide the title compound as a solid (29 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C(C#N)=[N:6][CH:7]=1.[OH-].[Na+].N.[C:13]([OH:16])(=[O:15])[CH3:14]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:14]([C:13]([OH:16])=[O:15])=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(Br)cn1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromopyridine-2-carbonitrile (commercially available from Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3 equivalents of sodium hydroxide as a 1.5 M aqueous solution and the resulting solution was allowed to reflux at a temperature of about 85° C. until no further evolution of ammonia gas was detected. The resulting solution was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water, acidified with acetic acid, and allowed to stir for about 16 h at a temperature of about 25° C. to provide a solid precipitate. The solid was collected by vacuum filtration and washed with acetone to provide 5-bromopyridine-2-carboxylic acid (Compound B) as a solid. 5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT, and 1 equivalent of EDCI were dissolved in DMF and combined with about 1.1 equivalents of 4-tert-butylaniline (Compound C; commercially available from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resulting mixture was allowed to stir for about 2 h at about 25° C. The reaction mixture was then diluted with about 80 mL of 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, 80 mL/extraction). The ethyl acetate layers were combined and the ethyl acetate was removed under reduced pressure to provide a solid. The resulting solid was suspended in water and filtered using vacuum filtration to provide Compound D as a solid. Compound D was dissolved in DMF (0.04M) and about 3 equivalents of the zinc bromide Compound F (commercially available from Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh3)4 (commercially available from Sigma-Aldrich) were added to the solution under a nitrogen atmosphere, and the resulting reaction mixture was allowed to stir for about 2 h at a temperature of about 100° C. The solvent was then removed under reduced pressure to provide Pyridylene Compound E35(a). Pyridylene Compound E35(a) was purified using preparative thin-layer chromatography with a 1:1 ethyl acetate:hexane mobile phase to provide purified Pyridylene Compound E35(a) as an off-white solid (yield 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[N+:31]([O-:33])=[O:32])[CH:14]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:22]=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
Into a 100-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3,4-dimethylbenzenamine (2 g, 16.53 mmol, 4.98 equiv) in N,N-dimethylformamide (50 mL), and sodium hydride (660 mg, 16.50 mmol, 4.97 equiv, 60%). The resulting solution was stirred for 1 h at room temperature. To this was added 4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine (1 g, 3.32 mmol, 1.00 equiv). The resulting solution stirred for an additional 1 h at 50-80° C. in an oil bath. The reaction mixture was cooled. The reaction was then quenched with 150 mL of H2O. The resulting solution was extracted with 3×60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×60 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:petroleum ether (1:1). The product was obtained as 500 mg (37%) of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)OCc3ccccc3)C2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCNC2)C1
Yield: 98.8 %

Procedure:
A solution of compound 5b (1.3 g, 3.46 mmol), 10% Pd/C (200 mg) in EtOH (50 mL) was hydrogenated under 40 psi hydrogen pressure in a Parr apparatus for 4.5 h. The reaction was filtered through a pad of diatomaceous earth and the organic solution was concentrated and dried under vacuum to give compound 5c as a thick oil (0.825 g). 1H NMR (300 MHz, CDCl3): δ 4.10 (m, 2H), 3.64-3.55 (m, 3H), 3.23 (m, 1H), 3.05 (m, 1H), 2.97-2.85 (m, 2H), 2.68 (m, 1H), 1.97 (m, 1H), 1.51 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-phenyl)-carbamic acid tert-butyl ester (1 g, 4.8 mmol), benzaldehyde (0.54 ml, 5.3 mmol) and acetic acid (0.41 ml, 7.2 mmol) in dry tetrahydrofuran (30 ml) were stirred at room temperature for 2 hrs. Sodium borohydride (0.172 g, 4.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with ethyl acetate to afford the title compound as an off white solid (1.27 g, 89%) HPLC retention time 6.4 min. Mass spectrum (ES+) m/z 198 (M+H-BOC)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:47][CH2:46][CH:45]([N:41]4[CH2:42][CH2:43][CH2:44][CH:39]([OH:38])[CH2:40]4)[CH2:50][CH2:49]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OC1CCCN(C2CCNCC2)C1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC(O)C2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxy-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H49N6O3Cl2 [(M+H)+] 707.3238, observed 707.3232.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: N#Cc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 5-methoxy-2-phenyl-1H-indole (200 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (dispersed in liquid paraffin, 50% or more, 45 mg) under ice-cooling. This mixture was stirred for 30 minutes at room temperature. Subsequently, 6-chloromethylpyridine-2-carbonitrile (216 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (228 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.55 (2H, s), 6.55-6.65 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 6.91 (1H, dd, J=1.5, 7.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.35-7.55 (5H, m), 7.85-7.95 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH3:27])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)cnc2c1

Procedure:
To a solution of the intermediate from step G (67 mg, 0.12 mmol) in 4 mL of 1:1 THF/MeOH was added sodium hydroxide (5N, 1 mL). After stirring the reaction at room temperature for 1 hour it was concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]3)[C:25]([Cl:49])=[CH:24][N:23]=1>>[Cl:49][C:25]1[C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]([CH3:47])[CH3:48])[CH2:42][CH2:41]3)=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]3)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C(C)C)CC4)c4c3C(=O)N(C)C4)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-N,N-dimethylacetamide (41 mg, 0.15 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (60 mg, 0.1 mmol) in an analogous manner to Example 946 to afford a tan foam (79 mg, 80%). Mp: 78-80° C. LCMS (m/e) 676 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.58 (s, 1H), 8.68 (d, J=9 Hz, 1H), 8.10 (s, 2H), 7.39 (s, 1H), 7.09 (d, J=9 Hz, 1H), 6.68 (s, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.54 (s, 3H), 3.35 (s, 2H), 3.24 (s, 3H), 3.20 (s, 3H), 3.11-2.88 (m, 6H), 2.80-2.65 (m, 8H), 1.82 (m, 1H), 1.12 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=3)[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A mixture of methyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoate (100 mg, 0.18 mmol) and NaOH (100 mg, 2.5 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 50° C. The mixture was concentrated and adjusted to pH=2 with 3M HCl. The precipitate was filtered and the solid was washed with MeOH (1 mL) and dichloromethane (1 mL) to give 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoic acid (24 mg, 25%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.62 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 8.26-8.21 (m, 2H), 8.09 (d, 1H, J=7.5 Hz), 7.75-7.67 (m, 4 h), 7.50 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.10 (d, 1H, J=8.4 Hz), 4.03 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H). LC-MS: [M+H]+, 541, tR=1.548 min, HPLC: 95.24% at 214 nm, 95.03% at 254 nm, tR=7.943 min.
Reaction SMILES: C[O:2][CH:3]([O:28]C)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[O-][Mn](=O)(=O)=O.[K+].O>C(O)(=O)C>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[C:3]([OH:28])=[O:2])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (23.0 g, 0.053 mole) in acetic acid is treated with 54 ml of 2.5N H2 SO4 and heated at 70° C. for 12 hours. A portion of the reaction solution is concentrated, diluted with acetone and treated portionwise, at 25°-38° C., with an aqueous solution of KMnO4 (23.7 g, 0.15 mole). Addition is continued until a persistent pink color is obtained at 27° C. The reaction mixture is filtered to remove MnO2 and the filtrate is concentrated in vacuo to give a residue. Addition of water to the thus-obtained residue precipitates the title compound as a pale yellow solid, 16.6 g. A sample is recrystallized twice from 75% aqueous ethanol to afford a crystalline solid, mp 174°-175.5° C., identified by elemental and NMR analyses.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.Cl[CH2:19][C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:19][C:20]([NH2:22])=[O:21])[CH2:13][CH2:14]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCNCC1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)CN1CCN(c2ccc(Br)cc2[N+](=O)[O-])CC1
Yield: 40.3 %

Procedure:
Using the same reaction conditions as described in step-i of example-82A, 1-(4-bromo-2-nitrophenyl)piperazine hydrochloride (1.2 g 3.69 mmol) was alkylated using 2-chloroacetamide (517 mg, 5.53 mmol) and sodium carbonate (930 mg, 11.07 mmol) in toluene/ethanol (15/15 mL) to get 510 mg (40.3% yield) of the titled compound. MS: m/z=343.0 (M+1).