Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:18][C:19]([O:21]CC)=[O:20])=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+:25].Cl>O1CCCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.[Na+:25]
Reactant: CCOC(=O)Cc1oc(-c2ccc(F)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])Cc1oc(-c2ccc(F)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-4-(2-thienyl)-oxazol-5-ylacetate (94 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was added 1N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for one hour. To the reaction mixture was added 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (5 ml), 0.5M sodium methoxide (556 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain sodium 2-(4-fluorophenyl)-4-(2-thienyl)oxazol-5-ylacetate (90 mg) as pale brownish powder.
Reaction SMILES: [Cl-].COC1C=C(OC)NN([N+]2(C)CCOCC2)N=1.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.[F:44][C:45]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:46]=1[NH2:47].O>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:47][C:46]4[C:45]([F:44])=[CH:51][CH:50]=[CH:49][C:48]=4[F:52])=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Reactant: Nc1c(F)cccc1F
Agent: COC1=CC(OC)=NN([N+]2(C)CCOCC2)N1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1c(F)cccc1F
Reaction time: 2 h
Yield: 76.8 %

Procedure:
4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholinium chloride (0.391 g, 1.32 mmol) was added in one go, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.400 g, 1.11 mmol) and 2,6-difluoroaniline (0.171 g, 1.32 mmol) in dimethylformamide (7 ml). The mixture was stirred for 2 hours and then poured into water (30 ml) the resultant solid was filtered to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,6-difluorophenyl)acetamide (0.403 g, 77% yield) as a pale brown solid:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:15])[N:13]=[CH:14][C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:7]=1)(=[O:4])=[O:3].O.O.Cl[Sn]Cl>CCO.C1COCC1>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:15])[N:13]=[CH:14][C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CS(C)(=O)=O)nc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc2c(-c3ccc(N)cc3)cc(CS(C)(=O)=O)nc21

Procedure:
In analogy to GP3, reaction of 1000 mg 6-methanesulfonylmethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 18.1; 2.89 mmol, 1 eq.) with 3.26 g SnCl2.2H2O (14.46 mmol, 5 eq.) in 56 mL 2.5:1 EtOH/THF at reflux for 3 h yielded after standard work-up the crude aniline which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.[OH-].C[N+](C)(C)C.[OH-].[Na+]>CO>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=Cc1ccncc1
Agent: C[N+](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccncc1)c1ccc(F)cc1

Procedure:
The procedure is as in Example 11 starting from 2.9 g of 4-fluoroacetophenone and 3 g of pyridine-4-carbaldehyde, but using a solution of tetramethylammonium hydroxide in methanol instead of the aqueous solution of sodium hydroxide. 1-(4-fluorophenyl) 3-(4-pyridyl) 2-propene-1-one which melts at 157° C. is obtained.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>O>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 175 °C
Reaction time: 0.33 h

Procedure:
In a 22 L flask was placed 3,500 g (20.09 moles) of suberic acid, and the acid melted with heat. The temperature was raised to 175° C., and then 2,040 g (21.92 moles) of aniline was added. The temperature was raised to 190° C. and held at that temperature for 20 minutes. The melt was poured into a Nalgene tank that contained 4,017 g of potassium hydroxide dissolved in 50 L of water. The mixture was stirred for 20 minutes following the addition of the melt. The reaction was repeated at the same scale, and the second melt was poured into the same solution of potassium hydroxide. After the mixture was thoroughly stirred, the stirrer was turned off, and the mixture was allowed to settle. The mixture was then filtered through a pad of Celite (4,200 g) (the product was filtered to remove the neutral by-product (from attack by aniline on both ends of suberic acid). The filtrate contained the salt of the product, and also the salt of unreacted suberic acid. The mixture was allowed to settle because the filtration was very slow, taking several days.). The filtrate was acidified using 5 L of concentrated hydrochloric acid; the mixture was stirred for one hour, and then allowed to settle overnight. The product was collected by filtration, and washed on the funnel with deionized water (4×5 L). The wet filter cake was placed in a 72 L flask with 44 L of deionized water, the mixture heated to 50° C., and the solid isolated by a hot filtration (the desired product was contaminated with suberic acid which is has a much greater solubility in hot water. Several hot triturations were done to remove suberic acid. The product was checked by NMR [D6DMSO] to monitor the removal of suberic acid). The hot trituration was repeated with 44 L of water at 50° C. The product was again isolated by filtration, and rinsed with 4 L of hot water. It was dried over the weekend in a vacuum oven at 65° C. using a Nash pump as the vacuum source (the Nash pump is a liquid ring pump (water) and pulls a vacuum of about 29 inch of mercury. An intermittent argon purge was used to help carry off water); 4,182.8 g of suberanilic acid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43](O)=[O:44])[C:38]2=[O:46])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:29][C:43]([C:39]2[C:38](=[O:46])[N:37]([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=3)[CH:42]=[CH:41][CH:40]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine 30 mg, 0.075 mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in DMF (1.0 mL) at room temperature were added HATU (57 mg, 0.15 mmol, Perseptive Biosystem), and DIEA (0.05 mL, 0.3 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and was then quenched by the addition of 2 mL of methanol. The reaction mixture was purified by preparative HPLC. The desired fractions were combined, concentrated in vacuo, and neutralized to pH 8 with aq. K2HPO4. The title compound (30 mg, 64%) was obtained as a white solid which was collected by filtration and dried under vaccum. 1H NMR (DMSO-d6) δ 12.09 (br s, 1H), 8.58 (dd, 1H, J=7.15, 2.20 Hz, 1H), 8.12 (dd, 1H, J=6.60, 1.65 Hz), 7.98 (s, 1H), 7.95 (d, 2H, J=3.85 Hz), 7.62-7.59 (m, 2H), 7.45-7.40 (m, 4H), 6.72 (t, 1H, J=9.90 Hz), 4.13 (t, 2H, J=5.5 Hz), 2.71 (d, 2H, J=5.5 Hz), 2.60-2.25 (m, 8H), 2.35 (s, 3H), 2.16 (s, 3H); MS(ESI30) m/z 616.40 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCl)(C)(C)C.CCN(C(C)C)C(C)C.[C:34]1([OH:44])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:34]1([O:44][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[O:18])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCOc1ccc(C=O)c2ccccc12
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(C)OCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCOc1ccc(C(=O)Oc2cccc3ccccc23)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of 4-pentyloxy-naphthalene-1-carbaldehyde (121 mg,.0.5 mmol) in CCl4 (2 mL) is treated with t-BuOCl (8.82 M, 170 μL, 1.5 mmol) and stirred at 50° C. for 1 h. After addition of DIEA (0.3 mL, 1.7 mmol) and 1-naphthol (216 mg, 1.5 mmol) the mixture is refluxed for 2 h and distributed between 1M KHCO3 (5 mL) and DCM (2×5 mL). The combined organic phases are dried over Na2SO4 and concentrated. Flash chromatography (cyclohexane/acetone) yields 82 mg (43%) of colourless crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:16]([OH:18])=O)[N:12]=[CH:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:52]1[CH:56]=[CH:55][N:54]=[C:53]1[NH:57][C:58]([C:60]1[C:68]2[NH:67][C:66]([NH2:69])=[N:65][C:64]=2[CH:63]=[CH:62][CH:61]=1)=[O:59]>CN(C=O)C>[NH:54]1[CH:55]=[CH:56][N:52]=[C:53]1[NH:57][C:58]([C:60]1[C:68]2[NH:67][C:66]([NH:69][C:16]([C:11]3[N:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:15]=4)=[O:18])=[N:65][C:64]=2[CH:63]=[CH:62][CH:61]=1)=[O:59]
Reactant: CS(=O)(=O)Nc1ccc2cc(C(=O)O)ncc2c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)Nc3nc4cccc(C(=O)Nc5ncc[nH]5)c4[nH]3)ncc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
To a solution of 30 mg (0.11 mmol) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid in DMF (0.8 mL) was added 60 mg (0.15 mmol) of HBTU and DIEA (0.1 mL). The mixture was stirred for 10 min and then 24 mg (0.1 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) was added. The reaction was heated at 80° C. for 1 h. After usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1 to 8:1) to afford 5 mg (9%) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 491 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7].[C:20]1(=[O:34])[N:24]([CH:25]([CH2:29][CH2:30][CH2:31][CH3:32])C(O)=O)[C:23](=[O:33])[CH:22]=[CH:21]1.CCN(C(C)C)C(C)C.CN([C:47]([O:51]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C>[O:34]=[C:20]1[CH:21]=[CH:22][C:23](=[O:33])[N:24]1[CH2:25][CH2:29][CH2:30][CH2:31][CH2:32][C:47]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])=[O:51]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CCCCC(C(=O)O)N1C(=O)C=CC1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
To a mixture of the amine 74 (200 mg, 0.75 mmol), 39 (190 mg, 0.9 mmol) and DIPEA (0.32 mL, 1.8 mmol) was added HATU (342 mg, 0.9 mmol) and the mixture was allowed to stir at an ambient temperature for 5 h. The mixture was poured into ethyl acetate (100 mL) and washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting residue was subjected to radial chromatography on a 2 mm radial chromatotron plate eluting with dichloromethane followed by an increasing gradient of 1 to 5% methanol in dichloromethane. Two additional purifications, both eluting with a gradient of 1 to 5% methanol in dichloromethane, first on a 2 mm plate and then on a 1 mm plate afforded 113 mg (33%) of 77 as an white solid: 1H-NMR (400 MHz, CDCl3) δ 4.63 (m, 1H), 4.41 (m, 1H), 3.82 (m, 1H), 3.63 (m, 1H), 3.55 (m, 1H), 3.45 (m, 3H), 2.38-1.83 (m, 10H), 1.70-1.50 (m, 5H), 1.45 (m, 9H), 1.35 (m, 2H); MS (ES+) m/z 462.33 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]([N:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16]CC)=O)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O.CCOC(C)=O>[O:16]=[C:14]1[CH2:13][CH2:12][N:11]([C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:10])[CH2:19][C@@H:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCN(CCC(=O)OCC)[C@@H](C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CN([C@@H](C)c2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
A suspension of NaH (2.24 g, 93.4 mmol) in THF (20 mL) was cooled to 0° C. and as solution of (S)-diethyl 3,3′-((1-phenylethyl)azanediyl)dipropanoate (15 g, 46.7 mmol) in THF was then added dropwise. The reaction mixture was allowed to warm to rt and then warmed to 60° C. and heated for 3 h. The mixture was diluted with water and EtOAc and the organic layer was then separated, dried (Na2SO4), filtered and concentrated. The residue was purified by FCC (5-7% EtOAc/hexanes) to give (5)-ethyl 4-oxo-1-((S)-1-phenylethyl)piperidine-3-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 1.98 mmol) in tetrahydrofuran (10 mL) was added azetidine (141 mg, 0.17 mL, 2.48 mmol) and diisopropylethyl amine (307 mg, 0.42 mL, 2.38 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in dichloromethane (50 mL), washed with water (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the organic phases combined and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (40 g, 1% to 5% methanol in dichloromethane) to give 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 90%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.97 (quin, J=6.99 Hz, 2 H) 3.15 (t, J=6.99 Hz, 4 H) 3.59 (s, 2 H) 3.88 (s, 3 H) 6.89 (s, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:15]([O:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>S(Cl)(Cl)=O.C(OCC)C.O>[C:15]([O:19][NH:20][C:9](=[O:11])[CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)ON
Reactant: O=C(O)CCOc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)(C)ONC(=O)CCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of 3-(4-iodophenoxy)propanoic acid (1.00 g, 3.42 mmol) in thionyl chloride (6.0 mL) was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl ether, and concentrated in vacuo. The residue was azeotroped three times with ethyl ether, dried under high vacuum, and taken up in dichloromethane (7 mL) under N2. To the solution was added a solution in dichloromethane of O-tert-butylhydroxylamine (8.60 mmol; prepared by dissolving O-tert-butylhydroxylamine hydrochloride in water, making the free base with aqueous 10% Na2CO3, and extracting the solution with dichloromethane, and drying the organic solution over MgSO4), and the reaction mixture was stirred for two hours. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil which crystallized on standing to give O-tert-butyl 3-(4-iodophenoxy)propanohydroxamic acid (1.22 g, 98%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:19][NH2:20]>O1CCCC1>[CH3:19][NH:20][S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Oc2ccncc2)cc1

Procedure:
A suspension of 35 g of [4-(4-pyridinyloxy) benzenesulfonyl chloride hydrochloride in 800 ml of tetrahydrofuran was added slowly to 163 ml of 2 M methylamine in tetrahydrofuran. An additional 550 ml of tetrahydrofuran was added and the suspension refluxed for 3 hours. The solvent was removed under vacuum and the residue partitioned between CH2Cl2 and H2O. The organic layer was separated, washed with saturated NaHCO3, brine and dried (Na2SO4). The solvent was removed to give 13.11 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide, m.p. 125-127° C. The aqueous layer was neutralized with 1 N NaOH (solid precipitated) and extracted with CH2Cl2. The extract was washed with brine and dried (Na2SO4). The solvent was removed to give an additional 15.9 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide. A 2.80 g (10.6 mmol) portion of the preceding compound was added to a stirred suspension of 0.424 g (10.6 mmol) of sodium hydride (60% in oil) in 20 ml of dry 1-methylpyrrolidinone. The mixture was stirred until gas evolution ceased and 2.8 g (10.0 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate was added followed by the addition of 20 ml of dry 1-methylpyrrolidinone. The mixture was heated at 80-90° C. for 58 hours. The solvent was removed under vacuum and the residue extracted with ethyl acetate (100 ml) and the extract washed with 100 ml of H2O. The extract was stirred with 40 ml of 1 N HCl for 1 hour and the aqueous layer separated and neutralized (pH 6-7) with 1 N NaHCO3. The mixture was extracted with ethyl acetate and the extract washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness and the residue crystallized with ethyl acetate-hexane to give 3.43 g of ethyl 4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as pale yellow crystals, m.p. 117-119° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].ClC1N=NC(N)=C(C)C=1.C([O-])(O)=O.[Na+].[Br:24]Br>CO.CCOC(C)=O>[Br:24][C:4]1[C:3]([CH3:9])=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Cc1cc(N)nnc1Cl
Reactant: BrBr
Agent: Cc1cc(Cl)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(Cl)nnc(N)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of 6-chloro-5-methylpyridazin-3-amine and 3-chloro-5-methylpyridazin-6-amine (1.45 g, 10 mmol) from 1a and NaHCO3 (2.1 g, 25 mmol) were suspended in MeOH (20 mL) and treated with Br2 (0.57 mL, 11 mmol). The mixture was stirred at room temperature for 4 h, then filtered. The filtrate was condensed in vacuo. The resulting residue was resuspended in EtOAc (100 mL) and washed sequentially with sat. aqueous NaHCO3 solution (2×20 mL) and aqueous NaCl solution (1×20 mL). The solution was dried over MgSO4. The solvent was removed in vacuo to give crude 4-bromo-6-chloro-5-methylpyridazin-3-amine (1 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:60])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]3[CH:25]=[C:26]([C:29]4[C:30]([C:53]5[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=5)=[N:31][N:32]([C:34]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)=[CH:16][CH:15]=1.O1CCCC1.N1C=CC=CC=1>O>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:60])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]3[CH:25]=[C:26]([C:29]4[C:30]([C:53]5[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=5)=[N:31][N:32]([C:34]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.014 mL acetic anhydride was added to a solution mixture of 50 mg N1-(3-aminopropyl)-4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}benzamide obtained in Example 43, 0.4 mL tetrahydrofuran and 0.2 mL pyridine under ice-cooling. The mixture was stirred at room temperature for 1 hour, water was added thereto, and the mixture was stirred for 30 minutes. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (acetic acid/methanol) to give 53 mg N1-[3-(acetylamino)propyl]-4-(6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}benzamide. This product was subjected to deprotection of the trityl group in the same manner as in Example 89, to give 27 mg of the title compound (colorless crystals; recrystallization solvent, methanol/diethyl ether).