Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Cs+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: [Cs+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 15.3 g (86.4 mmol) of 95% cesium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.0%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and 100 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous phase containing a cesium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to a 4% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 7.92 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 76.1%; yield: 76%) and 166 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 2.1%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[CH2:30]=[O:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][OH:31])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Product: OCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.5 mmol, obtained in example 1) in 30-40% aqueous formaldehyde (0.9 mL) was stirred at 130° C. under argon atmosphere for 4 h. The solvent was concentrated and the residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified on chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 140 mg of the title compound in solid form (yield: 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:25][C:26]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:19]([C:15]1[CH:14]=[C:13]([NH:12][C:8]2[C:9]3[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([NH:25][C:26]4[C:31]([C:32]5[CH:37]=[CH:36][N:35]=[CH:34][N:33]=5)=[CH:30][CH:29]=[CH:28][N:27]=4)[C:4]=3[CH:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: Cc1ccc2c(Nc3cccc(C#C[Si](C)(C)C)c3)nccc2c1Nc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cccc(Nc2nccc3c(Nc4ncccc4-c4ccncn4)c(C)ccc23)c1
Temperature: 70 °C

Procedure:
Suspended 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(2-(trimethylsilyl)ethynyl)phenyl)isoquinoline-1,5-diamine (0.110 g, 0.220 mmol) in methanol (2.5 mL) and added potassium carbonate (0.0607 g, 0.439 mmol). Heated to 70° C. in a sealed tube for 90 minutes. The crude mixture was diluted with water and extracted with two portions of EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The resulting yellow solid was recrystallized from MeOH/Et2O and filtered to afford N1-(3-ethynylphenyl)-6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine. MS (M+H)+ 429.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[ClH:22]>CO.[Pt](=O)=O>[ClH:22].[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)c(F)c2)C1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)isonicotinate (2.9 g, 9.69 mmol) was dissolved in methanol and hydrogen chloride (1.25 M in methanol, 11.63 mL, 14.54 mmol) was added. The solvent was evaporated and the residue redissolved in methanol (50 mL), platinum(IV) oxide (0.220 g, 0.97 mmol) was added and the reaction mixture was hydrogenated at 5 bar and room temperature in a Büchi hydrogenator for 2 h. The catalyst was removed by filtration and the solvent was evaporated to yield methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-piperidine-4-carboxylate hydrochloride (3.12 g, 94%). MS m/z 306 (M+H)+
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si](C(C)(C)C)(C)C>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(CCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.26 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 92 mg (0.31 mmol) of (6-bromohexyloxy)-tert-butyldimethylsilane. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off as already described using an HCl solution in dioxane. The product is in the form of the hydrochloride.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:11]([O:15][C:16]([NH:18][CH:19]1[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.494 ml of DMSO was slowly added dropwise to 10 ml of a methylene chloride solution containing 0.526 ml of oxalyl chloride under argon gas atmosphere at −78° C. After 15 minutes from the completion of the addition, 30 ml of a methylene chloride suspension containing trans-4-tert-butoxycarbonylaminocyclohexanol in was added dropwise, and further 30 minutes later, 2.52 ml of triethylamine was added thereto and the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 15 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The resulting residue was suspended in a hexane-isopropyl ether mixed solvent and collected by filtration to obtain 0.903 g of 4-(tert-butoxycarbonylamino)cyclohexanone.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:39]CC)[CH3:38]>>[C:37]([N:21]([CH2:20][C:19]([N:11]1[C@@H:12]2[CH2:18][CH2:17][CH2:16][C@@H:13]2[C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]1=2)=[O:32])[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:39])[CH3:38]
Reactant: O=C(CCc1ccccc1)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: CCOCC
Product: CC(=O)N(CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21)C(=O)CCc1ccccc1
Yield: 76 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-4-((3-phenylpropionamido)acetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 109 in a yield of 76%, m.p. 138°-140° C. (diethyl ether).
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:23][NH:24][C:25](=[O:35])[CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[C:10]1=[O:36])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:33]([O:32][P:27]([CH2:26][C:25]([NH:24][NH:23][C:11]1[C:10](=[O:36])[N:9]([OH:8])[C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)=[O:35])([O:29][CH2:30][CH3:31])=[O:28])[CH3:34]
Reactant: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(O)c1=O)OCC
Yield: 91.3 %

Procedure:
A solution of 1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-7-trifluoromethylquinoxalin-2(1H)-one (5.28 g, 10 mmol) in 500 ml of ethanol was hydrogenated at atmospheric pressure and room temperature for 1 h in the presence of 250 mg of 5% palladium on carbon. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. The residue was triturated with ether and light petroleum to give 4.0 g (91%) of the title compound. M.p. 193°-196° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32])[CH3:21]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:27][C:26]=1[F:32])[CH3:21]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.104 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuiran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) the title compound was obtained (0.14 g, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)=[O:19]>>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: ClCCCCCn1ccc2ccccc21
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(5-chloropentyl)-1H-indole and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 432.3 (M+H)+.
Reaction SMILES: NC1C=C(CCCCCC)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:24][C:25]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:28]=[CH:27][C:26]=1[S:37]([NH:40][C:41]([NH:43][CH:44]([CH3:46])[CH3:45])=S)(=[O:39])=[O:38]>>[CH2:31]([C:29]1[CH:28]=[CH:27][C:26]2[S:37](=[O:39])(=[O:38])[N:40]=[C:41]([NH:43][CH:44]([CH3:46])[CH3:45])[NH:24][C:25]=2[CH:30]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCc1ccc(S(=O)(=O)NC(=S)NC(C)C)c(N)c1
Agent: CC(C)N=C=S
Agent: CCCCCCc1ccc(S(N)(=O)=O)c(N)c1
Product: CCCCCCc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O

Procedure:
Starting from 2-amino-4-hexylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-hexylbenzenesulfonyl)-N′-isopropylthiourea was prepared. The crude product was obtained as an oil and used without purification. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 319-321° C.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[C:14]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][N:12]=[C:11]1[CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(O)(C)C>[CH2:3]([N:10]1[C:14]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][N:12]=[C:11]1[CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:33]([C:34]([NH2:35])=[O:1])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:26][CH2:27]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: N#Cc1cccnc1N1CCC(c2nnc(CN3CCOCC3)n2Cc2ccccc2)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cccnc1N1CCC(c2nnc(CN3CCOCC3)n2Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
Powdered potassium hydroxide (95 mg, 1.68 mmol) was added to a solution of the carbonitrile of example 52 (250 mg, 0.56 mmol) in 2-Methyl-propan-2-ol (10 ml). The mixture was heated at 100° C. for 18 hr before evaporating under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound (220 mg), as a white solid
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[NH:21]1CCNCC1.N1CCCCC1>>[N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5][NH:21][CH2:3][CH2:2]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Reactant: C1CNCCN1
Solvent: C1CCNCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCNCC2)S1

Procedure:
The preparation of the subject compound is carried out essentially as described for the 2-piperidino derivative (Example 28), two equivalents of piperazine replacing the piperidine. The crude project is recrystallized from 2-methoxyethanol to yield the pure compound melting at 240°-241° C. ;cl EXAMPLE 24
Reaction SMILES: CN(C)C=O.ClC1C=CC=C([N+]([O-])=O)C=1S[C:17]1[N:18]([CH2:25][C@:26]([OH:51])([CH3:50])[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)=[O:35])[CH2:30][CH2:29]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CC(C)([O-])C.[Na+].O>C(OCC)(=O)C>[CH3:50][C@@:26]1([CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:49])[F:48])=[CH:42][CH:41]=3)=[O:35])[CH2:32][CH2:33]2)[O:51][C:17]2=[N:21][C:20]([N+:22]([O-:24])=[O:23])=[CH:19][N:18]2[CH2:25]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1c(Cl)cccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To N,N-dimethylformamide (0.9 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred at the same temperature for 30 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5% potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate/methanol=15/15/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate (32 mg, yield: 51%) as pale yellow amorphous product.
Reaction SMILES: N.[CH3:2][O:3][CH2:4][CH2:5][CH:6]([NH:16][C:17]1[C:26]2[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>CO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH:6]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][O:3][CH3:2])[CH:12]=[CH:11][CH:10]=1
Reactant: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CO
Product: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reaction time: 72 h

Procedure:
To a solution of methyl 4-{([3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxylate (1.74 g; 4.40 mmol) in methanol was added methanolic ammonia (7N) (30.00 ml; 7.00 M; 210.00 mmol) and stirred for 3 days. Insoluble material was removed by filtration and concentrated. The crude 4-{[3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxamide (1.5 g) of was used for the next reaction without further purification. To a solution of 4-{[3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxamide (1.5 g) in MeOH (30 mL) was added palladium on active carbon (400 mg) and the mixture was hydrogenated at 40 psi for 4 h. Filtered through a pad of Celite and the solvent was removed. The crude product (1.2 g) was used as such for amide formation. LCMS [352 (M+1)].
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[O:23])[CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:9][CH2:10][C@H:11]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]3[O:23][CH2:26][C:25](=[O:28])[N:24]=3)[CH2:18]2)[C@@H:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)NC(=O)CCl)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of the intermediate from Step C (8.84 g, 12.43 mmol) in THF (600 mL) and DBU (3.75 mL, 24.86 mmol) was heated at 50° C. for 2.5 hr. The volatiles were removed, and the crude material was purified by column chromatography [(6% methanol/EtOAc)/EtOAC 0 to 66% for 2900 mL, then 66% to 80% for 1200 mL] to give the title compound. M++1: 613.60.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([C:27]2[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>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.[Pd].[Pd].C(OCC)(=O)C.O1CCCC1.C(O)(C)(C)C>[CH:14]1([C:12]([NH:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH:17][C:18]4[CH:19]=[C:20]([NH:24][C:25]([C:27]5[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=5)=[O:26])[CH:21]=[CH:22][CH:23]=4)=[N:7][N:6]3[CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: Cc1cc(C(=O)Nc2cccc(N)c2)n(C)n1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1cc(C(=O)Nc2cccc(Nc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Yield: 8.6 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (330 mg, 1.0 mmol), N-(3-aminophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (280 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (46 mg, 0.050 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (48 mg, 0.10 mmol), potassium tert-butoxide (170 mg, 1.5 mmol) and tert-butanol was heated under reflux for 2 days. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (37 mg, 9%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(C)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A mixture of methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (668 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (585 mg, yield 90%), which was then recrystallized from ethanol-hexane. melting point: 139–140° C.