Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].O.[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12](N)=[O:13]>C(O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([OH:1])=[O:13]
Reactant: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(N)=O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)O
Yield: 59.8 %

Procedure:
In an egg-plant type flask were charged 7.66 g of 85% potassium hydroxide, 3 ml of water, 60 ml of ethanol, and 3.0 g of the compound obtained in Step 6, and the mixture was refluxed for 10 hours. Ethanol was removed by distillation under reduced pressure, and 30 ml of water was added to the residue. The mixture was adjusted to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by distillation under reduced pressure to obtain 2.6 g of a crude product. Purification by silica gel column chromatography gave 1.8 g (59.77%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-[4-(4-Acetyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4′-hydroxyacetophenone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.67 (s, 3H), 2.94-3.04 (m, 2H), 4.02-4.10 (m, 2H), 5.00-5.04 (m, 1H), 7.48-7.50 (m, 2H), 8.08-8.10 (m, 1H), 8.32 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=438.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][NH2:26]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:26][CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: CN
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Solvent: CN(C)C=O
Product: CNC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing 1.0 mL of methylamine (2.0 M in tetrahydrofuran, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (29 mg, 0.078, 78%). ESI-MS m/z calc. 371.1. found 372.2 (M+1)+ Retention time 2.33 minutes. 1H NMR (400 MHz, MeOD) (δ 2.66 (s, 3H), 4.23 (s, 2H), 5.09 (s, 1H), 7.13-7.56 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].[H-].[Na+].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[N:17]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:16](=[O:20])[NH:15]2)[C:7]1=[O:21]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)OCN1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12

Procedure:
A solution of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (3.76 g.) in dry N,N-dimethylformamide (50 ml.) was stirred during the addition of sodium hydride (0.50 g.) [50% w/w dispersion in oil]. When the addition was complete, the solution was stirred until effervescence had ceased (about 1 hour). Chloromethyl pivalate (1.55 g.) was then added. The mixture was stirred for 18 hours and then poured into water (200 ml.). The aqueous mixture was carefully acidified by addition of concentrated hydrochloric acid and the precipitated material has extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×100 ml.) and then with brine (1×150 ml.), dried (MgSO4) and evaporated. The oil obtained was dissolved in ethyl acetate (100 ml.) and silica gel (10 g., type 7734 available from E. Merck Darmstadt, West Germany) was added. The mixture was evaporated and the residue was added to the top of a column of silica gel (150 g. Merck type 7734) made up in toluene. Elution with an increasing gradient of ethyl acetate in toluene with analysis by thin layer chromatography (SiO2 :50% ethyl acetate/toluene) of the fractions of eluate and combination and evaporation of those containing the major component (relative flow value: 0.6) gave 1'-(3,4-dichlorobenzyl)-1-pivaloyloxymethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione as a white solid (1.3 g.), m.p. 209°-211° C., after recrystallisation from a mixture of ethyl acetate and 60-80 petrol.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(OCCOc2ccc(C(=O)C(=O)O)cc2)cc1
Yield: 92.4 %

Procedure:
A mixture of 4-[[2-(4-methylphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.68 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.6 g of colorless 4-[[2-(4-methylphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 135-136° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([C:27](OC)=[O:28])=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:27][OH:28])=[N:3]1
Reactant: COC(=O)c1nc(NC(=O)CCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
A suspension of methyl 1-methyl-5-[[1-oxo-4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-carboxylate (1.25 g) and lithium aluminium hydride (1.0 g) in tetrahydrofuran (30 ml) was stirred under nitrogen at room temperature for 5 h, cooled to 0° and quenched with water. The mixture was diluted with ethyl acetate, filtered and the filtrate was evaporated in vacuo. The residue was chromatographed to give an oil, which crystallised on trituration with ether to yield the title compound as a white solid (0.33 g) m.p. 84°-5°, tlc System B,Rf 0.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH:23]1C(C(C)C)CCC(C)C1)([CH:13]1C(C(C)C)CCC(C)C1)[CH2:6][C:5]2=[O:33].C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CC(CC)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:40][CH3:41])[O:8][C:7]([CH3:13])([CH3:23])[CH2:6][C:5]2=[O:33]
Reactant: CC1CCC(C(C)C)C(C2(C3CC(C)CCC3C(C)C)CC(=O)c3cc(O)c(O)cc3O2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reaction time: 3 h
Yield: 85 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.2 g (2 (20 millimoles) of 6,7-dihydroxy-2,2-dimenthyl-4chromanone are dissolved. To the solution 4.1 (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is heated to boiling for 3 hours. The reaction mixture is worked up according to Example 17. Thus 4.0 g of the title compound are obtained, yield 85%. Mp.: 129°-130° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2:17].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[N+:22]([O-:25])([OH:24])=[O:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N+:22]([O-:25])([O-:24])=[O:23].[Ca+2:17].[N+:22]([O-:25])([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ca+2]
Product: O=[N+]([O-])[O-]
Temperature: 20 °C

Procedure:
303.9 g of phosphonitrate solution obtained by attacking 100 g of Morocco phosphate rock with 228 g of 58% nitric acid, having a content of CaO of 16.62% and of P2O5 of 11.83%, were introduced into a crystallizing vessel. The solution was cooled at a rate of cooling of 12° C/hour, and when the temperature of the solution reached 20° C, a temperature rise from 20° to 24° C was recorded. The solution was then further cooled at the same rate of 12° C/hour until it again reached 20° C. At this instant, into the solution were introduced under stirring 95 g of mother solution with washing acid, coming from the second step of another sample subjected to crystallization, which had a content of P2O5 of 14.94%, and CaO 4.28%, cooling being continued at a rate of 30° C/hour until reaching the temperature of -5° C. The crystal suspension was filtered and centrifuged, obtaining thus 210 g of calcium nitrate crystals having a content of CaO of 20% and of P2O5 of 0.51%, a largest size of 350 microns, minimum size of 110 microns and an average size of 200 microns. In this case the liquid: solid ratio had been of about 1:1.1. By centrifuging, an amount of 110 g of mother solution was also obtained, having a content of CaO of 2.61% and of P2O5 17.45%, the rest of the solution being included in the filtered crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:27])[N:3]=1.[F:28][C:29]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:4]1[N:3]=[C:2]([C:35]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([F:28])[CH:36]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: COc1cccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)c1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
A mixture of 4-chloro-6-(2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-2-pyrimidinamine (770 mg, 1.991 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (590 mg, 2.389 mmol), Na2CO3 (464 mg, 4.38 mmol) and Pd(PPh3)4 (138 mg, 0.119 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washing with EtOAc (100 mL), and concentrated to afford the crude title compounde (1.0 g) as a grey oil. This material was combined with another sample of the title compound (100 mg). The combined material was purified by silica gel chromatography, eluting with EtOAc in PE from 50% to 80% to afford the title compound (760 mg) as a brown solid. LC-MS (ES) m/z=472 [M+H]+.
Reaction SMILES: N.[Li].[CH2:3]1[CH2:16][O:15][C:10]23[O:11][CH2:12][CH2:13][O:14][C:5]2([C@:6]2([CH2:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[C:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:4]1.O>O1CCCC1>[CH2:13]1[CH2:12][O:11][C:10]23[O:15][CH2:16][CH2:3][O:4][C:5]2([C@:6]2([CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[C@H:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:14]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1

Procedure:
800 ml of ammonia is condensed at -70° C. and mixed with 1.39 g of lithium. After occurrence of the characteristic blue coloring, 18.6 g (40 mmol) of 17,17-bis-(ethylenedioxy)-11-(4-methoxyphenyl)-5,9(11)-estradiene dissolved in 400 ml of tetrahydrofuran is instilled. After 20 more minutes of stirring, the excess lithium is decomposed by the addition of water, the ammonia evaporates, the reaction mixture is poured on saturated ammonium chloride solution and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After chromatography of the crude product on silica gel with a mixture of ethyl acetate/hexane, 15.2 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estrene and 1.4 g of 17,17-bis-(ethylenedioxy)-11-(4-hydroxyphenyl)-5,9(11) -estradiene* are isolated as white foams.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[N:20]3[C:15]([CH:16]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:19]3)=[C:14]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]=2[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34]C)=[O:33])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].Cl>CO.[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[N:20]3[C:15]([CH:16]=[C:17]([CH:21]([CH3:22])[CH3:23])[CH:18]=[CH:19]3)=[C:14]([C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C:13]=2[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([OH:34])=[O:33])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C(N)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccn2c(C(=O)c3cccc(C(N)=O)c3)c(CC(C)(C)C(=O)O)c(C(=O)C(C)(C)C)c2c1
Temperature: 23 °C
Yield: 18.5 %

Procedure:
A solution of methyl 3-{3-[(3-carbamoylphenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (111 mg, 0.220 mmol) in MeOH (2 mL) and 6M aqueous NaOH (2 mL) is heated at 70° C. for 1 h then cooled to 23° C., acidified to pH=1 with concentrated aqueous HCl, then partitioned between CH2Cl2 and brine. The organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by reverse phase HPLC (35% CH3CN to 95% CH3CN in 0.1% TFA in water) gives the title compound (20 mg, 19%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(4-nitrophenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:33]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:32]4[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)=S)=[CH:4][CH:3]=1.[S]>[Hg]=O.O1CCCC1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:33]2[C:32]3[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=3[N:30]=[C:29]2[NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:17]3[N:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:16]=3)[CH2:23][CH2:24]2)=[CH:36][CH:37]=1
Reactant: Fc1ccc(CNc2ccccc2NC(=S)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)nc3ccccc32)cc1
Yield: 20 %

Procedure:
A mixture of 6 parts of N-{2-[(4-fluorophenylmethyl)amino]phenyl}-N'-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]thiourea, 3.2 parts of mercury (II) oxide, 0.1 parts of sulfur. and 90 parts of tetrahydrofuran is stirred and refluxed for 3 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1.2 parts (20%) of 1-(4-fluorophenylmethyl)-N-[1-{2-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]ethyl}-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 196.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.C(OO)(C)(C)C.[NH4+:23].[OH-]>N.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:23])=[N:13]2)[CH:7]=1
Reactant: [NH4+]
Reactant: CC1(c2cc(Br)ccc2F)COCC(=S)N1
Agent: CC(C)(C)OO
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC1(c2cc(Br)ccc2F)COCC(N)=N1
Temperature: 25 °C

Procedure:
To a suspension of 5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (14.0 g, 46 mmol) in 7N NH3/MeOH (308 ml) was added tBuOOH (72.8 ml of a 70% aq. soln.) and NH4OH (131.6 ml of a 25% aq. soln.). The reaction mixture was stirred over night at rt, quenched with aq. Na2S2O3 soln., concentrated and extracted with EtOAc to give the title compound that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cc(OC)ccc2OC)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl) pyrimidine (100 mg, 0.402 mmol) and 2,5-dimethoxyaniline (62 mg, 0.402 mmol) similar to Example 13 and isolated as a pale white solid (65 mg, 45%). 1H NMR (CDCl3): 8.30 (d, J=3.0 Hz, 1H), 8.26-8.23 (m, 2H), 7.37-7.25 (m, 3H), 6.81 (d, J=9.0 Hz, 1H), 6.73 (s, 1H), 6.55 (dd, J=3.0, 8.7 Hz, 1H), 4.52 (d, J=0.9 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])/[CH2:18][CH2:19][CH2:20][C:21]2[C:26]/1=[CH:25][CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C1\CCCc2ccccc21
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.112 ml, 8.26 mmol) and ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate (1.785 g, 8.26 mmol) in CH2Cl2 (33.3 ml) at 0° C. was added TFA (0.064 ml, 0.826 mmol) dropwise. Removed the ice bath and stirred at room temperature for 4 hours. Dilute with CH2Cl2 and wash twice with saturated NaHCO3. The organics were dried over sodium sulfate, concentrated, and purified on silica gel 20% EtOAc/Hex.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9](=O)[CH2:10][CH3:11]>CC(C)=O>[CH2:10]([C:9]1[S:3][C:2]2=[N:6][CH:5]=[CH:4][N:1]2[CH:8]=1)[CH3:11]
Reactant: CCC(=O)CBr
Reactant: Nc1nccs1
Solvent: CC(C)=O
Product: CCc1cn2ccnc2s1
Yield: 66.1 %

Procedure:
A solution of 3.0 g of 2-aminothiazole and 4.5 g of 1-bromo-2-butanone in 50 ml of acetone is heated under reflux for an hour and the precipitated crystals are collected by filtration. The crystals in 30 ml of aqueous HBr solution (1N) is heated at 80°-90° C. for an hour. After cooling, the reaction mixture is neutralized with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 3.0 g of the title compound as an oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].S(Cl)([Cl:21])(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:21][C:10]1[CH:11]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][C:9]=1[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CCc1ccc(CNC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCc1ccc(CNC(C)=O)cc1Cl

Procedure:
Methyl 3-(4-acetylaminomethylphenyl)propionate (5.00 g, 21.25 mmol) was added to a sulfuryl chloride (85 ml) solution of anhydrous aluminum chloride (14.2 g, 106 mmol) at -25° C. Thereafter, the temperature of the mixture was gradually elevated to 5° C., at which temperature the mixture was subjected to reaction under agitation for 24 hours.