Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+].[C:53]1([C:72]([OH:74])=[O:73])[C:62]2[C:61]([C:63]([OH:65])=[O:64])=[CH:60][CH:59]=[C:58]([C:66]([OH:68])=[O:67])[C:57]=2[C:56]([C:69]([OH:71])=O)=[CH:55][CH:54]=1.Cl.[Na][Na]>O>[C:58]12[C:66](=[O:68])[O:67][C:69](=[O:71])[C:56]3[C:57]1=[C:62]([C:53]([C:72]([OH:74])=[O:73])=[CH:54][CH:55]=3)[C:61]([C:63]([OH:65])=[O:64])=[CH:60][CH:59]=2
Reactant: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Agent: Cl
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c3c(ccc(C(=O)O)c13)C(=O)OC2=O
Reaction time: 3 h
Yield: 97 %

Procedure:
The suspension, present after the letting down, of the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid (called NTC below) was brought to a pH of 4.8-4.5 with about 150 g of a 31% strength hydrochloric acid at a temperature of 20° to 30° C. The mixture was subsequently stirred at 20° to 30° C. and pH 4.8 to 4.5 for 3 hours, until the disodium salt of NTC, which is sparingly soluble in water, had formed. The solid was then rapidly filtered off with suction. The filter cake was introduced into 1500 g of water. The mixture was heated to a temperature of 70° to 80° C., and a pH of 10 to 10.5 was established at this temperature by slow addition of about 46 g of a 33% strength aqueous sodium hydroxide solution. During this operation, the NTC dissolved as the tetrasodium salt. After addition of about 5 g of active charcoal and about 5 g of kieselguhr, the solid was filtered off hot, with suction, and rinsed with a little water. The clear filtrate was heated to 80° to 100° C. A pH of 0.5 to 1 was then established at 80° to 100° C. by slow addition of about 130 g of a 31% strength hydrochloric acid. The mixture was subsequently stirred at 80° to 100° C. for one hour. The coarsely crystalline product which had precipitated was then filtered off with suction and the filter cake was washed with about 500 g of a 1% strength hydrochloric acid. The product was dried at 100° C. 52 g of naphthalene-1,4,5,8-tetracarboxylic acid 1,8-monoanhydride of 96% purity, corresponding to a yield of 97% of theory, were obtained. The waste water obtained during the filtration was free from halogenohydrocarbons.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12](N1CCOCC1)=[O:13].C([Mg]Cl)(C)(C)C.Br[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:28]=1.C([Li])CCC>C1COCC1>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C:29]2[CH:28]=[C:27]([C:12]([C@@H:3]3[O:4][C@H:5]4[O:6][C:7]([CH3:10])([CH3:11])[O:8][C@H:9]4[C@@H:2]3[OH:1])=[O:13])[CH:32]=[CH:31][C:30]=2[CH3:33])=[CH:40][CH:39]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reactant: Cc1ccc(Br)cc1Cc1ccc(Cl)cc1
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (25.3 g, 92.6 mmol) in THF (200 mL) under nitrogen at 0° C. was added tert-butyl magnesium chloride (1 M in THF, 100 mL, 100 mmol). This solution was stirred at 0° C. for 30 minutes. Meanwhile, a solution of 4-bromo-2-(4-chlorobenzyl)-1-methylbenzene (3, 32.9 g, 111.1 mmol) in THF (330 mL) under nitrogen was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 48 mL, 120 mmol) was added dropwise via syringe and stirred for 10 min. The magnesium alkoxide solution was transferred via cannula into the aryllithium solution at −78° C. The reaction was stirred for 30 min at −78° C., allowed to warm to room temperature and stirred for 60 min, quenched with 500 mL of a 1:1 (v:v) solution of saturated aqueous NH4Cl/brine. The aqueous layer was extracted two times with 300 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was taken up in 100 mL of EtOAc and heated until most of the solids dissolved. 250 mL of hexanes was added and the flask was chilled in an ice bath for two hours. The white precipitate was filtered off and washed with 20% EtOAc/hexane, providing the title compound as a white solid (26.09 g, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (dd, J=7.8, 1.8 Hz, 1 H), 7.76 (d, J=1.5 Hz, 1 H), 7.29 (d, J=8.1 Hz, 1 H), 7.26 (d, J=8.3 Hz, 2 H), 7.05 (d, J=8.3 Hz, 2 H), 6.08 (d, J=3.8 Hz, 1 H), 5.28 (d, J=2.8 Hz, 1 H), 4.59 (d, J=3.5 Hz, 1 H), 4.57 (t, J=3.2 Hz, 1 H), 4.01 (s, 2 H), 3.06 (d, J=4.0 Hz, 1 H), 2.30 (s, 3 H), 1.37 (s, 3 H). MS (ES+) [M+H]+=403.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[CH3:23][C:24]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[C:26]([C:25]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[CH:31][C:24]=1[CH3:23])#[N:27]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)c(C)c3)c2OC)nc1

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (50 mg, 0.135 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (65.8 mg, 0.271 mmol), [1,1′-bis(di-tert-butylphosphino) ferrocene]dichloropalladium(II) (13.86 mg, 0.021 mmol) and sodium bicarbonate (56.9 mg, 0.677 mmol) in dioxane (599 μl) and water (150 μl) was heated at 110° C. in the microwave for 40 minutes. The reaction mixture was filtered through Celite® and concentrated in vacuo to give 6-(4-(4-cyano-3-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH2:35][CH3:36]>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:34]([CH2:35][CH3:36])[CH3:33]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C24H25ClN6O2, 464.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(F)cc1

Procedure:
Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-fluorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br-].[Li+].[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>COCCOC.CN(C)C=O.O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:7]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]2=[O:8])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=c1cccc(Br)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: O=c1cccc(Br)n1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
By referring to the synthetic method of Synthesis, 1974, 707, to a solution of 2,6-dibromopyridine (5.0 g) in tert-butanol (100 ml) was added potassium tert-butoxide (25 g), the solution was stirred overnight at 100° C., then ice was added to the reaction mixture, which was brought to pH 1 with 5N hydrochloric acid, then the solution was stirred overnight at room temperature. The solution was extracted with chloroform, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to provide 6-bromo-1H-pyridin-2-one (2.5 g). By referring to the synthetic method of Tetrahedron Lett., 1995, 36, 8917, to a solution of 6-bromo-1H-pyridin-2-one (1.9 g) in 1,2-dimethoxyethane (27 ml) and N,N-dimethylformamide (3 ml) was added 60% sodium hydride (470 mg) on an ice bath under a nitrogen atomosphere, the solution was stirred for 15 minutes, then lithium bromide (3.85 g) was added thereto followed by stirring for 25 minutes at room temperature, 4-benzyloxybenzyl chloride (5.4 g) was added thereto followed by stirring overnight at 70° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.3 g).
Reaction SMILES: [N:1]1([CH2:6][NH:7][C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([N:7]([CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:28])(=[O:25])=[O:24]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1cc(C)nc(NCn2cncn2)n1
Solvent: CC#N
Product: Cc1cc(C)nc(N(Cn2cncn2)C(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
4 g (0.019 mole) of 2-(1,2,4-triazol-1-ylmethylamino)-4,6-dimethylpyrimidine are suspended in 100 ml of absolute acetonitrile and then 4.3 g (0.019 mole) of 2-chlorophenylsulfonylisocyanate are stirred into the suspension. The batch is stirred for 24 hours at room temperature and the resultant solution is finally concentrated in a rotary evaporator. Crystals of the title compound precipitate and are recrystallised from ethyl acetate, affording 5 g (62% of theory) of the above urea, which melts at 152°-157° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1.[CH3:40][CH2:41][CH2:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([C:43]([OH:47])([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: CCCC(=O)CCC
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCCC(O)(CCC)c1c2cccc(Br)c2nn1C
Temperature: 2.5 °C
Yield: 77.9 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (1.5 g, 7.1 mmol) in 18 mL of THF at −78° C. was added a 2 M solution of lithium diisopropylamide in heptane/ethylbenzene/THF (5.3 mL, 11 mmol). The solution was stirred at 0-5° C. for 10 m, then rechilled to −78° C. To it was added 4-heptanone (1.49 mL, 10.6 mmol), and the solution was stirred overnight, allowing to slowly warm to room temperature. A saturated aqueous NaHCO3 solution (40 mL) was added, and the mixture was extracted with three 30 mL portions of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Column chromatography (0→20% EtOAc/hexanes) afforded 4-(7-bromo-2-methyl-2H-indazol-3-yl)-heptan-4-ol (42; 1.80 g; 78%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47](Br)[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47]([C:6](=[O:8])[CH3:7])[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.39 mL, 1.15 mmol) was added to a mixture of 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (440 mg, 0.77 mmol), prepared as in Example 2, and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.077 mmol) in toluene (5 mL). The reaction mixture was heated at 110° C. for 1 hour then cooled to room temperature. The solid so formed was collected by filtration and washed with toluene, then dried to give 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester. M++1: Calc'd. 534.6, Found 534.2.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1[C:11]2[CH2:19][C:18](=O)[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([CH2:8][NH:9][C:10]1[C:11]2[CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(NCCc2ccccc2)c2c(n1)N(c1ccccc1)C(=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(NCCc2ccccc2)c2c(n1)N(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1M BH3.THF complex in tetrahydrofuran (10.4ml, 9.2mM) was added dropwise, under an atmosphere of argon, to a stirred mixture of 4-(benzylmethylamino)-2-methyl-6-oxo-7-phenyl-5, 6-dihydro-7H-pyrrolo-[2,3-d]-pyrimidine (1.6g, 4.6mM) in dry tetrahydrofuran (105ml). The mixture was stirred at ambient temperature for 24 hours. The mixture was then added to 2M hydrochloric acid (100ml), the pH was adjusted to about pH7 using concentrated sodium hydroxide and then extracted with ethyl acetate (2×200ml). The organic layers were combined, dried and the solvent evaporated. The residue was purified by flash column chromotography on silica (Merck 9385), using a mixture of methylene chloride: hexane: ethyl acetate (10:8:1) as eluant to give 4[N-benzylmethylamino)-2-methyl-7-phenyl-5,6-dihydro-7H-pyrrolo-[2,3-d]-pyrimidine in the form of a pure solid with m.p. 105°-106° C.; microanalysis, found; C, 75.5; H, 6.7; N, 16.8%; C21H22N4.0.2H2 requires C, 75.6; H, 6.9; N, 16.8%. NMR: 2.47(3H,s,pyrimidine-CH3), 3.14(3H,s,N--CH3), 3.21(2H,t,N--CH2 --CH2 --), 3.91(2H,t,N--CH2--CH2--), 4.18(2H,s,N--CH2Ph), 6.99(1H,t,aromatic), 7.23-7.47(7H, complex, aromatic), 7.73(2H,d,aromatic); and a crude solid. The material was combined and used without further purification in the subsequent stage of the synthesis.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[C:27]([F:28])=[C:26](F)[N:25]=[CH:24][N:23]=1>CN(C)C=O>[Cl:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[C:27]=1[F:28]
Reactant: CNC(=O)C(=NOC)c1ccccc1O
Reactant: Fc1ncnc(Oc2ccccc2Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
With cooling, 0.4 g (0.01 mol) of sodium hydride (60%) are added to a mixture of 2 g (0.0096 mol) of 2-(2-hydroxy-phenyl)-2-methoxyimino-N-methyl-acetamide and 2.3 g (0.0095 mol) of 4-(2-chlorophenoxy)-5,6-difluoropyrimidine in 10 ml of dimethylformamide, and the mixture is stirred at 25° C. for 12 hours. The reaction mixture is poured onto water and extracted with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using a mixture of identical volumina of ethyl acetate and cyclohexane. 2.1 g (48.3% of theory) of 2-{2-[6-(2-chlorophenoxy)-5-fluoro-pyrimidine-4-yloxy]-phenyl}-2-methoxyimino-N-methylacetamide are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:10]=1[O:11][CH2:12][C@@H:13]1[O:18][C@@H:17]([O:19][CH:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21]Cl)[CH2:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][CH:20]([O:19][C@H:17]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:12][O:11][C:10]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:9]=3[Cl:8])[O:18]2)[CH2:21][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:26][CH:27]=1
Reactant: ClCC(CCc1ccc(Cl)cc1)O[C@H]1CCC[C@H](COc2ccc(Cl)cc2Cl)O1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CCC(Cn2ccnc2)O[C@H]2CCC[C@H](COc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
A solution of 90 mg of imidazole and 58 mg of 55% sodium hydride in 2 ml of dimethylformamide was stirred at 80° C. for 30 minutes and then left to cool to room temperature. 2 ml of a dimethylformamide solution containing 420 mg of trans-6-(2,4-dichlorophenoxymethyl)-2-[1-chloro-4-(4-chlorophenyl)-2-butoxy]tetrahydropyran and 132 mg of sodium iodide were then added to the mixture and stirring was continued at 90° C. for 4 hours. The mixture was then treated and the product purified essentially as described in Example 34(b)(i), to give 193 mg of the title compound as a colourless oil containing approximately B 1:1 mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[C:17]([CH3:25])[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:12])[F:1])[N:18]=[C:17]([CH3:25])[N:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 38 %

Procedure:
Part A. A solution of 2-trifluoromethylphenylboronic acid (prepared according to the methods described in thee review by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, p. 2457) (1.00 g, 5.27 mmol), 4,6-dichloro-2-methyl-5-nitropyrimidine (0.91 g, 4.39 mmol) and tetrakis(triphenyl-phosphine) palladium (147 mg) in benzene (15 mL) was treated with aq. sodium carbonate solution (6 mL, 1 M). This mixture was heated to reflux for 6 h, then cooled and partitioned between water and ethyl acetate (60 mL each). The organic layer was washed with brine, and the aqueous layers were back-extracted in sequence with more ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 15:85 ethyl acetate-hexane) to afford 4-chloro-2-methyl-5-nitro-6-(2-trifluoromethylphenyl)pyrimidine (0.64 g, 2.01 mmol, 38%) as a waxy solid. Spectral data: RF 0.40 (20:80 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3) 8 7.84-7.81 (1H, m), 7.69-7.53 (2H, m), 7.38-7.35 (1H, m), 2.84 (3H, s). MS (NH3 -CI) m/e 320 (24), 319 (26), 318 (100).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:34]1([NH2:41])[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1>CN1C(=O)CCC1.CO>[NH2:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:41][C:2]2[CH:3]=[C:4]([N:21]([CH:31]3[CH2:33][CH2:32]3)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:35][CH2:36]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1

Procedure:
A solution of 6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (60 mg, 0.129 mmol) and (trans)-cyclohexane-1,4-diamine (147 mg, 1.285 mmol) in NMP (2 mL) was heated in a microwave reactor at 90° C. for 40 min. The reaction mixture was diluted with methanol and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)] to afford 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide.