Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:42][CH3:43])[C:34]=1[F:44])[C:3]1[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[C:61]([N:65]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[N:60][CH:59]=[CH:58]2>CC#N.C(Cl)Cl.CCOC(C)=O>[C:8]1([C:6]2[N:7]=[C:3]([CH:2]([NH:54][C:55]3[CH:56]=[C:57]4[C:62](=[CH:63][CH:64]=3)[C:61]([N:65]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C:73]([O:75][C:76]([CH3:77])([CH3:78])[CH3:79])=[O:74])=[N:60][CH:59]=[CH:58]4)[C:33]3[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:42][CH3:43])[C:34]=3[F:44])[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCOc1cc(CC)cc(C(Cl)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.8 %

Procedure:
To a solution of the chloro intermediate (1.80 mmol) in 5 mL CH3CN and 2 mL CH2Cl2 at rt, was added DIEA (0.627 mL, 3.6 mmol), di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (712 mg, 1.98 mmol). The mixture was stirred at rt for 19 h, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc/hexanes gradient) to afford 1.41 g of Intermediate 448.4 as an off-white solid. LCMS (2 min gradient) RT=2.32 min, 682.29 (M+(H−Tr)+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-methoxy-5-pyrimidine-boronic acid in General Procedure A. Purification on silica and ether trituration gave 246. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 4.12 (3H, s), 7.32 (1H, br. s), 9.48 (2H, s). MS (ESI+): MH+ 506.2 (100%)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH3:2].[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[N:8]=[CH:9][C:10]([NH:13][C:28]([C:26]2[N:27]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:24][C:25]=2[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOCCN(C)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCOCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 67.1 %

Procedure:
(2-Ethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (150 mg, 0.666 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (171 mg, 0.666 mmol), Et3N (464 uL, 3.3 mmol) and BOP (309 mg. 0.699 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-ethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a yellow solid (194 mg). ES-MS calcd for C21H21F3N4O3 (m/e) 434.42, obsd 435.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(3 g, 13.4 mmol) in THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (13.5 ml, 13.5 mmol, Aldrich). The resulting orange solution was stirred at ambient temperature under nitrogen for 30 min. To the reaction was added a solution of 1-(bromomethyl)-4-chloro-2-(trifluoromethyl)benzene (3.7 g, 13.5 mmol, Fluorochem) in THF (5 ml). The resulting orange solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (125 ml) and aqueous sodium bicarbonate (75 ml). The phases were separated and the organic phase washed with aqueous sodium bicarbonate (50 ml). The combined aqueous phases were washed with ethyl acetate (75 ml). The organic phases were combined, dried, filtered and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 100 g×2 using a 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (2.83 g); LCMS: (System 4) MH+=416, tRET=3.14 min.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:22]1([C:20]([N:17]2[CH2:18][CH2:19][C@@H:15]([CH2:14][C:13]3[N:9]([C:5]4[CH:6]=[C:7]([CH3:8])[C:2]([C:35]5[CH:44]=[C:43]6[C:38]([CH:39]=[CH:40][CH:41]=[N:42]6)=[CH:37][CH:36]=5)=[CH:3][C:4]=4[F:26])[C:10](=[O:25])[NH:11][N:12]=3)[CH2:16]2)=[O:21])[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: Cc1cc(-n2c(C[C@@H]3CCN(C(=O)C4CC4)C3)n[nH]c2=O)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(-n2c(C[C@@H]3CCN(C(=O)C4CC4)C3)n[nH]c2=O)c(F)cc1-c1ccc2cccnc2c1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
To a microwave vial were added 4-(4-bromo-2-fluoro-5-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.160 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.20 mmol), cesium carbonate (0.39 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0062 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated for 15 h at 100° C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, and concentrated to afford the title product as a white solid (52 mg, 84%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:24]1[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (500 mg) was mixed with dioxane (15 ml), and methyl 5-bromopyridine-2-carboxylate (399 mg), palladium acetate (35 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (147 mg), and potassium phosphate (981 mg) were added thereto, followed by stirring at 100° C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain methyl 5-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridine-2-carboxylate (310 mg).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][OH:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:28][CH2:27][C:24]1([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirring solution consisting of (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (compound E, Example 1) (18.2 g) in tetrahydrofuran (200 mL) at room temperature under a nitrogen atmosphere is added a 1.0 M solution consisting of tetrabutylammonium fluoride in tetrahydrofuran (45.3 mL.) The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with hexanes-ethyl acetate (1:1 v/v) afforded 12 g of a residue. The residue is dissolved in warm methanol. Addition of hexanes caused precipitation of a solid that is collected by filtration (11 g.) The solid is redissolved in warm methanol and again is precipitated with hexanes to afford a new crop of solid product (8.1 g); melting point 210-211° C.; MS (APCI+) m/z 308 (MH+.)
Reaction SMILES: [OH-].[NH4+].O.C1(S([O-])(=O)=O)C=CC=CC=1.[NH:14]=[C:15]1[NH2+:19][C:18](=[NH:20])[CH2:17][S:16]1.[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=N)[NH:23]1>CO>[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[C:17]2[S:16][C:15](=[NH:14])[NH:19][C:18]2=[NH:20])[NH:23]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(=N)[NH2+]1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C1NC(=N)C(=C2NC(=N)c3ccccc32)S1

Procedure:
To a stirred solution of 61 parts of 28 percent aqueous ammonium hydroxide solution and 2500 parts of water under an atmosphere of nitrogen there was simultaneously added at ambient temperature during a period of ninety minutes 273 parts of 2,4-diiminothiazolidinium benzenesulfonate and 853 parts of a 17.1 percent by weight methyl alcohol solution of 1,3-diiminoisoindoline. A yellow solid separated during the addition. Stirring was continued at room temperature for approximately sixteen hours after the additions were complete and the thick yellow reaction slurry was then filtered. The product collected on the funnel was washed copiously with distilled water and finally dried at 50° C in vacuo to obtain 233 parts of 1-imino-3-(2,4-diimino-5-thiazolidinylidene)isoindoline as a yellow solid melting at 252°-263° C (dec).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:15][C:13]1[CH:14]=[CH:2][C:3]2[NH:4][C:5]3[C:10]([C:11]=2[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Fc1ccc(Nc2ccccc2)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: Fc1ccc2[nH]c3ccccc3c2c1
Yield: 34.1 %

Procedure:
A mixture of 23.4 g (106 mmole) 2-chloro-4-fluoro-N-phenylaniline, 0.27 g (5.3 mmole) of palladium(II)acetate, 2.1 g (10.6 mmole) of tri-tert-Butylphosphine, 50.8 g (530 mmole) of sodium tert-butoxide and 1,4-dioxane 150 ml were refluxed under nitrogen for about overnight. Allowed to cool and then quenched by addition of HCl (aq) (2 M, 140 ml). The organic phase was extracted with dichloromethane and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-ethyl acetate) to give product 6.7 g (35%)
Reaction SMILES: C([O:4][C@:5]1(O)[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[C@:6]1([C:19](C)([CH3:21])[CH3:20])C(C)C)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O:32]1CC[CH2:34][CH2:33]1>>[F:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C@@H:6]([CH:19]([CH3:20])[CH3:21])[C@@:5]([CH2:34][CH2:33][OH:32])([OH:4])[CH2:14][CH2:13]2
Reactant: CC(=O)O[C@]1(O)CCc2cc(F)ccc2[C@@]1(C(C)C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)[C@@H]1c2ccc(F)cc2CC[C@@]1(O)CCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 82.2 g (0.255 mol) of [1R,2R]-(-)-t-butyl-6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl acetate in 500 ml of abs. tetrahydrofuran was added within 30 minutes to a cooled suspension of 19.4 g (0.51 mol) of lithium aluminum hydride in 500 ml of abs. tetrahydrofuran in such a manner that the temperature did not exceed 30°. After stirring for a further 30 minutes the reaction mixture was cooled to 5° and carefully treated in succession with 30 ml of ice-water, 30 ml of 1N sodium hydroxide solution and 90 ml of ice-water. Thereafter, the mixture was stirred for a further 60 minutes and filtered, and the filtrate evaporated under reduced pressure. The oily residue was dissolved in a 20:1 mixture of chloroform and methanol and chromatographed on 900 g of silica gel, yielding [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethanol as white crystals, m.p. 78°-80°; [α]D20 =-83.1° (c=1, methanol).
Reaction SMILES: [OH-].[K+].[N+:3]([CH2:6][CH3:7])([O-:5])=[O:4].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl>O.CS(C)=O>[N+:19]([C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[CH:6]([N+:3]([O-:5])=[O:4])[CH3:7])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 19 °C

Procedure:
Potassium hydroxide pellets (8.42 g; 0.150 mol; 3 equiv) were crushed and placed in a 250-mL 3-necked flask equipped with a thermometer and an addition funnel. Reagent-grade DMSO (25 mL) was added and the mixture vigorously stirred. An ice-water cooling bath was then applied and when the temperature of the reaction mixture had cooled to 19° C. a mixture of nitroethane (3.95 mL; 0.055 mol; 1.1 equiv) and 4-chloro-3-nitrobenzotrifluoride (1; 7.46 mL; 0.050 mol) were added to the reaction mixture (addition funnel) over 15 min at a rate such that a temperature of 15-20° C. was maintained. After the addition was complete, the reaction mixture was cooled to 15° C. and the ice bath was replaced with a cool water bath (10-15° C.) and the reaction mixture was allowed to warm to 20° C. over 2 h, at which time GC analysis indicated >98% consumption of 1 and a ratio of 2:3 of 98:2. Toluene (25 mL) was added and the reaction mixture was cooled in ice-water. Aqueous hydrochloric acid (6 N; 15 mL; 0.090 mol) was added dropwise with vigorous stirring at such a rate that the temperature remained below 20° C. Water (40 mL) was then added and the layers were allowed to separate for 10 min. The bottom aqueous layer was decanted, and the top organic solution was used directly for the next step. An aliquot of this organic solution was analyzed by 1H NMR and indicated a 96:4 ratio of 2:3. 2: 1H NMR (CDCl3) δ 8.349 (s, 1H); 7.976 (dd, 1 H, J=1.71, 8.24 Hz); 7.788 (d, 1H, J=8.24 Hz); 6.296 (q, 1H, J=6.96 Hz); 2.036 (d, 3H, J=6.78 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15/min; 280° C., 1 min): tR 10.71 min 3: 1H NMR (CDCl3) δ 10.815 (s, 1H); 8.435 (d, 1H, J=1.77 Hz); 7.830 (dd, 1H, J=2.19, 8.79 Hz); 7.315 (d, 1H, J=8.91 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15°/min; 280° C., 1 min): tR 5.53 min.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29]C(=O)OC(C)(C)C.CN1C(=O)CCC1.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Temperature: 130 °C
Reaction time: 60 h
Yield: 24.3 %

Procedure:
A pressure tube was charged with 6-chloro-4-(6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (230 mg, 752 μmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (242 mg, 1.13 mmol) and NMP (4 mL). The yellow solution was stirred at 130° C. for 2.5 days. After that, the NMP was distilled off using a Kugelrohr apparatus under high vacuum to afford a light brown solid. The crude solid was dissolved in dichloromethane and MeOH and adsorbed on silica gel, then purified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min) to give a light brown solid. The crude product was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The mixture was stirred at room temperature for 4 h. After that, the TFA and the dichloromethane were removed in vacuo, the brown solid obtained dissolved in dichloromethane, adsorbed on silica gel and then purified by flash column (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH over 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-5-methylpyridin-2-ylamino)pyridazine-3-carboxamide (70 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (br. s., 1H), 8.37 (br. s., 1H), 7.92 (s, 1H), 7.61 (br. s., 1H), 7.48 (d, J=8.34 Hz, 1H), 6.71 (d, J=8.08 Hz, 1H), 6.66 (d, J=8.08 Hz, 1H), 3.24 (dt, J=13.39, 6.70 Hz, 1H), 3.08 (d, J=2.53 Hz, 1H), 2.26 (s, 3H), 1.30-1.75 (m, 11H), 1.26 (dd, J=6.70, 1.39 Hz, 6H). LC-MS 384 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCC(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCC(=O)NCCCCn1c(CC)nc2c(N)nc3ccccc3c21
Yield: 62.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with butyryl chloride (0.40 mL, 3.9 mmol) to provide 0.77 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide as a light brown solid, m.p. 147.7-148.8° C. Analysis: Calculated for C20H27N5O.0.4 H2O: % C, 66.60; % H, 7.77; % N, 19.42. Found: % C, 66.84; % H, 7.77; % N, 19.36.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[F:15][C:16]1([F:34])[CH2:21][CH2:20][C:19]([CH2:32][NH2:33])([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[F:34][C:16]1([F:15])[CH2:17][CH2:18][C:19]([CH2:32][NH:33][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=[CH:5][C:6]=2[CH3:12])([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: Cc1ccc(C(F)(F)F)cc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 5-trifluoromethyl-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=481.1, tR (minutes, Method D)=0.86
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2].[OH-].[K+].[Na+].[I-].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>CC(C)=O>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCc1ccc(Oc2ccc(O)cc2F)c(OC)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1ccc(Oc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2F)c(OC)c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenol (0.32 mmol; 85 mg) in dry acetone (3 mL), under argon, were added potassium hydroxide (0.39 mmol; 54 mg), NaI (0.065 mmol; 10 mg) and N-(3-bromopropyl)phtalimide (0.40 mmol; 107 mg). The reaction was stirred 3 days at 50° C. The mixture was concentrated in vacuo, hydrolysed with NH4Cl sat.(5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (75 mg; 0.17 mmol; 51%) was obtained as an oil, after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).