Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1>O>[CH3:21][C:17]1[CH:16]=[C:15]([N:14]([CH2:12][CH3:13])[CH2:22][CH3:23])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1

Procedure:
A mixture of phthalic anhydride (60 g.), N,N-diethyl-m-toluidine (162.8 g.), aluminum chloride (120 g.) and chlorobenzene (360 ml.) was heated (75°-95° C.) during one and one-half hours, then diluted with water (200 ml., then more). More chlorobenzene (200 ml.) was added and the chlorobenzene layer was separated and steam distilled. Addition of sodium hydroxide solution (10%) to a solution of the residue in dilute sulfuric acid (20%, 250 ml.) afforded 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCN(CCCCCCCCCCOC3CCCCO3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: C(CCCCCN1CCNCC1)CCCCOC1CCCCO1
Reaction time: 8 h
Yield: 82 %

Procedure:
A 583 mg (1.40 mmoles) quantity of 1-benzyl-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine was dissolved in 20 ml of ethanol, and 200 mg of 10% palladium-carbon was added thereto and the mixture was shaken at 3 atm. for 8 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated to dryness, giving 375 mg (yield: 82%) of N-[10-(2-tetrahydropyranyloxy)decyl]piperazine. Then, using N-t-butoxycarbonylphenylglycine and N-[10-(2-tetrahydropyranyloxy)decyl]piperazine, 1-(2-amino-2-phenylacetyl)-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine was prepared in the same manner as in Reference Example 1. The obtained product was treated by the same procedure as in Reference Example 3, giving 384 mg (yield: 75%) of 1-(2-amino-2-phenylethyl) -4-[10-(2tetrahydropyranyloxy)decyl]piperazine.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>>[CH3:31][N:30]([CH3:32])[C:28]([CH3:29])=[CH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)=[O:25]
Reactant: CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: COC(C)(OC)N(C)C
Product: CC(=CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)N(C)C

Procedure:
A mixture of 1-[4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-ethanone (2.0 g) and dimethylacetamide dimethylacetal (15 ml) was refluxed in an inert atmosphere for 15 hours and the volatiles were removed at reduced pressure. The crude solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate followed by several volumes of dichloromethane. The combined eluant was concentrated and hexane was gradually added until crystallization occurred. The cooled solution was filtered to recover the title compound (1.03 g) as a crystalline solid, m.p. 183-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)[N:23]=2)=[CH:15][CH:14]=1.C[O-].[Na+]>CN1C(=O)CCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[O:32][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=3[C:9]([OH:10])=[O:8])[N:23]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc2c1C(=O)OC2
Reactant: Oc1cccc(OCc2coc(-c3ccc(F)cc3)n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cccc(OCc3coc(-c4ccc(F)cc4)n3)c2)c1C(=O)O
Temperature: 130 °C

Procedure:
1 g (6.8 mmol) of 7-methylphthalide and 2 g (7.0 mmol) of 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenol are dissolved in NMP. 3.9 ml of methanolic sodium methoxide (30% strength) are added, the methanol is distilled off, and the mixture is heated to 130° C. No formation of 2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenoxymethyl}-6-methyl-benzoic acid is observed. The 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenol decomposes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S:13]([O-:15])=[O:14].[Na+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
8 g of 3,4-difluoronitrobenzene and 1.01 eq of sodium methanesulfinate (95%) was dissolved in 10 ml of DMSO. The solution was stirred at 60° C. for 3 hours. When the reaction was completed, the solution was added to 100 ml of water to form pale yellow solid, followed by filtration and washing with 50 ml of cool water and 30 ml of n-hexane separately to give 8.8 g of the title compound as a pale yellow solid (yield 79%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>[Cu]I.N(CC)CC>[CH3:16][Si:17]([C:20]#[C:21][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:19])[CH3:18]
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a flask containing a mixture of 4-bromobenzophenone (1.31 g, 5.0 mmol). PdCl2 (PPh3)2 (70 mg. 0.10 mmol), and CuI (10 mg, 0.050 mmol) was added Et2NH (50 mL) and trimethylsilyl-acetylene (0.85 mL, 6.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane to afford pale brown crystalline 4-(trimethylsilylethynyl)benzophenone in 93% yield (1.30 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 9 H, CH3) 7.44-7.74 (m 9 H, Ph and C6H4); MS (EI) : m/e 278 (M+ --CH3) To a Et2O solution (100 mL) of 4-(trimethylsilylethynyl)benzophenone (1.39 g, 5.0 mmol) prechilled to -30° C. was slowly added a solution of phenyllithium (3.33 mL, 6.0 mmol, 1.8 M in cyclohexane-ether). The solution was slowly warmed to room temperature and stirred for 4 hours. 1 mL of H2O was added and the solution was stirred for 30 minutes. Additional H2O (>200 mL) was added and the organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was chromatographed using CH2Cl2 /hexane (2:1) as eluent to afford (4-ethynylphenyl)-diphenylmethanol as a pale yellow oil in 81% yield (1.24 g).
Reaction SMILES: [CH:1]1([CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[NH2:17]>>[CH:1]1([C:8]2[C:12]([CH3:13])=[N:17][N:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=3)[C:9]=2[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)C(C(C)=O)C1C=CC=CC=C1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1C1C=CC=CC=C1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-cyclohepta-2,4,6-trien-1-ylpentane-2,4-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (EI) m/z 306 [M]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cnc(N)nc3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 71.1 %

Procedure:
A mixture of 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (285 mg, 1.00 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (440 mg, 1.99 mmol), Pd(PPh3)2Cl2 (70 mg, 0.10 mmol) and sodium carbonate (3.3 mL, 3.3 mmol, 1M aqueous solution) in acetonitrile (7 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was diluted with methanol and DCM and absorbed onto diatomaceous earth. The resulting residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM then SiO2, gradient 0-100% ethyl acetate in cyclohexane) affording 104 as a white solid (245 mg, 71%). LCMS: RT=3.28 min, [M+H]+=345. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.00 (2H, s), 3.97 (2H, s), 3.70 (8H, s), 1.35 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:16])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Yield: 281.9 %

Procedure:
5-Hydroxyanthranilic acid (9.5 g, 62 mmol) was suspended in dioxane (50 mL), bis(trichloromethyl)carbonate (6 g, 20 mmol) was added (slightly exothermic), the suspension was refluxed for 1 h, allowed to cool to rt, the solid was filtered off and washed with dioxane, affording brown crystals (10.1 g, 90%), mp. 236° C. (dec).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9](OC)=[CH:8][C:7]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1.[CH2:17]([OH:19])C>>[CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][CH:9]=[C:10]([O:19][CH3:17])[CH:11]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Reactant: CCO
Product: COc1ccc(N)c(NCC2CC2)c1
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
N-(Cyclopropylmethyl)-4-methoxy-2-nitroaniline (175 g) was dissolved in ethanol (1750 mL) and was added to a 4.0 L Hast ‘C” Shaker can. The mixture was cooled to 10° C. and treated with 3% Pt/0.6% VG/C, deGussa (4.5 g). The vessel was sparged under nitrogen and then sparged three times with hydrogen at a setting of 40 psi and agitated for 2.5 hours. To a pre-washed solka-flok with ethanol, the mixture was filtered through solka-flok through a sintered glass funnel to have about a ½ inch depth of solka-flok. The solka-flok was then washed with 1 L ethanol and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22]([NH:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[O:23])=[CH:17][CH:16]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1)NOC1CCCCO1
Reaction time: 3 h

Procedure:
A solution of (2E)-3-[5-(1,3,4,9-tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]acrylic acid in DCM (2 mL) and DIEA (0.11 mL) was sequentially treated with HOBT (32 mg), EDCI (64 mg) and NH2OTHP (40 mg). After three hours, the solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with EtOAc. (2E)-3-[5-(1,3,4,9-Tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide was obtained as a yellow oil (37 mg), m/e=438 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]12[O:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][N:11]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]3[N:8]([CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[N:9]=[CH:10][C:5]=13)[CH2:12]2
Reactant: CN(C)CCO
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Yield: 100.8 %

Procedure:
To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1 g, 3.8 mmol), 2-(dimethylamino)ethanol (0.57 mL, 5.7 mmol) triphenylphosphine (1.5 g, 5.7 mmol) in THF (25 mL) is added DIAD (1.1 mL, 5.7 mmol) in drops over 5 min. After 2 h the mixture is concentrated in vacuo, diluted with ether and extracted with 1N aq HCl (2×). The aqueous layers are neutralized with NaOH and extracted with CH2Cl2. The organic layers are treated with 4N HCl in dioxane and concentrated in vacuo. The resulting solid was triturated with ether. Material from a reaction conducted with 0.37 g of pyrazolopyrimidine was combined with this material to give 1.29 g of 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylethanamine as a solid. This material (0.5 g, 1.34 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.44 g, 2.0 mmol), aq. Na2CO3 (1.84 mL, 2M), and tetrakis triphenylphosphine palladium (50 mg) in 1:1 toluene:ethanol (10 mL). The reaction mixture was heated in a microwave at 12° C. for 60 min. The reaction was repeated. The combined reaction mixtures were diluted with EtOAc and filtered to give a solid (0.51 g). The aq. Phase was washed with EtOAc and the combined organic layers concentrated in vacuo. Trituration of the residue gave a solid (0.28 g). The precipitates were combined to give 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-(dimethylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a solid (0.79 g). A solution of this material (550 mg, 1.4 mmol) and triethylamine (1.05 mL) in dichloromethane was treated with triphosgene (208 mg, 0.7 mmol). After 30 min one eleventh of the solution was treated with excess methylamine (2N in THF). Reverse phase HPLC gave the title compound (39 mg) MS m/s=451.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cc2)CC1
Yield: 17 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (17% yield). M.p. (foam), LCMS: m/z=499.43 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.36-2.52 (m, 4H), 3.26-3.33 (m, 2H), 3.52-3.56 (m, 2H), 3.52-3.86 (m, 4H), 4.53 (s, 2H), 5.00 (bs, 1H), 6.97-7.04 (m, 1H), 7.10 (s, 1H), 7.11-7.17 (m, 1H), 7.44 (dd, J=8.4 Hz, 1.8 Hz, 2H), 7.52 (dd, J=8.3 Hz, 1.8 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:56])[C@H:34]1[C@H:38]2[CH2:39][CH2:40][C@@H:35]1[C@H:36]([O:41][C:42](=[O:55])[C:43]([OH:54])([C:49]1[S:50][CH:51]=[CH:52][CH:53]=1)[C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)[CH2:37]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:56][N:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[O:23])[C@H:34]1[C@H:38]2[CH2:39][CH2:40][C@@H:35]1[C@H:36]([O:41][C:42](=[O:55])[C:43]([OH:54])([C:49]1[S:50][CH:51]=[CH:52][CH:53]=1)[C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)[CH2:37]2
Reactant: CN(CCCCCCCCCO)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCCCCCCC=O)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 25 °C

Procedure:
Dess-Martin periodinane (450 mg, 1.06 mmol) was added to a solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-[(9-hydroxy-nonyl)-methyl-amino]-bicyclo[2.2.1]hept-2-yl ester (370 mg, 0.732 mmol) in dry DCM (3 mL) at 0° C., and the reaction mixture allowed to warm to RT. After 1 h at RT the reaction mixture was treated with satd NaHCO3 (aq) and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The residue was triturated with ether, and the solids removed by filtration. The filtrate was concentrated to afford an orange/brown viscous oil and used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=S)[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10]([NH:25][CH2:23][CH3:24])=[N:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccc(Cl)cc1
Solvent: O
Product: CCNc1nc(=O)n(Cc2ccc(Cl)cc2)c2nc(C(C)C)[nH]c12

Procedure:
5.02 g of 3-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine and 60 ml of 70% ethylamine in water was heated in a 450 ml reactor to 150° C.: the pressure rose to 270 psi. After 20 hours the reaction mixture was cooled, filtered and evaporated to dryness. The residue was taken up in water, acidified with 2N HCl to pH 2, and neutralized with 2N NaOH to pH 7. The solid was collected, washed, redissolved in a mixture of 20 ml of methanol, 20 ml of THF and 100 ml of 2N NaOH, treated with 0.5 g of charcoal and filtered. Methanol and THF were removed in vacuo, and the solution neutralized to pH 7 with 5N HCl. The amorphous solid was collected, washed and dried to give the crude product (5.70 g). Recrystallization from methanol gave the title compound (4.42 g) as an off-white solid mp 187-196° C.;
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[C:26]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:2]=1[C:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (140 mg; 0.379 mmol) in tetrahydrofuran (0.5 mL) at −78° C. was added dropwise n-butyllithium (0.4 mL; 0.64 mmol; 1.6M in hexanes). The reaction was stirred at −78° C. for 15 minutes. Cyclohexanone (0.8 mL; 7.7 mmol) was added stirred at −78° C. for 10 minutes. The reaction was then stirred at room temperature for 15 minutes. The reaction was quenched with 2 drops of water. It was diluted with ethyl acetate and filtered through a column containing silica gel and sodium sulfate. The crude was then purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-40% ethyl acetate in heptane) to give 112 mg (76%) as a liquid. MS (ES+): Calc: 388.5, Found: 433.2 (M+HCO2−) 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.51 (d, J=8.30 Hz, 1H), 7.45 (d, J=8.30 Hz, 1H), 5.05 (s, 2H), 3.92 (s, 1H), 1.94-1.73 (m, 6H), 1.68-1.6 (m, 2H), 1.31 (m, 2H), 0.93 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH:29]=O>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc5ccccc5[nH]4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-2-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([C:3]1[CH:43]=[CH:42][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([C:34]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[O:35])[CH2:30][CH2:29]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:5][CH:4]=1)#N.[F:44]C1C=CC(C(N=C=S)=O)=CC=1>>[F:44][C:3]1[CH:43]=[CH:42][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@H:28]3[CH2:29][CH2:30][C@@H:31]([C:34]([N:36]4[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]4)=[O:35])[CH2:32][CH2:33]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)N3CCNCC3)CC2)cc1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Product: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)N2CCNCC2)CC1)c1ccc(F)cc1

Procedure:
The title compound was prepared using a method analagous to the preparation of (E)-4-cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide, using 4-fluorobenzoyl isothiocyanate. MS m/z=578.2 [M+H], calc 577.69 for C31H40FN7O3. 1H NMR (CDCl3) δ ppm: 8.35 (dd, J=8.7, 5.7 Hz, 2H), 8.09 (s, 1H), 7.01-7.20 (m, 3H), 4.75-4.96 (m, 1H), 4.50 (t, J=1.0 Hz, 2H), 3.64-3.77 (m, 2H), 3.46-3.59 (m, 2H), 2.80-3.03 (m, 10H), 2.53-2.69 (m, 4H), 2.08-2.19 (m, 2H), 1.72-1.90 (m, 5H), 1.60-1.71 (m, 4H), 1.40-1.55 (m, 2H).