Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([CH3:34])([CH3:33])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:24])=[O:23])=[C:13]([O:25]CC2C=CC=CC=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([CH3:34])([CH3:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:24])=[O:23])=[C:13]([OH:25])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)NC(=O)OC(C)(C)C

Procedure:
A solution of {(E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-1,1-dimethylallyl}-carbamic acid tert-butyl ester (105 mg, 0.2 mmol) in ethanol (5 mL) is hydrogenated over 10% Pd/C at 1 atm for 18 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure to give the title compound. It is converted to a potassium salt by addition of 1 equivalent of KHCO3. 1H NMR (400 MHz, MeOD) δ ppm 1.17 (s, 6 H) 1.34 (s, 9 H) 1.77-1.87 (m, 2 H) 2.35-2.44 (m, 2 H) 4.20 (s, 2 H) 6.59 (dd, J=8.08, 1.77 Hz, 1 H) 6.65 (d, J=1.77 Hz, 1 H) 7.20 (d, J=8.08 Hz, 1 H) LCMS (method A) retention time=1.32 min, (M−H)−=142
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[C:12]#[CH:13])=[CH:6][CH:5]=1)#[C:2][CH3:3].I[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1>ClCCl.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[C:12]#[C:13][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)#[C:2][CH3:3]
Reactant: Ic1ccc(CCN2CCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(C#CC)cc1
Solvent: CO
Solvent: ClCCl
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(CCN3CCCC3)cc2)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4-prop-1-ynylphenyl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 20 mg (11% of theory); melting point: 198° C.-199° C.; C24H24N2O (M=356.47); Rf value: 0.1 (silica gel, dichloromethane/methanol (10:1))
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.C([Cl:26])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[Cl:26]
Reactant: CC(=O)Cl
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)c1ccccc1F
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccccc2)c2ccccc2F)cc1
Reaction time: 12 h

Procedure:
(2-Fluorophenyl)-(4-fluorophenyl)phenylmethanol (1.47 g, 5.0 mmol) was added to a 20% solution of acetyl chloride in dichloromethane (10 mL) at rt. The resulting solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (2×20 mL) was added to the residue and evaporated to afford crude 2-fluorophenyl-(4-fluorophenyl)phenylchloromethane which was used without purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](O)[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[CH3:1][N:2]1[CH:7]=[C:6]([Cl:25])[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1
Reactant: CN1C=C(O)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1C=C(Cl)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1

Procedure:
Reflux a mixture of 2-methyl-4-hydroxy-8-(3,4-dichlorophenyl)pyrido[2,3-c]pyridazine (3) (3.0 g, 10 mmol) in phosphorous oxychloride (10 mL) for 2 hrs. Cool the reaction mixture, pour onto cracked ice and neutralize the solution with 1N NaOH. Extract the solution with ethyl acetate (2×100 mL) and wash the combined organic layers with brine. Dry the solution (Na2SO4) and evaporate in vacuo to obtain 4.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C(N(CC)C(C)C)(C)C.[CH:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[CH:26]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:2]([CH3:1])[C:3]4[CH:16]=[CH:15][CH:14]=[CH:13][C:4]3=4)=[O:37])=[CH:39][CH:40]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: CN1c2ccccc2CNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1c2ccccc2CN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of 10,11-dihydro-5-methyl-dibenzo[b,e][1,4]diazepine of Step C (0.42 g) in dichloromethane (10 mL) containing N,N-diisopropylethyl amine (0.29 g) was treated with 4-cyclohexylbenzoyl chloride (0.50 g). After stirring overnight at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. Evaporation of all volatiles gave a glassy residue which was triturated with anhydrous diethyl ether to provide the title compound as an off-white crystalline solid (0.66 g), m.p. 111–112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:16]=[C:15](Br)[S:14][C:13]=1[Br:18])[N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5]2.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[Br:18][C:13]1[S:14][C:15]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[CH:16][C:12]=1[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(Br)sc1Br
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1Br
Temperature: 100 °C
Yield: 40.8 %

Procedure:
A mixture of tert-butyl 6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (177.0 mg, 0.3486 mmol), pyridine-4-boronic acid (51.43 mg, 0.4184 mmol) tetrakis(triphenylphosphine)palladium(0) (20.1 mg, 0.0174 mmol) and cesium carbonate (0.341 g, 1.04 mmol) in 1,4-dioxane (6.0 mL, 77 mmol) and water (2.0 mL, 110 mmol) was degassed and heated at 100° C. for 1 h. The mixture was extracted with EtOAc. The organic layer was separated and washed with water. The organic layer was dried and evaporated to leave a residue which was purified by chromatography to afford tert-butyl 1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid (72 mg, 41%). LCMS AA ES+ 505.1, 507.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].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>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1ccc(-c2ccccc2Br)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Yield: 93.4 %

Procedure:
Under nitrogen, 200 mg of Pd(PPh3)4 was added to a stirred solution of 500 mg (2.0 mmol) of 1-bromo-2-(4-fluorophenyl)benzene (Step 1) and 500 mg (3.0 mmol) of 4-methylthiophenylboronic acid (Step 2) in 7 mL of toluene, 7 mL of ethanol and 7 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (2:98) as the eluent gave 550 mg of 1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]benzene as a semi-solid: NMR (CDCl3) δ 2.46 (s, 3H), 6.92 (t, J=8 Hz, 2H), 7.02-7.14 (m, 6H), 7.37-7.42 (m, 4H). MS (EI): m/e (rel intensity) 294 (100), 279 (39), 277 (56), 246 (74), 227 (40), 190 (43), 190 (38), 140 (44).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Li]CCCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:19]
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccccn1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 2-ethynyl-pyridine (309 mg, 3 mmol) in THF (6 mL) was added BuLi (1.6 M in hexane, 1.88 mL, 3 mmol) dropwise at −75° C. and the reaction mixture was stirred at −75° C. for 30 min, then ethyl chloroformate (286 μL, 3 mmol) was added dropwise at −75° C. and the reaction mixture was stirred at −75° C. for 1 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (349 mg, 66%) as a brown solid. MS: m/e=176.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1>[CH3:8][S:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])=[O:10]
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 61.3 %

Procedure:
A mechanically stirred solution of aniline (139.7 g, 1.5 mole) in pyridine (2 liters), under N2 is cooled in an icebath. Methanesulfonyl chloride (171.8 g, 1.5 mole) is added dropwise to this solution while the temperature is maintained at 15°-20° C., which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at ambient temperature. By TLC on silica gel (2.5% MeOH:CH2Cl2) the reaction is complete after 21/2 hours. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material. This material is filtered and washed several times with water. The filtered material is dissolved in CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is dissolved in hot ethyl acetate, treated with Darco (decolorizing carbon) and crystallized to yield four crops of methanesulfonanilide 157.37 g, 19.27 g, 26.55 g, 5.07 g which had a mp: 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with 4-chloro-benzaldehyde (1.91 g, 13.6 mmol) (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.34 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield: 3.3 g, 100%).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[C:11]3[NH:12][C:13](=O)[C:14]4[C:19]([C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:18][N:17]=[CH:16][CH:15]=4)[NH:4][CH:5]=1.P(Cl)(Cl)([Cl:23])=O>C(#N)C>[Cl:23][C:13]1[C:14]2[C:19](=[CH:18][N:17]=[CH:16][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[C:11]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(-c3nnc[nH]3)cccc2c2cnccc12
Solvent: CC#N
Product: Clc1nc2c(-c3nnc[nH]3)cccc2c2cnccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, 7-(4H-1,2,4-triazol-3-yl)benzo[c][2,6]naphthyridin-5(6H)-one (1.8 g, 6.84 mmol) was mixed with Phosphorus oxychloride (3.2 ml) in acetonitrile (20 ml). The mixture was stirred overnight at 100° C. The volatiles were removed in vacuo. The resulting solid was suspended in CH2Cl2 and a little bit of MeOH. After filtration and drying, crude 5-chloro-7-(4H-1,2,4-triazol-3-yl)benzo[c][2,6]naphthyridine (2.04 g) was isolated as a greenish solid. LCMS (ES) m/z 282 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 19.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid (150 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 methylene chloride/methanol) afforded 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (37 mg, 19.3%) as a white solid: mp 164-167° C.; EI-HRMS m/e calcd for C22H27N3OS (M+) 381.1874, found 381.1879.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([S:71][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(Br)cc(SCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1,3-Dibromo-5-tert-butylbenzene (2.89 g, 10 mmol) in dioxane (160 mL) was stirred under Ar. Then DIPEA (3.09 mL, 16 mmol), Xantphos (0.28 g, 0.48 mmol) and Pd2(dba)3 (0.24 g, 0.24 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.94 mL, 8 mmol) was slowly added and the reaction was stirred for 6 h, quenched by the addition of H2O (15 mL) and extracted with EA (3×). The combined organic layers were washed with water, dried over Na2SO4, filtered, evaporated and purified by CC to afford compound P21a (1.7 g, 72%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[N:18]=[CH:19][C:20]([C:22]5[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=5)[C:25](O)=[O:26])=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.O>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:20]2[CH:19]=[N:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)[CH:23]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid (Ex. 52) (1 eq, 0.127 mmol, 50 mg), 3-dimethylamino-1-propylamine (3.0 eq, 0.38 mmol, 0.049 ml) and triethylamine (1.30 eq, 0.165, 0.023 ml) are dissolved in DCM (2 ml) and BOP (1.30 eq, 0.165 mmol, 73 mg) is added and the reaction mixture is stirred at room temperature for 20 h. At the completion of this time water and EtOAc are added. The organic phase is separated and the aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford N-(3-dimethylamino-propyl)-3-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzamide as a light yellow solid; [M+H]+=477
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][C:32]1[C:27]2[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: NCCO
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NCCO)ncnc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 2-aminoethanol to obtain the title compound (see Table 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Nc1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 2-aminopyrimidine (10 g, 105 mmol) in DMF (100 mL) cooled to 5° C. was added 60% sodium hydride in mineral oil (5.47 g, 137 mmol) and the resulting mixture was stirred one hour with cooling. 1-fluoro-2-nitrobenzene (14.83 g, 105 mmol) in DMF (30 mL) was added dropwise over a 20 minute period to the cooled, stirring solution. The solution was allowed to warm slowly to ambient temperature and stirred 3 h. The product was precipitated with the addition of water (300 mL), separated by filtration, and dried to give the title compound (13.39 g, 61.9 mmol) as an orange solid: 1H NMR (Acetone-d6, 400 MHz): 10.34 (br s, 1H), 9.00 (d, 1H, J=8.6 Hz), 8.60 (d, 2H, J=4.8 Hz), 8.23 (d, 1H, J=8.4 Hz), 7.74 (t, 1H), 7.17 (t, 1H), 7.06 (t, 1H); TLC (EtOAc/Hexanes (3:17)): Rf =0.27.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH2:17].NC(N)=S>CC(C)=O>[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH:17][C:11]([NH2:12])=[S:10]
Reactant: N#C[S-]
Reactant: Nc1c(Br)cccc1Br
Agent: NC(N)=S
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1c(Br)cccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 4.6 ml. of benzoyl chloride in 10 ml. of acetone was added over a period of 5 minutes to a solution of 3.32 g. of ammonium thiocyanate in 60 ml. of dry acetone at reflux. The resulting solution was refluxed for 10 minutes and a solution of 10.0 g. of 2,6-dibromoaniline in 40 ml. of acetone was added over a period of 10 minutes. After 15 minutes at reflux, the reaction mixture was poured onto 300 ml. of water and filtered. The resulting solid was suspended in 30 ml. of 10% sodium hydroxide and boiled for 10 minutes. The clear solution was acidified, neutralized to pH 8 with ammonia and filtered, giving 12.0 g. (97%) of 1-(2,6-dibromophenyl(thiourea, m.p. 186°-189°. Recrystallization from aqueous methanol gave the analytical sample, m.p. 192°-193°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(O)C(N)(CO)CO>ClCCCl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 4-fluoro-benzenesulfonyl chloride (53 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 6.9 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH2:11](B1OC(C)(C)C(C)(C)O1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH2:11]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cncc(Br)c1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cncc(Cc2ccccc2)c1
Yield: 37.2 %

Procedure:
To a solution of 3-bromo-5-nitropyridine (LXXVII) (295 mg, 1.45 mmol) in dioxane (14 mL) was added 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (LXXVIII) (420 μL, 1.89 mmol), PdCl2(dppf)2, (120 mg, 0.15 mmol) and 2M aqueous K3PO4 (2.2 mL, 4.36 mmol). The reaction was microwaved at 90° C. for 2 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane 6:94 EtOAc:hexane) to give 3-benzyl-5-nitropyridine (LXXIX) as brown oil (117 mg, 0.54 mmol, 37% yield). 1H NMR (DMSO-d6) δ ppm 4.16 (s, 2H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 4H), 8.45-8.46 (m, 1H), 8.93 (d, J=2 Hz, 1H), 9.21 (d, J=3 Hz, 1H); ESIMS found for C12H10N2O2 m/z 215 (M+H).