Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:38]([C:42]1[N:46]([CH2:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:45]2[CH:54]=[CH:55][C:56]([S:58]([N:61]3[CH:65]=[C:64]([C:66](O)=[O:67])[CH:63]=[N:62]3)(=[O:60])=[O:59])=[CH:57][C:44]=2[N:43]=1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[C:38]([C:42]1[N:46]([CH2:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[C:45]2[CH:54]=[CH:55][C:56]([S:58]([N:61]3[CH:65]=[C:64]([C:66]([NH:4][CH2:1][CH2:2][CH3:3])=[O:67])[CH:63]=[N:62]3)(=[O:60])=[O:59])=[CH:57][C:44]=2[N:43]=1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 53, Step A, using n-propylamine (8 mg, 0.13 mmol), HATU (37 mg, 0.09 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 32 mg (59%); 1H NMR (400 MHz, CD3OD) δ 0.93 (t, J=7.52 Hz, 3 H), 1.43-1.52 (m, 2 H), 1.52-1.62 (m, 4 H), 1.64 (s, 9 H), 2.25-2.37 (m, 1 H), 3.28-3.36 (m, 4 H), 3.91 (dd, J=11.43, 3.22 Hz, 2 H), 4.48 (d, J=7.62 Hz, 2 H), 7.99-8.11 (m, 3 H), 8.39 (d, J=1.37 Hz, 1 H), 8.77 (s, 1 H); MS (ESI) (M+H)+=487.8; Anal. Calcd for C24H33N5O4S+1.7 TFA+1.8H2O: C, 46.10; H, 5.41; N, 9.81. Found: C, 46.15; H, 5.56; N, 9.48.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][C:25](N)=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:32])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(=O)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1C=O.C([BH3-])#[N:45].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][C:25]([C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)=[CH:26][CH:27]=4)[N:22]([NH2:45])[C:21]3=[O:32])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cccs1
Reactant: Nc1ccc2c(=O)n(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3)c(=O)[nH]c2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Nn1c(=O)n(-c2ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc2)c(=O)c2ccc(-c3cccs3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
Compound 5-Chloro-N-[(4-(7-amino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenylamino)carbonyl]thiophene-2-sulfonamide (40 mg, 0.08 mmol) was dissolved in methyl sulfoxide (0.5 mL). To it was added acetic acid (1.0 mL) and thiophene-2-carbaldehyde (18 mg, 0.16 mmol). The mixture was stirred for 15 minutes at room temperature. To it was then added sodium cyanoborohydride (21 mg, 0.32 mmol). The mixture was stirred for 30 minutes and quenched with water (2 mL). The reaction mixture was then directly subjected to preparative HPLC purification to yield the title compound (26 mg, 55%). ES+ MS showed 588 m/z and ES− MS 586 m/z, the correct mass for the product.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[CH2:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[CH2:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
H2O2 (70%, 0.18 mL, ca. 3.6 mmol) was added dropwise to a stirred solution of TFAA (0.51 mL, 3.6 mmol) in DCM (6 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 207 (100 mg, 0.36 mmol) and TFA (0.06 mL, 0.78 mmol) in CHCl3 (6 mL) at 0° C. and the solution stirred at 20° C. for 4.5 h. The solution was cooled to 0° C., made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×10 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-16%) of MeOH/DCM to give 1,4-dioxide 208 (56 mg, 53%) as an orange solid: mp 186-189° C.; 1H NMR δ 8.13 (t, J=1.6 Hz, 1H, H-9), 7.48 (br s, 2H, H-5, NH), 4.81 (t, J=8.3 Hz, 2H, H-7), 3.62 (t, J=6.0 Hz, 2H, CH2N), 3.37 (dt, J=8.3, 1.6 Hz, 2H, H-8), 2.62 (t, J=8.3 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2]; 13C NMR δ 167.2, 149.9, 140.6, 132.0, 117.9, 93.8, 87.9, 73.4, 57.5, 45.2 (2), 38.8, 28.5. HRMS (FAB+) calcd for C13H18N5O3 (MH+) m/z 292.1410, found 292.1409.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])/[CH:27]=[CH:28]/[C:29]#[CH:30]>C(#N)C.C(N(CC)CC)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.[Cu]I>[NH2:25][C:4]1[C:3]([C:30]#[C:29]/[CH:28]=[CH:27]/[CH2:26][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#C/C=C/CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#C/C=C/CNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 45.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl (2E)-2-penten-4-yn-1-ylcarbamate (194 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1.[I-].[Na+].[CH3:36]N(C)C=O>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:28]2[CH2:33][CH2:32][CH2:36][CH2:30][CH2:29]2)=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCCl)o1
Reactant: C1COCCN1
Reactant: CN(C)C=O
Agent: [I-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCN2CCCCC2)o1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a solution of the above prepared 3-chloropropyl 5-(tetradecyloxy)furan-2-carboxylate (0.272 g, 0.68 mmol) in 6 mL of N,N-dimethylformamide was added morpholine (0.535 mL, 6.1 mmol) and sodium iodide (10 mg). The resulting solution was stirred at 55° C. for 36 hrs at which time HPLC analysis of the reaction mixture indicated near complete consumption of the starting material. The solution was diluted with EtOAc (30 mL), brine (10 mL) and water (10 mL) such that both phases were clear solutions. The phases were separated and the organic phase was washed with water (20 mL) and brine (20 mL) and then dried and concentrated. The crude material was purified by flash chromatography eluting with 5-40% EtOAc in hexanes to yield 0.217 g of the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.10 (d, 1H), 5.30 (d, 1H), 4.30 (t, 2H), 4.10 (t, 2H), 3.7 (t, 4H), 2.40-2.50 (m, 6H), 1.90 (p, 2H), 1.76 (p, 2H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).
Reaction SMILES: [OH-].[K+].[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[C:16](=[S:18])=[S:17].[CH3:19]O>>[CH:3]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[S:18])[S:17][CH3:19])[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: S=C=S
Reactant: CC(C)N1CCN(CCCN)CC1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: CSC(=S)NCCCN1CCN(C(C)C)CC1
Reaction time: 3.5 h

Procedure:
To a solution of potassium hydroxide (4.9 g) in methanol (40 ml) was added 3-(4-isopropyl-1-piperazinyl)propylamine (14.7 g) and thereto was added carbon disulfide (6.0 g) under ice cooling over a period of 20 minutes. The resulting mixture was stirred for 3.5 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (40 ml) and washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (11.3 g) with stirring over a period of about 5 minutes. The resulting mixture was stirred for 2 hours under ice-cooling extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then evaporated to give an oil of methyl N-[3-(4-isopropyl-1-piperazinyl)propyl]dithiocarbamate (15.6 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(=O)C)[CH2:22][CH2:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75 %

Procedure:
1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanone was refluxed in 1,4-dioxane (5 mL) and concentrate HCl (2.5 mL) for 2 h. The reaction was then diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, dried (Na2SO4), filtered and concentrated to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (1.03 g, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.48-7.20 (m, 4H) 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33 (m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:23]1([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][CH:12]([C:14]5[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=5[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:25]1
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3ccc(C(=O)NC4CC4)cc3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [4-(cyclopropylcarbamoyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]([C:22]1[CH:27]=[C:26]([N:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[Cl:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:23]1[CH:24]=[CH:25][C:26]([N:28]([CH3:29])[CH3:30])=[CH:27][C:22]=1[N:8]([CH2:7][C:6]([OH:32])=[O:5])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2cc(N(C)C)ccc2Cl)cc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)c2cc(N(C)C)ccc2Cl)cc1OC

Procedure:
To a solution of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-acetic acid tert-butylester (1.160 g) in dry DCM (5.5 mL) were added successively triethylsilane (0.423 mL) and TFA (4.8 mL).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([S:16]([CH3:15])(=[O:18])=[O:17])[CH3:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a stirred solution of (4-methylamino-phenyl)-acetic acid ethyl ester (Preparation 269, 418 mg, 2.16 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (0.25 mL, 3.24 mmol) and the mixture stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a gum in 78% yield, 460 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].[C:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)#[CH:26]>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][C:25]([C:27]5([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]5)=[CH:26][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml: 0.3 ml) was degassed with N2 and Cl2Pd(PPh3)4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45° C. under N2, diluted to 20 ml with saturated NH4Cl and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.11 g, 78%), as pale paste. 1H-NMR (CDCl3) 8.34 (d, 1H, J=1.29 Hz); 8.24 (d, 1H, J=2.13 Hz); 8.08 (t, 1H, J=1.56 Hz); 8.05 (t, 1H, J=1.56 Hz); 7.53 (d, 1H, J=8.67 Hz); 7.03 (d, 1H, J=8.67 Hz); 6.75 (s, 1H); 4.26-4.19 (m, 4H); 4.06 (t, 2H, J=5.49 Hz); 1.94-1.87 (m, 2H); 1.41 (s, 9H); 1.36 (s, 6H); 1.1 (t, 3H, J=7.44 Hz).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:18]=2)[N:12]=[C:13](Cl)[CH:14]=1)C1C=CC=CC=1.C1[CH2:47][O:46][CH2:45]C1.C(N(CC)CC)C.C[OH:56]>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]>[C:32]([O:31][C:30]([NH:29][C:25]1([C:22]2[CH:21]=[CH:20][C:19]([C:17]3[N:18]=[C:10]4[C:9]([OH:8])=[CH:14][C:13]([C:45]([O:46][CH3:47])=[O:56])=[N:12][N:11]4[C:16]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:24][CH:23]=2)[CH2:26][CH2:27][CH2:28]1)=[O:36])([CH3:34])([CH3:33])[CH3:35]
Reactant: C1CCOC1
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(OCc5ccccc5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-17 (0.91 g, 1.48 mmol) in MeOH (20 mL) and THF (2 mL) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.24 g, 0.30 mmol, 0.20 equiv) and triethylamine (0.23 mL, 1.63 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.), heated to 100° C., and stirred at this temperature for 18 h. The resulting solution was concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 6.0 min, 50% hexane/50% EtOAc 6.5 min, gradient to 10% hexane/90% EtOAc 6.0 min, gradient to 100% EtOAc 2.7 min, 100% EtOAc 26.7 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.34 g, 44%):
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.5 g, 1.69 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.19 g, 5.1 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then methoxyacetyl chloride (0.27 g, 2.5 mmol) was added dropwise and the reaction mixture was stirred at RT for 24 hours. After this time, water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 50% hexane, 50% EtOAc) gave the title compound (0.47 g, 76% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].N1[C:31]2[C:22](=[CH:23][CH:24]=[C:25]3[C:30]=2N=CC=C3)C=CC=1>>[C:10]1([N:6]([C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=2)[C:22]2[CH:31]=[CH:30][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Ic1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 180 °C
Reaction time: 12 h
Yield: 161.9 %

Procedure:
To a 500 ml flask, 17.2 g (0.1 mol) of 4-bromoaniline, 50 g (0.24 mol) of iodobenzene, 32 g (0.8 mol) of potassium hydroxide, 0.04 g (0.04 mol, 0.4 eq.) of cuprous chloride and 0.08 g (0.04 mol, 0.4 eq.) of phenanthroline were introduced and stirred for 12 hours at 180° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and the insoluble solid salt was filtered off. The filtrate was extracted with toluene and distilled water two times and then the organic layer was collected. Toluene was removed from the organic layer under reduced pressure to provide an organic compound. The organic compound was purified by column chromatography using n-hexane as an eluent. Then, the product was precipitated with a small amount of ethanol to provide 21 g of diphenylamino 4-bromobenzene (yield 65%). m/z 324 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([NH2:38])[CH:32]=1>>[NH2:38][C:33]1[CH:32]=[C:31]([O:30][CH3:29])[CH:36]=[CH:35][C:34]=1[NH:37][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1ccc(N)c(N)c1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1ccc(NC(=O)c2cccc3cc(Oc4ncnc5cc(OC)c(OC)cc45)ccc23)c(N)c1
Yield: 87 %

Procedure:
The title compound (43.2 mg, 87% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-methoxy-o-phenylenediamine (16.5 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.70 (s, 3H, —OCH3), 4.01 (s, 6H, 2×OCH3), 5.00 (s, 2H, benzene-NH2), 6.23 (dd, J=2.6 and 8.6 Hz, 1H, Ar—H), 6.40 (d, J=2.6 Hz, 1H, Ar—H), 7.22 (d, J=8.6 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.59 (dd, J=2.2 and 9.1 Hz, 1H, Ar—H), 7.62-7.66 (m, 2H, Ar—H), 7.86 (d, J=6.9 Hz, 1H, Ar—H), 7.96 (d, J=2.0 Hz, 1H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.70 (s, 1H, benzene-NH). LC-MS (m/z) 497 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]([OH:20])=O)[CH:14]=[CH:13]2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH:14]=[CH:13]2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc2cccc(Br)c2n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
At 0° C., oxalyl chloride (2.0 M solution in DCM, 2.73 mL, 5.47 mmol) was added to a suspension of 8-bromoquinoline-2-carboxylic acid (Princeton BioMolecular Research, Monmouth Junction, N.J.; 690 mg, 2.74 mmol) in 5 mL of DCM followed by 3 drops of DMF. The heterogeneous mixture was stirred at RT for 1 h, and it became homogeneous. The volatiles were removed in vacuo, and the residual brown solid was dissolved in 10 mL of DCM and cooled with an ice bath. Morpholine (0.29 mL, 3.28 mmol) and Et3N (0.46 mL, 3.28 mmol) were added. The reaction was stirred at RT for 1 h. The mixture was then diluted with 50 mL of DCM, washed sequentially with 5 mL of 0.5 N HCl, 5 mL of water, 5 mL of 0.5 N NaOH and 5 mL of brine. The DCM solution was dried over Na2SO4 and concentrated to give a brown oil. Re-crystallization from ether/hexanes gave (8-bromoquinolin-2-yl)(morpholino)methanone (855 mg, 97% yield) as a tan crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (1H, d, J=8.6 Hz), 8.22 (1H, m), 8.10 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.4 Hz), 7.61 (1H, t, J=7.8 Hz), 3.79 (4H, br.), 3.69 (4H, br). m/z (ESI, +ve) 321/323 (M+H)+.