Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2(C)C)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Temperature: 95 °C
Yield: 55.5 %

Procedure:
In a 10 mL sealed cap glass vial, 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (50 mg, 0.125 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (53.2 mg, 0.250 mmol) were dissolved in ACN (2 mL). N-ethyldiisopropylamine (0.033 mL, 0.188 mmol) was added, the cap was sealed, and the reaction mixture heated at 95° C. for 72 h. The reaction mixture was subsequently purified by preparative HPLC and basified to give the title compound as a light yellow solid (40 mg, 55%). [M+H] calc'd for C29H38ClFN4O5, 578.1. found, 577.4.
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:28].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.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].[Cu]I>[CH2:17]([C:16]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)([C:13]1[CH:14]=[CH:15][C:10]([C:5]#[C:4][C:3]([CH2:6][CH3:7])([OH:8])[CH2:1][CH3:2])=[C:11]([CH3:28])[CH:12]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: C#CC(O)(CC)CC
Reactant: CCC(CC)(c1ccc(O)cc1)c1ccc(Br)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(O)cc2)cc1C)CC
Temperature: 160 °C
Yield: 37 %

Procedure:
3-Ethyl-1-pentyn-3-ol (0.754 mL, 5.85 mmol), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (482 mg, 0.59 mmol) and copper (I) iodide (112 mg, 0.59 mmol) were added to a solution of 4-[1-(4-bromo-3-methyl-phenyl)-1-ethyl-propyl]-phenol (Example 39-(1); 1.95 g, 5.85 mmol) in triethylamine (10 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (0.79 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:32]([CH3:34])[C:30]([CH2:29][NH:28][C:23]([C:21]1[CH:20]=[CH:19][C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:22]=1)=[O:24])=[O:31]
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 24.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (24 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (80 mg), 2-amino-N,N-dimethyl-acetamide (40 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 486.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.57-8.56 (m, 1H), 8.11 (s, 1H), 8.01-8.00 (d, 1H), 7.84-7.82 (m, 1H), 7.63-7.61 (d, 1H), 7.57-7.54 (d, 1H), 7.46-7.44 (m, 1H), 4.43-4.40 (t, 2H), 4.14-4.13 (d, 2H), 3.75-3.72 (t, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 2.87 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[CH2:9][CH2:8][CH:7]([OH:11])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CO>[O:20]1[CH2:19][CH:18]1[CH2:16][O:12][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]2
Reactant: ClCC1CO1
Reactant: Oc1cccc2c1CCC(O)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2c(cccc2OCC2CO2)C1
Reaction time: 8 h

Procedure:
A solution of 2.46 g. (0.015 mole) of 5,6,7,8-tetrahydro-1,6-naphthalenediol and 810 mg. (0.015 mole) of sodium methoxide in 30 ml. of methanol is prepared under nitrogen and the solvent removed in vacuo. The resulting foam is stirred overnight with 20 ml. of dimethylsulfoxide and 1.40 g. (0.015 mole) of epichlorohydrin, poured into 200 ml. of water and extracted with four 125 ml. portions of ether. Drying and solvent removal gives 3.06 g. of oil which is purified by chromatography on silica gel (75 g.). Elution with hexane-chloroform mixtures gives a total of 1.56 g. (49%) of material with one spot on TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 80 °C
Yield: 48.6 %

Procedure:
Palladium(II) acetate (0.393 g, 1.75 mmol) was added to 2,5-dichloro-4-iodopyridine (12 g, 43.81 mmol), 2-amino-N-methylbenzamide (6.58 g, 43.81 mmol), cesium carbonate (28.6 g, 87.63 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.521 g, 2.63 mmol) in dioxane (600 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours, allowed to cool to room temperature and then filtered. The filtrate was evaporated and the residue triturated with CH2Cl2 to leave 2-[(2,5-dichloropyridin-4-yl)amino]-N-methylbenzamide (6.306 g, 48% yield). The CH2Cl2 solution was evaporated and the residue triturated with CH2Cl2 to leave a second crop of 2-[(2,5-dichloropyridin-4-yl)amino]-N-methylbenzamide (1.87 g, 14% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.78 (2H, d), 7.19-7.21 (2H, m), 7.54-7.60 (2H, m), 7.73 (1H, d), 8.28 (1H, s), 8.70 (1H, d), 10.41 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=296.0 and 298.0 and 300.0.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc(OC)cc3nc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -4-methoxyanthranilic acid (13.3 g, 0.051 mol) and POCl3 (125 ml) was refluxed for 3 hours, then was allowed to sit overnight. The volume of POCl3 was reduced, then ice/water, followed by NH4OH was added. A precipitate formed which was collected by filtration and dried in a vacuum oven at 50° C. to afford 11.51 g (87%) of 1-ethyl-4-chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 95°-98° C.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>[Cu]I.CS(C)=O>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][CH:35]=1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Temperature: 130 °C
Reaction time: 4.5 h
Yield: 59 %

Procedure:
Copper(I) iodide (0.507 g) was added to a mixture of picolinic acid (0.328 g), 4-(2-aminopyridin-3-yl)phenol (2.48 g), tripotassium phosphate (8.48 g), 1-iodo-4-methylbenzene (3.19 g) and DMSO (150 mL). The mixture was stirred at 130° C. under nitrogen for 4.5 hr. The insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the mixture was extracted. The extracted organic layer was washed with brine. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (2.17 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.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.CC([O-])(C)C.[Na+]>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].O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: C1COCCN1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), morpholine (0.053 mL, 0.6 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol), and NaOtBu (67.3 mg, 0.7 mmol) in 1,4-dioxane (2.5 mL) was stirred for 2 h at 90° C. under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (148 mg, 66% yield) as off-white crystals: mp 226-228° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.16-3.19 (4H, m), 3.83-3.87 (4H, m), 3.89 (3H, s), 6.31 (1H, t, J=9.0 Hz), 6.45 (1H, dd, J=2.6, 9.0 Hz), 6.58 (1H, dd, J=2.6, 14.7 Hz), 7.26 (1H, d, J=1.9 Hz), 7.33-7.45 (5H, m), 7.74 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 448 [M+H]+. Anal. Calcd for C24H22FN5O3: C, 64.42; H, 4.96; N, 15.65. Found: C, 64.33; H, 4.98; N, 15.59.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:14])([CH3:13])[CH3:12]>CC(=O)OCC>[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]([OH:20])[CH2:21][NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: CCOc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(NC[C@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Yield: 62 %

Procedure:
Starting from 4-ethoxyaniline (3.2 mL; commercial) and tert-butyl-dimethyl-((R)-2-oxiranyl-ethoxy)-silane (5.0 g; prepared according to WO 2007/144423) and following procedure A, the title compound was obtained after CC (EA/Hept 1:1) as a brown oil (5.22 g; 62% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: CCNC1CCCCC1
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(Cc1cc(OC)ccc1N)C1CCCCC1

Procedure:
2-Amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-ethyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to r.t. overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to give 6.5 (80%), m.p. 143–145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](=[O:10])[CH3:9])[CH2:7][CH2:6]1)=[O:4].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1(C2(C)OCCO2)CC1

Procedure:
18.7 g of 4 is dissolved in 500 ml of benzene, 30 ml of ethylene glycol and 1 g of p-toluenesulfonic acid are added and heated under nitrogen in a water separator for 12 hours. After cooling, sodium bicarbonate solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation, whereby 23 g of title compound 5 accumulates as a colorless oil.
Reaction SMILES: CN(C)C=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:28](#[N:31])[CH:29]=[CH2:30].[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](Br)=[CH:36][C:35]=2[N:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([OH:49])([CH3:50])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37]([CH:30]=[CH:29][C:28]#[N:31])=[CH:36][C:35]=2[N:34]=1
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 74.7 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (225 mg, 1.00 mmol), acetonitrile (50 mL), N,N-dimethylformamide (20 mL) triethylamine (8.25 mL, 59.3 mmol), tri-o-tolylphosphine (900 mg, 2.97 mmol), acrylonitrile (770 mg, 21.8 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (7.50 g, 19.8 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 18 hours. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (300 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (4×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 5.2 g of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile as an off-white solid.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH:3]([CH3:5])[CH3:4].Cl.[CH:15]([N:18]([CH2:22][CH2:23]Cl)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:22][N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)COc1ccccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(C)COc1ccccc1OCCN(C(C)C)C(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (3.45 g; 150 mmole), o-isobutoxyphenol (12.45 g; 75 mmole) and diisopropylaminoethylchloride hydrochloride (15.0 g; 75 mmole) in 200 ml of ethanol. Yield 11.2 g (51%) of product, boiling at 111°-113° C under a pressure of 0.001 mm.Hg, nD25 : 1.4920.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[C:19][Si](C)(C)C)[C:15]([CH3:24])=[N:14]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([CH3:24])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl4-trimethylsilylethynylpyrazole (0.82 g) in methanol (15 ml) was added potassium carbonate (0.75 g). After 3 hours at room temperature the reaction mixture was poured into water (100 ml) and extracted with ether (50 ml, ×2). The combined organic layers were washed with brine, dried and evaporated to provide the title compound as a light beige gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=3)=[O:34])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)(C(F)F)COC1
Reaction time: 8 h

Procedure:
To a solution of 325 mg (0.952 mmol) [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester, 212 mg (1.047 mmol) 5-bromo-pyridine-2-carboxylic acid, 168 mg (1.238 mmol) HOAt and 0.34 ml (2.38 mmol) Et3N in 5 ml DCM were added 237 mg (1.24 mmol) EDC.HCl. The mixture was stirred overnight. The mixture was diluted with EtOAc and washed with water, 1N HCl, brine and 5% aqueous NaHCO3. The organic phase was dried with MgSO4.H2O, filtered and purified by chromatography on silica gel (hexane/14-18% EtOAc) to give the desired product as colorless foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:3][CH2:4]4)[CH:10]=[C:11]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a solution of 62B (30.0 mg, 0.052 mmol) in DCM (2 mL) was added DIEA (0.036 mL, 0.206 mmol) and methyl 2-bromoacetate (11.84 mg, 0.077 mmol) and the reaction solution was stirred at 45° C. for 14 h. The solvent was removed under reduced pressure and the residue was treated with TFA (0.238 mL, 3.09 mmol). The reaction mixture was stirred at 65° C. for 1 h, and then concentrated, diluted with MeOH and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain methyl N-(trans-4-((3-((2-fluoro-4-pyridinyl)carbamoyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate (9.6 mg, 0.018 mmol, 34.9% yield).). HPLC Rt=1.528 minutes (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=534.18.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.048 mMol) 2-nitrobenzoyl chloride, 0.015 gm (92%) of the title compound were prepared essentially by the procedure described in Example 7.