Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:18])[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)=[O:5])C.[OH-].[Na+]>CCO>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[O:9][C:8]([CH3:18])=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(C)oc1-c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid ethyl ester (0.56 mmol), EtOH (0.63 mL) and aq. NaOH solution (2.0 M, 0.63 mL) is stirred for 2 h at RT and washed once with ether. The aq. layer is made acidic by addition of conc HCl and extracted twice with ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired acid as a pure yellow solid. LC-MS (basic): tR=0.49 min; [M−H]−=220.3.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[OH2:14]>O1CCCC1>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:14])[CH:5]=[CH:6]1
Reactant: O=C1NC2C=CC1C2
Reactant: O
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 35 °C
Yield: 0.6 %

Procedure:
A solution of (−)-2-azabicyclo [2.2.1] hept-5-en-3one (97.45 g, 0.8929 mol, Enzymatix Ltd.) in tetrahydrofuran (500 mL) was filtered and warmed to 35° C. A solution of methanesulfonic acid (63.7 mL, 0.9817 mol) in water (24.1 mL, 1.34 mol) was added over the course of 1.5 hours such that the ensuing exotherm did not exceed 45° C. The resulting slurry was heated at 60° C. for three hours, then allowed to coot to room temperature over the course of 15 hours. The slurry was filtered and the cake washed twice with anhydrous tetrahydrofuran (200 mL). An analytical sample of the wet cake was removed and dried to give the title compound as a white solid (1.264 g); m.p. 167-169.2° C.; 1H-NMR (DMSO-d6) δ: 12.6 (brs, 1H, CO2H), 8.04 (br s, 3H, NH3−), 6.10 (dt, J=5.6, 2.0, 2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3, 2.3, 2.3 Hz, 1H, vinyl), 4.19 (br s, w½=20 Hz, 1H, allytic H), 3.61 (m, w½=22 Hz, 1H, altylic H), 2.53 (quintet, J=5.3 Hz (overlapping with DMSO peak), ½ CH2), 2.39 (s, 3H), CH3SO3H), 1.93 (dt, J=6.7, 6.7, 13.7 Hz, 1H, ½ CH2); [α]20589-83.8°, [α]20578-87.4°, [α]20546-101.2°, [α]20436-186.7°, [α]20365-316.2° (c=1.42, methanol); CI-MS (CH4): 128(M+1); EI-MS; 127(M).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]1[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21](=[O:29])[N:22]([CH3:28])[CH2:23]4)[C:15]([Cl:30])=[CH:14][N:13]=2)[C:8]([O:31][CH3:32])=[CH:7][C:3]=1[C:4]([NH:71][CH:68]1[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]1)=[O:5]
Reactant: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reaction time: 0.08 h

Procedure:
2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoic acid (65 mg), TBTU (60 mg) and DIPEA (0.1 mL) are suspended in DMF (0.50 mL) and stirred for 5 min. 1-methylpiperidin-4-amine (18 mg) is added and the reaction mixture is stirred for a further 20 min. The reaction mixture is purified by HPLC without working up. (IC50=1 nmol).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:27][CH2:28]4)=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (13.80 g, 34.45 mmol) in dichloromethane (50 mL), was added trifluoroacetic acid (25 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was titrated in methanol (50 mL), the solid was collected by filtration and dried to give the title compound as a colorless solid (10.10 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 12.77 (br s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.83 (d, J=13.2 Hz, 1H), 3.59 (s, 2H), 2.04-1.92 (m, 4H), 1.71-1.58 (m, 12H), 0.91-0.83 (m, 2H), 0.59-0.52 (m, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:23](=NOC)[C:24]#[N:25])=[C:17]([F:35])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[NH:47][NH2:48]>>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[N:47]1[C:23]([C:24]#[N:25])=[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][C:17]=2[F:35])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:48]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F

Procedure:
The title compound is prepared by reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Example 8, Step J) with 2-bromo-5-nitrophenylhydrazine hydrochloride [prepared from 2-bromo-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)], following the procedure of Example 1, Step G.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.ClCCl>[N:15]([CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(CBr)cc1O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-bromomethylsalicylate (4.8 g, 18.6 mmoles) was dissolved in dry N,N-di-methylformamide (50 mL) and sodium azide (1.2 g, 18.9 mmoles) was added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (150 mL) and extracted with 1N aqueous hydrochloric acid (100 mL), water (100 mL), and saturated aqueous sodium chloride (50 mL). Finally, the solution was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give ethyl 4-azidomethylsalicylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[Cl:16]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16]
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Yield: 163.1 %

Procedure:
Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (634 milligrams (mg), 2.73 mmol) was slurried in acetonitrile (11 mL). 1,3-Dichloro-5,5-dimethyl-hydantoin (303 mg, 1.54 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 2.5 h. Additional 1,3-dichloro-5,5-dimethylhydantoin (50 mg, 0.25 mmol) was added, and the reaction mixture was stirred at reflux for an additional hour. Water (20 mL) was added. Acetonitrile was then removed by rotary evaporation to give an oily, yellow solid which was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with 10% sodium bisulfite (NaHSO3) solution, satd aq NaHCO3 solution and brine, dried (MgSO4) and concentrated under reduced pressure to provide a pale orange solid (671 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 5.29 (septet, J=6.3 Hz, 1H, CHMe2), 5.19 (br s, 2H, NH2), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 19F NMR (376 MHz, CDCl3) δ −136.5.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH2:12]([O:19][C:20]([CH:22]([NH:28][CH3:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.ClCCl>[CH2:12]([O:19][C:20]([CH:22]([NH:28][CH3:29])[CH2:23][CH2:24][C:25]([O:27][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:26])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(CCC(=O)O)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CNC(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To dichloromethane (1000 ml) was added at room temperature anhydrous magnesium sulfate (50.6 g) and then concentrated sulfuric acid (6.0 ml). The mixture was stirred at room temperature for 15 minutes, and to the mixture was added 4-[(benzyloxy)carbonyl]-4-methylaminobutyric acid (26.3 g) and then tert-butanol (50.5 ml). The mixture was sealed completely and stirred at room temperature for 18 hours. To the mixture was added saturated sodium hydrogen carbonate solution to dissolve all of the magnesium sulfate, and the mixture was stirred. The organic layer was separated, washed with saturated brine (400 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (250 g, hexane:ethyl acetate=5:1) to give tert-butyl 4-[(benzyloxy)-carbonyl]-4-methylaminobutyrate (17.2 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclobutylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 7 H), 1.80 (bs, 2 H), 2.10 (s, 1 H), 3.27-3.28 (m, 5 H), 6.32 (s, 1 H), 6.98 (d, 1 H), 7.15 (d, 1 H), 7.36-7.54 (m, 3 H), 7.57-7.62 (m, 3 H), 7.80 (d, 1 H), 7.95 (d, 1 H), 8.20 (s, 1 H), 10.41 (s, 1 H).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC.CN(C)C=O>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.O>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:21]2[S:20][CH:19]=[CH:23][CH:22]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(Br)sc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(-c2cccs2)sc1-c1cccs1
Temperature: 100 °C
Yield: 85 %

Procedure:
The procedure described by Taranekar et al30 was modified to synthesize G03TCOOR. Ethyl 2-(2,5-dibromothiophen-3-yl)acetate (6.4 g, 10 mmol) and 2-(tributylstannyl) thiophene (1.5 g, 20 mmol) were added to a 30 mL dry dimethylformamide (DMF) solution of dichlorobis(triphenylphosphine)palladium (Pd(dpp)Cl2) (1.3 g, 1.5 mmol). After three freeze thaw cycles, the mixture was heated at 100° C. for 48 hr. The mixture was cooled to room temperature and poured into a beaker containing 150 mL of water and subsequently extracted with CH2Cl2. The extracted CH2Cl2 mixture was dried with Na2SO4. After filtration and evaporation of the solvent, the crude product was purified by chromatography on silica gel using toluene as an eluent. The final product was obtained in 85% yield as pale yellow oil. The characterization of the compound was found in accordance with the literature.1 1H NMR (CDCl3): δ 6.8-7.2 (m, 7H), 4.19 (q, 2H, J=7.15 Hz), 3.72 (s, 2H), 1.27 (t, 41-1, J=7.14 Hz) as shown in FIG. 29.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[Cu](C#N)[C:32]#[N:33].O>CN1CCCC1=O>[C:32]([C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30])#[N:33]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1C#N)C2(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
2-[5-Bromo-6-oxo-4{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (100 mg, 0.21 mmol) in N-methylpyrrolidone (2.5 mL) was mixed with copper cyanide (100 mg, 1.05 mmol) at room temperature and stirred at 110° C. for 24 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (4.3 mg, 5% yield).
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:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:15]3[S:16][CH:17]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Cl)cs1
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)cs1
Yield: 61 %

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.2 g, 7.2 mmol) was reacted with 4-chloro-thiophene-2-carbaldehyde (1.05 g, 7.2 mmol) and pyrrolidine (0.7 g, 9.9 mmol) to give E/Z-6-chloro-3-(4-chloro-thiophen-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.3 g, 62%)
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl.[CH:10]12[CH2:15][CH:14]1[CH2:13][NH:12][CH2:11]2.CCN(CC)CC>O>[CH:10]12[CH2:15][CH:14]1[CH2:13][N:12]([C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1)[CH2:11]2
Reactant: Nc1cccc(F)n1
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cccc(N2CC3CC3C2)n1
Temperature: 205 °C
Yield: 76.3 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (448 mg, 4 mmol), 3-aza-bicyclo[3.1.0]hexane hydrochloride (576 mg, 4.8 mmol) and Et3N (808 mg, 8 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=10:1) to give 6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-amine (535 mg, 76%) as a colorless oil. LC-MS: [M+H]+, 176.2, tR=1.042 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].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(=O)([O-])[O-].[Cs+].[Cs+].[CH:63]1([NH2:68])[CH2:67][CH2:66][CH2:65][CH2:64]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]>[C:13]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[NH:68][CH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1)#[N:14]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1ccc(C#N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(C#N)c(NC2CCCC2)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 71.9 %

Procedure:
A mixture of ethyl 3-bromo-4-cyanobenzoate (500 mg, 1.97 mmol), XANTPHOS (228 mg, 0.39 mmol), cesium carbonate (1.282 g, 3.94 mmol), cyclopentylamine (233 mg, 2.75 mmol), and tris(dibenzylideneacetone)dipalladium (180 mg, 0.20 mmol) in dioxane (5 mL) was stirred at 100° C. for 17 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes:ethyl acetate 9:1) afforded ethyl 4-cyano-3-(cyclopentylamino)benzoate (366 mg, 72% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): 7.43 (m, 2H), 7.35 (m, 1H), 7.27 (m, 1H), 4.62 (d, 1H), 4.38 (q, 2H), 3.93 (m, 1H), 2.10 (m, 2H), 1.78 (m, 2H), 1.67 (m, 2H), 1.53 (m, 2H), 1.39 (t, 3H). MS (EI) for C15H18N2O2: 259 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>O>[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(F)c1Nc1cc(Cl)nn2ccnc12
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3c(F)cccc3F)c3nccn3n2)CC1
Reaction time: 24 h

Procedure:
To crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine (0.186 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000 mg, 8.77 mmol). The mixture was allowed to melt at 160° C. for 24 hrs. The melt was then cooled, water was added, followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and the resulting residue purified by reverse phase preparative HPLC to provide 50.6 mg (46%) of the titled compound as a TFA salt. LC/MS, m/e 359 (M+1). HPLC Rt, 1.7 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min. Examples prepared in a similar manner are indicated in Table 2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.N>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]2[C:6]([C:5](=[O:9])[CH2:4][CH2:3][O:9]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: N
Product: O=C1CCOc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared from 3-trifluoromethyl-phenol according to EP1908753. MS (DCI/NH3) m/z 234 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](=[O:17])=[O:16]>[OH-].[Na+]>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccccc1F
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C

Procedure:
Pentamethylenediethylenetetramine (31.2 ml) was added to a solution of 2-fluoroanisole (15.0 g) in TB (450 ml). The reaction mixture was cooled to −78° C. and n-butyllithium (59.6 ml, 2.5M solution in hexanes) was added dropwise. Stirring was maintained for 2 h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30 min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution (300 ml) and extracted with Et2O (3×). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with H2O, dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7.1 g.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CCO>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1cccc(I)c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2cccc(C(F)(F)F)c2)c1Br

Procedure:
A solution of 2-bromo-1-iodo-3-methylbenzene (200 mg, 0.67 mmol), 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (220 mg, 0.81 mmol), sodium carbonate (214 mg, 2.02 mmol) and tetrakis(triphenylphosphine) palladium (38.9 mg, 0.034 mmol) in toluene (2.0 mL)/EtOH (1.2 mL)/Water (0.2 mL) was heated in an oil bath at 80° C. overnight. The reaction was concentrated and the resultant residue purified by column chromatography (100% Hexanes) to yield 2-bromo-3-methyl-3′-(trifluoromethyl)biphenyl.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[O:4][C:3]2[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)ncnc23)c1F
Yield: 13.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-22, 300 mg, 0.93 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 322 mg, 1.12 mmol), oxalyl chloride (212 mg, 1.68 mmol), DMF (1 drop) and DIPEA (360 mg, 2.79 mmol) in CH2Cl2 (10 mL) to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.92-8.90 (d, J=7.2 Hz, 1H), 8.81 (s, 1H), 8.19-8.10 (m, 3H), 7.89-7.84 (m, 2H), 7.77-7.71 (t, J=9.9 Hz, 1H), 7.40-7.32 (m, 2H), 4.31-4.29 (d, J=6.0 Hz, 2H), 1.13 (s, 9H); MS (m/z): 593.31 (M+H)+.