Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2.I[CH3:25]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH3:25])([CH3:23])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)(C)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
NaH (60%, 18 mg) was added to a solution of 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22, 96 mg, 0.318 mmol) in THF (6 mL). After stirring for 15 minutes, iodomethane (0.1 mL, 0.57 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc, filtered and purified using Biotage silica gel column chromatography eluting with 25% EtOAc/cyclohexane to give the title compound as yellow oil (57 mg, 57%).
Reaction SMILES: [CH2:1]([C:5]1[N:13]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]#[N:27])=[CH:19]3)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:13]([C:14]2[C:15]3[C:20](=[CH:19][C:18]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]4[NH:38][N:37]=[N:36][N:27]=4)=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C#N)ccc12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3-c3nnn[nH]3)ccc12
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[5-(2-butyl-imidazo[4,5-b]pyridin-3-yl)-naphthalen-2-yl]-benzonitrile (85 mg, 0.21 mmol) and trimethyltin azide (108 mg, 0.50 mmol) in xylene (2.5 mL) was heated under reflux for 17 hours. The reaction mixture was cooled to 23° C. and the solvent was removed in vacuo. The crude residue was dissolved in EtOH (5 mL) and 2N NaOH (5 mL) was added. After 0.5 hour, the reaction mixture was concentrated in vacuo. The residue was dissolved in saturated aqueous NaCl (2 mL) and neutralized with concentrated HOAc. The aqueous solution was extracted with CHCl3 (3×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was azeotroped with heptane, diluted with EtOAc (1 mL) and hexanes (25 mL). The solid that precipitated was filtered and dried. 1H NMR (250 MHz, d6 -DMSO): d 8.13 (m, 3 H), 7.96 (s, 1 H), 7.65 (m, 6 H), 7.30 (m, 1 H), 7.12 (dd, 1 H), 6.86 (d, 1 H), 2.55 (m, 2 H), 1.63 (m, 2 H), 1.22 (m, 2 H), 0.74 (t, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:22][C@@H:23]1[CH2:27][N:26]([C:19](=[O:20])[CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[O:10][C:11]=3[CH:17]=2)[C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1
Reactant: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.5 %

Procedure:
In DMF (5 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (357 mg, 1.26 mmol), methyl 5-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)pentanoate (295 mg, 1.26 mmol), EDC•HCl (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and triethylamine (0.88 ml, 6.30 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 70 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (1.05 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH2:19](O)[CH3:20].[K+].[Br-]>C(O)(=O)C>[CH2:19]([O:13][C:12]1[NH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1)[CH3:20]
Reactant: CCO
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1nnc(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 24 °C

Procedure:
5-[4-(Trifluoromethyl)phenyl]1,3,4-oxadiazol-2-amine (10 g, 44 mmol) and potassium hydroxide (7.4 g, 0.132 mol) dissolved in abs. ethanol (300 ml) were heated at reflux for 3 h. After being cooled to 24° C., the solution was neutralized with acetic acid and concentrated by rotary evaporation. The residue was taken up in ethyl acetate and washed with water and brine. Recrystallization from acetonitrile/ether (2:1) gave 9 g (82%); mp 151°-152° C.; IR(KBr, ν=cm-1) 2996, 1534, 1460, 1330, 1162, 1130, 1070; 1H NMR (300 MHz, DMSO-d6) δ1.35 (3H, t, J=7.1 Hz), 4.38 (2H, q, J=7.0 Hz), 7.82 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.1 Hz), 13.64 (1H, br. s); MS(DCl)m/z: 258 (MH+)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:20]>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[NH:10][C:11](=[O:20])[CH2:12][CH2:13]2)=[O:8]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(C(=O)CCl)ccc2N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a 10 L, 4-neck flask, fitted with a mechanical stirrer and under N2, AlCl3 (408 g, 3.06 mol) and dry CH2Cl2 (2.7 L, 18 vol) was added. Chloroacetylchloride (89 mL, 1.22 mol) was then added from an addition funnel gradually over 15 minutes at room temperature. The resulting mostly clear solution was maintained at that temp for 30 minutes and turned into a muddy mixture. A solution of 3,4-dihydroquinolin-2(1H)-one (150 g, 1.02 mol) and CH2Cl2 (0.3 L, 2 vol) was added, over 1.5 hours, at such a rate as to keep the internal temperature below 30° C. The resulting brown mixture was stirred at that temp for 2 hours, then heated at 40° C. for an additional 2 hours, and then left to stir overnight at room temperature. The reaction mixture was cooled in an ice bath and connected to an HCl gas trap. Ice-cold H2O (total 3 L) was then added, over 1.5 hours, at such a rate as to keep the internal temperature below 30° C. The resulting mixture was stirred at room temperature for 1 hour and then heated at 40-50° C. to remove the CH2Cl2. To this mixture, THF (1 L) was added and the mixture was stirred at room temperature overnight. The solids were collected by filtration. The yellow cake was washed with H2O (500 mL), THF (200 mL) and hexane (1 L×2) and it was dried in a vacuum oven (@50° C., 1 day) to afford 6-(2-chloroacetyl)-3,4-dihydroquinolin-2(1H)-one (221 g, 97%). 1H NMR (270 MHz, d-DMSO) δ 10.48 (s, 1 H), 7.86-7.77 (m, 2 H), 6.96 (d, J=8.2 Hz, 1 H), 5.08 (s, 2 H), 2.96 (t, J=7.6 Hz, 2 H), 2.51 (t, J=7.6 Hz, 2 H)
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1
Reactant: NN
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccc(C(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (740 mg, 1.5 mmol) produced in Synthesis Example 15 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 291 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(3-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (364 mg, yield 50%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1.C(N(C(C)C)CC)(C)C>ClCCl.[Cl-].[NH4+]>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(I)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Methanesulfonyl chloride (1.5 mL, 1.2 eq.) was added dropwise to a stirred solution of 2-(3-iodophenyl)ethanol (3.6 g) in dichloromethane (100 mL) and diisopropylethylamine (3.8 mL, 1.5 equiv.) at 0° C. The solution was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with dichloromethane. The organic layers were combined, washed with aqueous sodium hydrogencarbonate solution, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified using column chromatography (SiO2 cartridge) using DCM-cyclohexane (70:30) to afford the title compound (3.2 g, 45% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (358 mg).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[C:6]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[CH3:25]>CN(C)C=O.O>[CH2:24]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][NH:2]3)([OH:17])[CH2:12]1)[CH3:25]
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCC(O)(c2cccc3[nH]ccc23)C1

Procedure:
A mixture of 10 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride in 200 ml of dimethylformamide was agitated for 4 hours under an inert atmosphere with 13.44 g of sodium carbonate and 4.2 ml of ethyl bromide. The mixture was taken up in water and was extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure at 50° C. The residue was purified by chromatography over silica and eluted with a 6-3-1 mixture of cyclohexane-chloroform-triethylamine to obtain 6.6 g of 1-ethyl-3-(1H-indol-4-yl)-3-piperidinol which was used as is for the following step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]C1C=C(CC(O)=O)C=CC=1>>[Br:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Product: CCOC(=O)Cc1cccc(Br)c1

Procedure:
Employing the same general procedure as for the preparation of ethyl (4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of 3-bromophenylacetic acid was converted into the title compound (yellow oil) using 2 g of conc. H2SO4 and 500 ml of ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([NH:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH2:32][NH:31][C:30]2[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)CNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(CNc1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dibenzyloxyphenethylamine (36.2 g) and p-chloroanilinoacetic acid (20 g) was stirred for 3 hours at 190° C. The reaction mixture was dissolved in benzene. The solution was washed with a diluted potassium carbonate aqueous solution and dried. The solvent was distilled off from the benzene solution and the residue obtained was purified by column chromatography on silica gel to give N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(p-chloroanilino)acetamide (27.2 g), mp 121° C.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:31]([CH:33]4[CH2:35][CH2:34]4)=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:25]=2)=[O:23])=[C:18]([F:45])[N:17]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:39]1([S:36]([N:26]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([CH:33]4[CH2:34][CH2:35]4)[C:32]=3[C:24]([C:22]([C:19]3[C:18]([F:45])=[N:17][C:16]([NH:7][C:8]4[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)=[CH:21][CH:20]=3)=[O:23])=[CH:25]2)(=[O:38])=[O:37])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 81.9 %

Procedure:
To [5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (77, 0.340 g, 0.527 mmol) in 10 mL of 1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.4 mmol) is added. The reaction is stirred at 80° C. for 45 minutes, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (78, 235 mg). MS (ESI) [M+H+]+=545.4.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 40, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (336 mg) as a foamy white solid. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.42 (s, 3H) 2.46 (td, J=5.84, 0.80 Hz, 2H) 2.58 (td, J=5.78, 1.13 Hz, 2H) 3.52-3.63 (m, 2H) 3.63-3.72 (m, 2H) 6.45 (s, 1H) 6.65 (dt, J=8.21, 0.69 Hz, 1H) 6.90-6.97 (m, 2H) 6.99 (dt, J=7.16, 0.48 Hz, 1H) 7.04-7.11 (m, J=8.10, 1.21, 0.84, 0.63 Hz, 1H) 7.36 (dd, J=8.86, 7.71 Hz, 1H) 7.59 (dd, J=9.11, 4.65 Hz, 1H) 7.68 (dd, J=8.08, 7.52 Hz, 1H) 8.12 (d, J=8.87 Hz, 1H) 8.79 (d, J=3.90 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[I:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[I:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(I)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(I)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Iron powder (12.5 g, 224 mmol) was added to a suspension of 2-benzyloxy-5-nitroiodobenzene (Description 13; 10 g, 28 mmol) in water (300 ml) and acetic acid (75 ml) and the mixture was stirred at 80° C. for 12 hours. The mixture was allowed to cool to room temperature and filtered through Hyflo™, washing with 4:1 water:acetic acid and ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic extract was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (9 g, 99% yield). 1H NMR (360 MHz, CDCl3) δ 7.49−7.47 (2H, m), 7.40−7.28 (3H, m), 7.19 (1H, d, J 2.4 Hz), 6.70 (1H, d, J 8.6 Hz), 6.62 (1H, dd, J 2.4, 8.6 Hz), and 5.04 (2H, s). m/z (ES+) 326 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[N:4][N:3]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31](=[O:40])[N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:36]2[CH2:35][CH2:34][CH:33]([N:32]([CH3:39])[C:31](=[O:40])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:38][CH2:37]2)=[N:3][N:4]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Brc1nnc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Br)c3ccccc23)CC1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
Combine 1,4-dibromophthalazine (0.70 g, 2.38 mmol), N-methylpyrrolidone (7.0 mL), potassium carbonate (395 mg, 2.86 mmol), and methyl-piperidin-4-yl-carbamic acid tert-butyl ester (532 mg, 2.38 mmol). Heat at 80° C. overnight. Cool and pour into water. Collect the solid and dry in a vacuum oven at ambient temperature overnight to obtain the final product (0.96 g, 95%). ES/MS m/z (81Br) 421.0 (M+1).
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[F:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:34])[C:32]=1F>>[F:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:34])[C:32]=1[O:25][C:22]1[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1cncc(F)c1F
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: Nc1ccc(Oc2c(F)cncc2F)cc1

Procedure:
{4-[(3,5-Difluoropyridin-4-yl) oxy]phenyl} amine (2E) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-aminophenol and 3, 4, 5-trifluoropyridine, MS ES: 223 (M+H)+, calcd 223, RT=0.50 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1>[CH:38]1([C:42]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:43])[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) in tetrahydrofuran (5 mL) were added dropwise triethylamine (75 μL, 0.544 mmol) and cyclobutanecarbonyl chloride (50 μL, 0.435 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (98 mg, 54%) as a white powder.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: ClCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=Cc1ccccc1OCCCCCCl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 100 g (0.82 mol) of salicylaldehyde in 2000 ml of iPrOH was added 228 g (1.23 mol) of 1-bromo-5-chloro-pentane, followed by 113 g (0.82 mol) of potassium carbonate. The reaction was refluxed under nitrogen and followed by TLC. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to remove all solvent. The liquid residue was purified by fractional distillation under reduced pressure: 1st fraction: 45°-50° C., 0.4 mm Hg [Br(CH2)5Cl] 2nd fraction: 159.8 g (86% yield), 145°-150° C., 0.3 mm Hg colorless liquid product. The remaining residue proved to a dialdehyde by-product. TLC: Starting aldehyde Rf=0.46 (30% ether/pet. ether). Desired aldehyde: Rf=0.35. By-product: Rf=0.15.