Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:36]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccc4Cl)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 2-chlorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL) and then washed with H2O (40 mL), 1N HCl (40 mL), brine (40 mL), and dried over MgSO4. The organic layer was concentrated in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min):) to afford 2-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.55 g, 60%): mp, 209-211° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.87-2.93 (m, 1H), 4.92 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 7.39-7.57 (m, 4H), 7.82-7.89 (m, 3H), 9.12 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.91, 38.10, 48.86, 121.95, 127.15, 128.97, 129.62, 129.83, 130.94, 131.54, 133.10, 134.80, 136.49, 138.74, 166.77, 166.93, 167.48, 169.80, 172.74. Anal Calcd for C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87; Cl, 8.33. Found: C, 59.24; H, 3.45; N, 9.71; Cl, 8.32.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>O>[NH:17]([C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1)[NH2:18]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(O)c2c1
Solvent: O
Product: NNc1nc(O)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The wet product from Step A was dissolved in a mixture of 90 ml hydrazine hydrate and 900 ml of water and the mixture was stirred at 90°-100° C. until crystallization took place. The mixture was allowed to cool and was filtered. The product was washed with water and methanol and dried to obtain 97.2 g of 2-hydrazino-4-hydroxy-6-nitro-quinazoline in the form of a high melting, orange crystalline solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]#[C:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.CO>[Pd].C(O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C#CCN(C)C)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(CCCN(C)C)cc2c1=O
Yield: 69.4 %

Procedure:
N-Cyclopropyl-3-[6-[3-(dimethylamino)prop-1-yn-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.097 g) and 10% Palladium on carbon (0.01 g) were stirred in ethanol (2 ml) and methanol (0.5 ml) under an atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.068 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.78 (m, 2H), 2.15 (s, 9H), 2.23 (t, 2H), 2.78 (t, 2H), 2.86 (m, 1H), 7.53 (d, 1H), 7.71 (d, 1H), 7.78 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.02 (s, 1H), 8.25 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C:12]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:13]=3[NH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C@@H:12]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C@@H:13]3[NH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Yield: 36 %

Procedure:
A 0° C. solution of 10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride from above (286 mg, 0.87 mmol) in trifluoroacetic acid (4 mL) was treated with a solution of sodium cyanoborohydride (278 mg 4.42 mmol) in methanol (1 mL). The reaction was allowed to slowly warm to room temperature over 3.8 hours then diluted with water and concentrated in vacuo to remove the majority of acid. The residue was made basic with 15% NaOH, extracted with CH2Cl2 dried over MgSO4 and concentrated in vacuo and passed through a column of silica gel with 1:19 methanol/chloroform with 1% NH4OH to give 91 mg (36%) of a white foam as the title compound: 1H NMR (400 MHz, Acetone-d6) δ 7.34-7.30 (m, 1H), 7.17 (dd, J=7.4 Hz, 1.7 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 7.00-6.92 (m, 2H), 6.47 (d, J=7.7 Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 4.90 (br s, 1H), 4.19-4.14 (m, 1H), 3.78 (s, 3 H), 3.65-3.60 (m, 1H), 2.97-2.93 (m, 1H), 2.64-2.56 (m, 2H) 2.35-2.29 (m, 1H), 1.98-1.94 (m, 1H), 1.48-1.44 (m, 1H), 1.28-1.23 (m, 1H); HRMS (FAB) calcd for C19H22N2O1+H1 295.1810, found 295.1798.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Br:10])[N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:10][C:4]1[N:3]=[C:2]([NH:1][C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(Br)nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry reaction flask equipped with a nitrogen inlet and magnetic stirring bar was charged with 2-amino-6-bromo-3-methoxypyridine (33) (0.170 g, 0.84 mmol), pyridine (0.126 mL, 1.26 mmol) and CH2Cl2 (5 mL). To this at 0° C. was added pivaloyl chloride (0.113 mL, 0.92 mmol) and then the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with water (25 mL), extracted with CH2Cl2 (2×25 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to afford 6-bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34). LCMS: purity: 80%; MS (m/z): 287 (MH+).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Reactant: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Anhydrous 2-propanol (1.803 g, 30 mmol) and anhydrous tri-ethylamine (2.024 g, 20 mmol) were added drop-wise at 5-10° C. to the solution of 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight. The mixture was discharged from the vessel and the salts were removed by filtration and washed with a little acetonitrile. The solvent was removed with a rotary evaporator. The crude mixture was re-dissolved in ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (4/50) as eluent to give 3.77 g (79% yield, 99% GC purity, 97% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (32%), 178 (100%), 150 (49%), 100 (33%), 43 (75%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.82 to 159.74 (m), 149.22 to 148.85 (m), 148.02 to 147.89 (m), 146.47 to 146.17 (m), 145.63 to 145.47 (m), 138.54 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.3, 11.4 Hz), 129.03 to 128.74 (m), 70.98 (s), 21.61 (s). 19F NMR (376 MHz, CDCl3) δ−80.26 to −80.44 (m), −135.99 to −136.13 (m), −137.07 to −137.22 (m), −149.77 to −149.91 (m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1.CCN(CC)CC>ClCCl>[CH:16]1([N:19]2[CH:24]=[CH:23][C:22]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1cc(O)ccn1C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)ccn1C1CC1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask charged with a stir bar, 1-cyclopropyl-4-hydroxy-1H-pyridin-2-one (0.10 g), NEt3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 2 h and at ambient temperature for another 2 h. Then, the solution was diluted with dichloromethane and washed in succession with water, aqueous NaHCO3 solution, and water. The organic solution was dried (MgSO4), the solvent was removed, and the residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->90:10) to afford the title compound as a resin-like solid. Yield: 0.07 g (36% of theory). Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([I:1])=[N:3]1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde was prepared from 3-Iodo-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](N)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([Cu])#N>C(O)(=O)C.O.C(OCC)(=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccn4)ccc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 37 mg of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 79) in acetic acid (1.0 mL) was added NaNO2 (7.7 mg) in H2O (0.5 mL). The mixture was stirred 1 h at 0° C. Pyridine (1 mL) was added followed by CuCN (9.8 mg). Gas evolution was observed. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The product mixture was purified by silica gel chromatography eluting with a gradient solvent system of 100% CH2Cl2 going to 10% MeOH CH2Cl2 giving 18.3 mg of the title compound. Mass spectrum (ESI): 293.3 (M+1).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1.CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.C(N=C=NCCCN(C)C)C>ClCCl>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])=[CH:9]1
Reactant: CCCC(=O)O
Reactant: NC1=CC(=O)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)NC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 10 %

Procedure:
Butyric acid (465 mg, 5.28 mmol) and 3-amino-2-cyclohexene-1-one (645 mg, 5.81 mmol) were dissolved in dichloromethane (50 mL). Dimethylaminopyridine (750 mg, 5.81 mmol), diisopropylethylamine (774 mg, 6.34 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide (1.13 g, 5.81 mmol) were added to the resulting mixture, followed by stirring at room temperature for about 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=6/4) to obtain the N-(3-oxo-cyclohexen-1-yl)butyramide (1a-1) shown by the formula below.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: COCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Yield: 94.2 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (29.54 g, 102.7 mmol) was reacted with 3-methoxy propyl amine (10.07 g, 113.0 mmol) according to the method described in Part A of Examples 125–135 to provide 32.9 g of (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine as a yellow solid. The product was not recrystallized.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccc(I)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (0.500 g, 3698 μmol) in benzene (5 mL) was added 4-iodobenzaldehyde (858 mg, 3698 μmol) and MgSO4 (1.000 g, 8308 μmol) and the suspension stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-iodobenzylidene)-1-phenylpropan-2-amine as a yellow oil which was used without purification in the next step.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:13]([O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH3:14]>ClCCl.CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH3:14]
Reactant: N#CCC(=O)O
Reactant: CCOCCNc1ccccc1C(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCCN(C(=O)CC#N)c1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of commercially available cyanoacetic acid (1.1 eq, 0.118 g, 1.39 mmole) in dichloromethane was added oxalylchloride (0.353 g, 2.78 mmole, 0.236 mL) and 2 drops N,N′-dimethylformamide). The reaction was stirred for 2 hours at RT until homogenous solution developed. 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester (1 eq, 0.300 g, 1.26 mmole) was added and the resulting solution was allowed to stir at RT overnight. Reaction mixture was diluted with saturated sodium bicarbonate water (20 mL) and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively With water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-[(2-Cyano-acetyl)-(2-ethoxy-ethyl)-amino]-benzoic acid ethyl ester as clear liquid (0.292 g, 76%, LCMS calc M+H 305, obs M+H 305).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].[Cl:10]CCCl.P(Cl)(Cl)(Cl)=O>O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1cc(O)ncn1
Reactant: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(Cl)ncn1

Procedure:
To 12.4 g (0.1 mole) of 6-ethyl-4-hydroxypyrimidine was added 50 ml of 1,2-dichloroethane, and 18.4 g (0.12 mole) of phosphorus oxychloride was added thereto. The mixture was refluxed by heating for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 10.38 g of 4-chloro-6-ethylpyrimidine as slightly red liquid.
Reaction SMILES: Br[C:2]1[CH:3]=CC(O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH:37]1C=CC=C1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[NH:37][CH:3]=[CH:2][CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc[nH]4)ccc3c1)n2C1CCCCC1
Yield: 9 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(1H-pyrrol-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (11 mg, 9% yield).
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCI
Reactant: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2-H-1,4-benzoxazine [prepared in Preparation 9(1)] (6.0 g) in dimethylformamide (60 ml) were added 60% sodium hydride (in oil) (1.02 g) and ethyl iodide (4.37 g) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:31])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.C(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:33])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:31])[CH2:23][NH:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate (Preparation 14) in methanol (10 mL) was added a methanolic solution of HCl (10 mL of 1.25 M). Reaction mixture warmed to 65° C. for 1.5 hours. Reaction concentrated via rotavap to yield a viscuous oil. CH2Cl2 was added and a precipitate formed. Volatiles removed under reduced pressure to yield 573 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.8-9.6 (br s, 2H) 7.9-7.8 (m, 3H), 7.75 (d, 2H), 7.63 (d, 2H), 4.64-4.29 (m, 6H)). LC/MS retention time=3.039 minutes, MS calculated for (C19H14Cl2F4N2O), 432.04; found 433.0 M+H.
Reaction SMILES: [Cl:1][C:2]([CH3:14])([CH3:13])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([Cl:11])=[C:7](Cl)[CH:6]=[N:5]1.[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=1.[OH-].[K+]>CN(C)C=O>[Cl:11][C:8]1[C:9](=[O:10])[N:4]([CH2:3][C:2]([Cl:1])([CH3:14])[CH3:13])[N:5]=[CH:6][C:7]=1[O:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([I:15])=[N:17][CH:18]=1.[Cl:11][C:8]1[C:9](=[O:10])[N:4]([CH:3]=[C:2]([CH3:14])[CH3:13])[N:5]=[CH:6][C:7]=1[O:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([I:15])=[N:17][CH:18]=1
Reactant: CC(C)(Cl)Cn1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(I)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(Cl)Cn1ncc(OCc2ccc(I)nc2)c(Cl)c1=O
Product: CC(C)=Cn1ncc(OCc2ccc(I)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.4 g of 2-(2-chloro-2-methylpropyl)-4,5-dichloro-3(2H)-pyridazinone and 1.29 g of 2-iodo-5-pyridyl methanol, and thereto was added 0.33 g of powdery potassium hydroxide under ice-cooling. The mixture solution was stirred for one day at room temperature. Then, the procedures in Preparation Example 2 were repeated to give 0.74 g of 4-chloro-2-(2-chloro-2-methylpropyl)-5-[(2-iodo-5-pyridyl)methoxy]-3(2H)-pyridazinone (m.p.: 119°-123° C.) and 0.24 g of 4-chloro-5-[(2-iodo-5-pyridyl)-methoxy]-2-(2-methyl-1-propenyl)-3(2H)-pyridazinone (m.p.: 141°-142° C.).
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1>CO>[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: CC(C)(N)CCOc1ccc(Cl)nn1
Reactant: Cc1ccccc1OCC1CO1
Solvent: CO
Product: Cc1ccccc1OCC(O)CNC(C)(C)CCOc1ccc(Cl)nn1
Yield: 82.6 %

Procedure:
A mixture of 645 mg of 3-(3-amino-3-methylbutoxy)-6-chloropyridazine, 650 mg of 1-(2-methylphenoxy)-2,3-epoxypropane and 15 ml of methanol was refluxed for 5 hours, and the solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, and the organic layer was washed with 5% sodium carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 938 mg of 1-(2-methylphenoxy)-3-[1,1-dimethyl-3-(chloro-6-pyridazinyloxy)propylamino]-2-propanol as an oil.