Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:20]([Mg]Cl)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:20][CH2:21][CH3:22])[N:11]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2)nc1Cl
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of product from Step 2 (73.0 g, 0.245 mol) and Fe(acac)3 (4.3 g, 12.2 mmol) in THF (1.2 L) cooled at −30° C. was added a solution of n-propylmagnesium chloride (2 M in Et2O, 245 mL, 0.49 mol) over 45 min, while maintaining the reaction temperature below −30° C. The dark-colored reaction mixture was stirred for an additional 15 min and poured into a saturated aqueous solution of NH4Cl (1.5 L). The organic layer was separated and washed with brine (1×250 mL). After removal of the solvent, the crude product was purified by chromatography on silica gel eluting with 100% hexane and then with 15:1 hexane:ethyl acetate to furnish the title product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(C(F)(F)F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-trifluoromethylphenylboronic acid (163 mg, 0.86 mmol) the subtitle compound was obtained, (120 mg, 51%). 1H NMR (DMSO) δ 8.70(s, 1H), 8.52(d, 1H), 8.24(s, 1H), 8.11(s, 1H), 7.97(d, 1H), 7.86(d, 1H), 7.81(s, 2H), 7.68(d, 1H), 4.11(s, 3H). MS 415 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[N:46]1[CH:51]=[CH:50][CH:49]=[C:48](B(O)O)[CH:47]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.O>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:48]2[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=2)[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(I)ccc1-c1cc(C(C)C)ccc1OC
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(-c2cccnc2)ccc1-c1cc(C(C)C)ccc1OC

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl][(4-iodo-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]carbamate from Example 10 (0.03 g, 0.045 mmol), potassium carbonate (0.012 g, 0.09 mmol), 3-pyridyl boronic acid (0.0066 g, 0.054 mmol) and a catalytic amount of palladium acetate (1 mg) in 4:1 acetone/water (2 ml) was heated to and maintained at reflux for 5 h. Acetone was removed and the organic was extracted with methylene chloride (3×10 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The title compound was obtained after preparative thin layer chromatography using 3:7 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.90 (m, 1H), 8.65 (m, 1H), 7.90 (m, 1H), 7.72 (s, 1H), 7.70 (m, 1H), 7.60 (dd, J=8.0, 2.5 Hz, 1H), 7.48 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.25 (m, 1H), 7.00 (s, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.20-4.62 (m, 4H), 3.77 (s, 3H), 3.72 (s, 3H), 2.90 (m, 1H), 1.22 (s, 6H). LC-MS (M+1) 617.0 (3.76 min).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
6-Bromo-3-pyridinecarboxaldehyde (1.05 g, 5.64 mmol) was dissolved in ethanol (30 mL). The mixture was cooled to 0° C., and stirred at 0° C. for 10 minutes after adding sodium borohydride (213 mg, 5.64 mmol). A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (2-bromopyridin-5-yl)methanol (874 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:32][CH2:31][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:25]=[C:24]5[C:20]([C:21]([CH3:30])([CH3:29])[CH2:22][N:23]5C(=O)C)=[CH:19][CH:18]=4)[C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CCO>[ClH:1].[Cl:1][C:2]1[C:3]([N:8]2[CH2:32][CH2:31][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:25]=[C:24]5[C:20]([C:21]([CH3:29])([CH3:30])[CH2:22][NH:23]5)=[CH:19][CH:18]=4)[C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)ccc21
Temperature: 55 °C
Reaction time: 10 h
Yield: 236.3 %

Procedure:
A mixture of 1-{6-[6-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3,3-dimethyl-2,3-dihydro-indol-1-yl}-ethanone (30 mg), EtOH (5 mL), and 5N aqueous HCl (1 mL) was stirred at 55° C. for 10 h. The mixture was concentrated in vacue to give the HCl salt as a light yellow solid (35 mg).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]([O:15]C3CCCCO3)[CH2:13][OH:14])[CH:10]=[CH:11][C:4]1=2.Cl.[CH2:23]([N:25]([CH2:28][CH2:29][Cl:30])[CH2:26][CH3:27])[CH3:24].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(O)C.CC(C)=O.O.C1(C)C=CC=CC=1>[ClH:30].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]([OH:15])[CH2:13][O:14][CH2:24][CH2:23][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:10]=[CH:11][C:4]1=2
Reactant: OCC(OC1CCCCO1)c1ccc2sccc2c1
Reactant: CCN(CC)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)CCOCC(O)c1ccc2sccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 10 ml of toluene and 100 ml of a 50% aqueous sodium hydroxide solution were added 10 g of (-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol, 8.04 g of 2-(N,N-diethylamino)ethyl chloride hydrochloride and 610 mg of tetra-n-butylammonium hydrogensulfate, and the resulting mixture was refluxed for 1.5 hours. The reaction mixture was cooled to 20° C., and thereto were then added 90 ml of toluene and 150 ml of water, after which the organic layer formed was separated. The aqueous layer was extracted with 30 ml of toluene, and the extract obtained was combined with the organic layer previously separated, and the mixture was washed with water. Thereafter, 60 ml of water was added to the organic layer, and the pH was adjusted to 0.5 with 6N hydrochloric acid, after which the mixture was stirred at 25° C. for 1 hour. The aqueous layer was separated and washed with ethyl acetate, and thereto was added 40 ml of ethyl acetate, after which the pH was adjusted to 10.2 with potassium carbonate. The organic layer formed was separated, washed successively with water and an aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained were dissolved in 60 ml of ethyl acetate and 40 ml of acetone to form a solution. To the solution was added 7 ml of a solution of hydrogen chloride in ethanol (6.1N). The solution was stirred at 20° C. for 2 hours, and the crystals thus separated were collected by filtration to obtain 10.7 g (yield: 90%) of (-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride. This was recrystallized from ethyl acetate-ethanol to obtain colorless needle crystals having a melting point of 120°-121° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:31](CC)CC)C.CN.Cl>C(Cl)Cl.CN(C=O)C>[CH3:29][NH:31][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(-c2cc(C(=O)N3CCCCC3)cs2)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cc(C(=O)N3CCCCC3)cs2)cc1
Reaction time: 1 h
Yield: 17 %

Procedure:
4-[4-(Piperidine-1-carbonyl)-thiophen-2-yl]-benzoic acid was taken up in DCM (5 mL) and oxalyl chloride (0.099 mL, 3 eq.) added with a drop of DMF. The mixture was then stirred for 1 hour and then evaporated and the residue taken up in DCM (5 mL). Triethylamine (0.106 mL, 2 eq.) was added followed by methylamine.HCl (28 mg, 1.1 eq). The mixture was stirred for 2 hours and then evaporated and the residue purified by column chromatography (EtOAc/iso-hexane) to give the desired product (21.9 mg, 17%). LCMS m/z 329 [M+H]+ R.T.=2.47 min (Analytical Method 3).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:38])[CH:13]=[N:12][C:11]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(C(O)c3ccccc3)cc2OCc2ccccc2)n1
Yield: 48.5 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 1; 0.350 g, 0.930 mmol), MeLi (0.727 ml, 1.16 mmol), butyllithium (0.465 ml, 1.16 mmol), and benzaldehyde (0.0987 g, 0.930 mmol) were reacted according to Example 7 to provide (5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)(phenyl)methanol (0.182 g, 48.5% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.55 (d, 2H), 7.40-7.28 (m, 7H), 7.22 (m, 1H), 6.81 (s, 1H), 5.75 (s, 1H), 5.29 (s, 2H), 2.30 (s, 3H). Mass spectrum (apci) m/z=404.1 (M+H-HCl).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([NH:18][C:8]4[CH:9]=[CH:10][C:11]([N:12]5[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]5)=[C:6]([O:5][CH3:4])[CH:7]=4)[S:20][C:21]=3[CH2:22]2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(s2)CN(Cc2ccc(F)cc2)CC3)ccc1-n1cnc(C)c1
Reaction time: 0.17 h

Procedure:
90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride was suspended in tetrahydrofurane (3 ml). At room temperature under nitrogen 103 mg (0.8 mmol) N,N-diisopropyl ethyl amine was added and the reaction was stirred for 10 minutes. 28 mg (0.22 mmol) 4-fluorobenzaldehyde, 24 mg (0.4 mmol) acetic acid and 127 mg (0.6 mmol) sodium triacetoxyborohydride were added and the reaction was stirred at room temperature over night. 2N aqueous NaOH solution (6 ml) was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 58 mg (65%) [5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 450.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.25 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.39 (dd, 2H), 7.30 (d, 1H), 7.24 (d, 1H), 7.16 (t, 2H), 7.01 (s, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.48 (s, 2H), 2.78 (m, 3H), 2.64 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[Cl:24][CH2:25][C:26]#[C:27][CH2:28][OH:29]>C(Cl)Cl.C(Cl)Cl.O>[C:6]([Si:10]([O:29][CH2:28][C:27]#[C:26][CH2:25][Cl:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: OCC#CCCl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCC#CCCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of imidazole (691 mg, 10.2 mmol) and tert-butylchlorodiphenylsilane (2.65 ml, 10.1 mmol) in DCM (15.3 mL) at 0° C. was added 4-chlorobut-2-yn-1-ol (824 μL, 9.18 mmol). After 2 h of stirring at rt it was diluted with DCM/water and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue dissolved in dioxane and reconcentrated (2×) then used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Cl)=[C:8]([O:17][CH3:18])[CH:7]=1)[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[C:8]([O:17][CH3:18])[CH:7]=1)[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)c(OC)c1
Yield: 93.3 %

Procedure:
A mixture of 40.5 g (0.141 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester and 27.2 g (0.144 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide was stirred and heated at reflux for 5 h, then was stirred at ambient temperature overnight. The solvent was evaporated under reduced pressure to give 52.3 g (93%) of a gummy residue which solidified upon standing. An analytical sample, mp 70°-72° C., was prepared from ethyl ether-petroleum ether (30°-60° C.) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:21].Cl.[N:23]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:21])=[C:2]([N:30]4[CH2:31][CH2:32][C@H:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[N:11]=3)[C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn([C@H]2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CC[C@H](n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 24.2 %

Procedure:
Ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (250 mg, 0.8 mmol) was reacted with 350 mg (2 mmol) of 3(S)-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 8 ml of pyridine in the presence of 305 mg (2 mmol) of DBU at 80°-90° C. for 6 h. The reaction was then stirred at r.t. for 4 days. The solvent was then evaporated under reduced pressure and to the residue, water was added and extracted with chloroform. The organic layer was dried and evaporated to dryness. The residue was then chromatographed over alumina (neutral, activity III) using chloroform as solvent to yield 80 mg (24%) of the desired product. 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.05 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 5.46-5.32 (m, 1H), 4.46-4.26 (m, 4H), 4.15-4.0 (m, 2H), 3.56-3.42 (m, 1H), 2.71-2.57 (m, 2H), 1.4 (t, 3H), 1.26-0.95 (m, 4H).
Reaction SMILES: C(OC(N[C@H:9]([C:13]([CH2:17]C)([CH3:16])[CH2:14][CH3:15])[C:10](O)=O)=O)(C)(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:9]([C:13]([CH3:17])([CH2:14][CH3:15])/[CH:16]=[N:26]/[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:10]
Reactant: CCC(C)(CC)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)(/C=N/C(c1ccccc1)c1ccccc1)CC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 100-mL round-bottomed flask containing crude 2-ethyl-2-methylbutanal (15) was charged with CH2Cl2 (20 mL) and Na2SO4 (10 g). Aminodiphenylmethane (9) (8.83 mL, 80 mmol, 0.80 equiv) was added via syringe. The flask was capped with a plastic stopper, and the mixture was stirred at room temperature for 14 h. The reaction mixture was filtered through a medium porosity fritted disk funnel and rinsed with CH2Cl2 (4×10 mL). The filtrate was concentrated under reduced pressure and maintained at 1 torr with stirring for 1 h to provide a slightly cloudy, colorless oil. A 5-cm diameter fritted disk funnel was filled with a 3-cm high layer of silica gel. The funnel was rinsed with a solution of 20:1:0.5 hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a solution of 20:1 hexanes/Et2O (50 mL). The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and rinsed through the frit into a 250-mL round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O (4×25 mL). The mixture was concentrated under reduced pressure (30 torr→1 torr) to provide a clear, colorless oil that was slightly cloudy. The oil was maintained at 1 torr for 1 h while stirring to provide (E)-N-(2-ethyl-2-methylbutylidene)diphenylmethanamine (2b) in 95% 1H-NMR purity. Yield: 18.7 g (67 mmol, 84% from aminodiphenylmethane, 67% from 2-ethyl-2-butanal).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([CH3:12])=[C:4]([CH:3]=1)[O:13][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 55 °C
Yield: 80 %

Procedure:
A mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (500 mg, 2.492 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (752 mg, 3.74 mmol) and triphenylphosphine (1307 mg, 4.98 mmol), stirred in THF (10 mL) until completely dissolved, then DIAD (1.530 mL, 7.48 mmol) was slowly added dropwise via syringe over 5 minutes. The reaction heated at 55° C. for 4 h under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The orange oil residue was purified by flash column chromatography (30% EtOAc/hexanes). The desired fractions were combined, concentrated, then triturated with EtOAc to give tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (0.765 g, 1.99 mmol, 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.26 (m, 1 H) 1.41 (s, 9 H) 1.49-1.63 (m, 2 H) 1.79-1.92 (m, 2 H) 2.28 (s, 3 H) 3.15-3.30 (m, 2 H) 3.51-3.66 (m, 2 H) 3.83 (s, 3 H) 4.63-4.81 (m, 1 H) 7.31 (d, J=2.02 Hz, 1 H) 7.37 (d, J=2.02 Hz, 1 H) MS (ES) [M+H]+ 384.1.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:5](=O)[NH:4][N:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Cc1n[nH]c(=O)c2cc3ccccn3c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc(Cl)c2cc3ccccn3c12
Temperature: 0 °C
Yield: 52 %

Procedure:
The stirred suspension of the 4-methyl-2H-pyridazino[4,5-b]indolizine-1-one (10.0 g, 0.050 mole) in phosphoryl chloride (75 ml) was refluxed under nitrogen for 3 hours. After cooling, the reaction mixture was poured into ice-water (1 L) with vigorous stirring. Then, the solution was made alkaline (pH 8-9) by addition of a 50% W/W sodium hydroxide solution (cooling). The suspension was filtered and the solid was washed with water and dried to yield 1-chloro-4-methylpyridazino[4,5-b]indolizine (10.33 g). For analysis, a sample was recrystallized from dichloromethane and ether.
Reaction SMILES: Br[CH:2]([CH3:20])[C:3]([O:5][C:6]([CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:7])=[O:4].C(=O)(O)[O-].[Na+].[CH3:26][NH:27][CH3:28]>C(#N)C>[CH3:26][N:27]([CH3:28])[CH:2]([CH3:20])[C:3]([O:5][C:6]([CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:7])=[O:4]
Reactant: CCCCCCCCCCCC(C)(C)OC(=O)C(C)Br
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCC(C)(C)OC(=O)C(C)N(C)C
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a stirred solution of 74 (2 g, 5.7 mmol) in acetonitrile (10 mL) was added sodium bicarbonate (0.48 g, 5.74 mmol) and followed by dimethyl amine (40% in water) (10 mL, 88.8 mmol) at 25-30° C. The reaction mixture was stirred for 3 hours at 25-30° C.; the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum. The solvent was concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 75 (1.49 g, yield: 83%) as a liquid.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][N:4]([S:6]([NH:9]C(=O)OCC2C=CC=CC=2)(=[O:8])=[O:7])[CH2:3]1.CC1CCC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1([F:20])[CH2:5][N:4]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:3]1
Reactant: O=C(NS(=O)(=O)N1CC(F)(F)C1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC1=CC=CCC1
Agent: [OH-]
Solvent: CO
Product: NS(=O)(=O)N1CC(F)(F)C1
Yield: 91.2 %

Procedure:
To a solution of benzyl (3,3-difluoroazetidin-1-yl)sulfonylcarbamate (Preparation 22, 800 mg, 2.61 mmol) in methanol (20 mL) was added 10% palladium hydroxide on charcoal (150 mg) and methylcyclohexadiene (4.9 g, 52.3 mmol) and the mixture heated at reflux for 18 hours. Once cooled the reaction mixture was filtered through Celite™ and concentrated to give the title compound as an amber oil (410 mg, 91%).