Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5](C)=[O:6])[CH:2](C)C.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.C(Cl)(=O)C=C>C(N(CC)CC)C>[C:5]([O:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:6])[CH:1]=[CH2:2]
Reactant: CC(=O)CC(C)C
Reactant: OCc1ccc(O)cc1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccc(O)cc1
Reaction time: 0.5 h
Yield: 26 %

Procedure:
1400 g of methyl isobutyl ketone, 50 g of 4-hydroxybenzyl alcohol and 40 g of triethylamine were charged into a separable flask having a capacity of 3 liters, provided with a stirrer and a nitrogen gas feed tube, and deaerated for 30 minutes, and then 33 g of acrylic acid chloride was dropwise added thereto at 3° C. over 50 minutes. Then, stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was recovered by filtration. The filtrate was washed with 0.5N hydrochloric acid and with water, dehydrated over anhydrous sodium sulfate, and then subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1 by volume) to obtain the desired fraction. By distilling off the methyl isobutyl ketone solvent from the fraction under reduced pressure, 15 g of 4-hydroxybenzyl acrylate of the following chemical formula was obtained (yield: 26%): ##STR1##
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[C:25]([Br:37])[CH:24]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].C(N(CC)C(C)C)(C)C.[N:47]1([C:53](Cl)=[O:54])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(Cl)Cl.CN(C)C=O>[Br:37][C:25]1[CH:24]=[C:23]([CH2:22][C@H:2]([NH:1][C:53]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:54])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:4])[CH:28]=[CH:27][C:26]=1[CH:29]1[S:33](=[O:34])(=[O:35])[NH:32][C:31](=[O:36])[CH2:30]1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)N1CCOCC1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 2-[4-((2S)-2-amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoylamino)butoxy]-6-hydroxybenzoate (30.0 mg, 0.0501 mmol) in methylene chloride (0.4 mL) and N,N-dimethylformamide (0.10 mL) was added N,N-diisopropylethylamine (26.4 μL, 0.152 mmol) and morpholine-4-carbonyl chloride (6.48 μL, 0.0556 mmol) at room temperature. The resulting solution was stirred for 2 h. The reaction was quenched with 1 N HCl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by preparative LCMS to afford a white solid (30 mg, 80%). 1H NMR (400 MHz, CD3OD): δ 7.61 (dd, J=9.6, 1.8 Hz, 1H), 7.47 (dd, J=11.3, 8.0 Hz, 1H), 7.35 (m, 1H), 7.24 (t, J=8.3 Hz, 1H), 6.48 (m, 2H), 5.36 (m, 1H), 4.44 (dd, J=8.8, 6.6 Hz, 1H), 3.98 (t, J=5.8 Hz, 2H), 3.87 (s, 3H), 3.59 (m, 4H), 3.43 (dd, J=17.6, 8.4 Hz, 1H), 3.23 (m, 1H), 3.16 (m, 3H), 2.96 (m, 1H), 1.64 (m, 4H). LCMS found for C29H36BrN4O10S (M+H)+: m/z=711, 713.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1N2CN3CN(C2)CN1C3.[C:31](O)(C(F)(F)F)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=1)[CH:31]=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichloro-4-(4-methoxy-phenoxy)-nitrobenzene (3.14 g, 10.0 mmol) in TFA (30 ml) was added hexamethylenetetramine (2.10 g, 15.0 mmol). The resulting mixture was stirred at 75° C. for 2 h then concentrated to a viscous oil. The residue was taken up in 30 ml H2O and stirred at RT. To this suspension was added sufficient sat'd aqueous NaHCO3 to neutralize the residual TFA and the mixture was then extracted with EtOAc (3×30 ml). The combined EtOAc extracts were washed with sat'd aqueous NaHCO3 (2×30 ml) and dried over Na2SO4. Dried extracts were filtered and concentrated to give the title compound of step A (3.67 g) as a yellow solid. The title product of Step A was used in the next step without further purification. MS (APCI−) Calc.: 341.0, Found: 340.1 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][C:3]=1[F:17].[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:17]
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Reactant: O=C1CCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 75.5 %

Procedure:
To a stirred suspension of zinc powder (0.90 g, 13.8 mmoL) in anhydrous THF (20 mL) was slowly added TiCl4 (0.75 mL, 1.3 g, 6.8 mmoL) via syringe at RT under a nitrogen atmosphere. (Note: significant fuming occurred upon addition of TiCl4.) The reaction mixture was heated at reflux with stirring under nitrogen for 2.25 h. A solution of (4-bromo-3-fluorophenyl)(4-hydroxyphenyl)methanone (186) (0.50 g, 1.7 mmoL) and cycloheptanone (0.6 mL, 0.57 g, 5.09 mmoL) in THF (10 mL) was added to the reaction mixture via syringe. The reaction mixture was heated at reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (10 mL) followed by 10% K2CO3 (10 mL). The quenched reaction mixture was filtered through a pad of Celite with the aid of EtOAc and H2O. The pad was washed with EtOAc and the filtrate was transferred to a separatory funnel. The layers were separated and the organic phase was allowed to stand at RT over the weekend. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give 0.48 g (75%) of compound 187 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 8H), 2.20 (m, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.88 (dd, J=1.9 Hz, 8.3 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 7.08 (dd, J=1.8 Hz, 10.0 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 9.33 (s, 1H). LRMS (ESI): m/z 373 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][Cl:10])=[N:7][CH:6]=[CH:5][N:4]=1.[CH2:11]([O:13][C:14](=[O:25])[CH:15]([NH:21][C:22](=[O:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]>C(Cl)Cl>[C:22]([NH:21][C:15]([CH2:2][C:3]1[C:8]([CH2:9][Cl:10])=[N:7][CH:6]=[CH:5][N:4]=1)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:13][CH2:11][CH3:12])=[O:25])(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1nccnc1CCl
Solvent: ClCCl
Product: CCOC(=O)C(Cc1nccnc1CCl)(NC(C)=O)C(=O)OCC
Reaction time: 48 h
Yield: 56 %

Procedure:
To a solution of 2,3-bis(chloromethyl)pyrazine (2.06 g, 11.64 mmol) in 60 mL DCM was added diethyl(N-acetylamino)malonate (2.66 g, 11.7 mmol)anhydrous potassium carbonate (4.83, 34.9 mmol) and 18-C-6 (154 mg, 5 mol %) and the reaction was stirred for 48 h. The reaction was filtered through a sintered glass funnel, concentrated, and flash chromatographed on SiO2 using a 50% to 75% EtOAc in hexane gradient. Obtained 3.06 g or 56% yield of the product. MS found: (M+H)+=359.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CN1C(=O)[C@H](NC(=O)OC(C)(C)C)Cc2ccccc21
Yield: 72.4 %

Procedure:
(R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (26 mg), as prepared in Example 5, was dissolved in tetrahydrofuran (5 mL) at room temperature under argon. To the stirring solution was added methyl bromoacetate (31 mg), followed by sodium methoxide (26 mg). The resulting suspension was stirred for 30 min before dilution with ethyl acetate (25 mL) and water (25 mL). The organic phase was separated, washed with water (25 mL), and dried over anhydrous sodium sulfate. After solvent evaporation under vacuum, the crude product was purified by reverse phase preparative HPLC to provide (R)-3-t-butyloxycarbonylamino-1-carbomethoxymethyl-3,4-dihydrocarbostyril (24 mg).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), phenylboronic acid (121 mg), and tetrakistriphenylphosphine palladium (23 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (0.5 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (74 mg, yield 100%).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:16])([CH:14]([OH:15])[CH:1]([CH3:3])[CH3:2])[CH3:17])[C:9](=[O:18])[C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C(C)C)CO1
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (5 ml of a 2M solution in tetrahydrofuran) was added during 10 minutes to a stirred solution of 2-(2,3-dihydro-6-methyl-4-oxo-5 -phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (2 g) in tetrahydrofuran at 0° C. under an inert atmosphere. The mixture was allowed to warn to 10° C. over 1 hour, poured onto saturated ammonium chloride solution and extracted (ether). The organic phase was dried (magnesium sulphate) and evaporated to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethylpentan-3-ol (2.26 g) as a yellow gum, m.p. 42-54° C., NMR 1H δ0.85(d,3H), 0.95(d,3H), 1.4(s,3H), 1.5(s,3H), 1.65(m,1H), 1.85(s,3H), 3.25(dd,1H), 5.0(d,1H), 5.1(d,1H), 5.25(d,1H), 7.15-7.35(m,5H).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.[C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:25])[CH3:24].C(=O)=O.C(O)(C)C.[Cl-].[NH4+]>ClCCl>[OH:25][C@H:23]([CH3:24])[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CCCC(C)=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)CCC[C@@H](C)O
Temperature: 0 °C
Yield: 64.1 %

Procedure:
A 250 mL, round bottom flask was equipped with a magnetic stirrer, a N2 inlet, a type-J teflon covered thermocouple, and charged with 6 g of (S)-methyl-CBS-borane complex 2 (20.6 mmol) dissolved in 40 mL of dichloromethane (DCM). The solution was cooled to −40° C. before ethyl 4-acetylbutyrate (3 g, 18.9 mmol) in 5 mL of DCM was added dropwise at a rate which kept the internal temperature below −20° C. At the end of addition, the dry ice/isopropanol cooling bath was substituted with an ice bath maintaining the internal reaction temperature at 0° C. for an additional hour. G.C. analysis showed less than 5% starting ketone. The reaction was worked up after 2 h at 0° C. by cautious addition of saturated aqueous ammonium chloride (100 mL). The mixture was transferred to a reparatory funnel and extracted with ethyl acetate (2×100 mL). The separated combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 7 g of crude products. Flash column chromatography (FCC) on 120 g of flash grade silica gel eluting with 20% EtOAc-hexanes yielded 1.94 g (65%) of alcohol 3 as an oil. G.C. analysis indicated a purity of 97.4 A %. 1H NMR (CDCl3): 1.20 (d, J=3 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.47 (m, 2H), 1.71 (m, 3H), 2.34 (t, J=7.5 Hz, 2H), 3.89 (m, 1H), 4.13 (q, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].[C:23]1([CH2:29][CH2:30][CH2:31]O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:31][CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (1.7 g, 6.07 mmol), 3-phenylpropanol (1.65 g, 12.14 mmol) and triphenylphosphine (3.18 g, 12.14 mmol) were dissolved in tetrahydrofuran (100 ml). Diethyl azodicarboxylate (2 ml, 12.14 mmol) dissolved in tetrahydrofuran (20 ml) was added dropwise thereto at 0° C. After stirring for 6 hours at room temperature, the mixture was washed with brine, extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (diethyl ether:hexane=1:10) to obtain the title compound (yield 85%) as a dark red solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([CH3:49])[CH3:38])=[O:48])[CH2:47][CH2:46]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C36H46N7O3Cl2 [(M+H)+] 694.3034, observed 694.3035.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.O1CCOCC1>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[N:6]3[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Nc1cc(-c2cnc3ccc(Cl)nn23)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 10-mL, reaction vial was added 3-bromo-6-chloroimidazo[1,2-b]pyridazine (0.100 g, 0.43 mmol, Combi-Blocks, San Diego, Calif.), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.213 g, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium, complex with dichloromethane (24 mg, 0.032 mmol), sodium carbonate (0.137 g, 1.29 mmol), dioxane (2 mL) and water (1 mL). The vial was sealed and purged with nitrogen for several minutes. The reaction mixture was stirred at 100° C. for 1 h and then allowed to cool to room temperature. The organic phase was taken and the solvents eliminated under vacuum. The crude reaction mixture was purified first by silica gel chromatography (1 to 3% MeOH/CH2Cl2) followed by preparative HPLC (30-90% ACN 0.1% TFA/water 0.1% TFA) and free based by treatment with a sat aqueous solution of sodium bicarbonate and extraction with dichloromethane (3×). The combined organics were dried over Na2SO4, filtered and the solvents were eliminated under vacuum. The title compound was obtained as a white solid. MS (ESI positive ion) m/z: 438.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (t, J=8.7 Hz, 2H) 7.52 (d, J=9.6 Hz, 1H) 7.86-7.94 (m, 2H) 8.36 (d, J=9.4 Hz, 1H) 8.49 (s, 1H) 8.57 (d, J=1.8 Hz, 1H) 8.89 (s, 1H) 10.52 (s, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:22]=[C:21]2[C:34]1[N:35]=[N:36][N:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=2)[CH:38]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:48][O:47][C:45]([C:42]1[CH:43]=[CH:44][C:39]([N:37]2[CH:38]=[C:34]([C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[C:18]([CH2:17][N:13]5[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:6]6[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=6)=[N:14]5)[CH:19]=4)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:22]=3)[N:35]=[N:36]2)=[CH:40][CH:41]=1)=[O:46]
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(CBr)cc34)nn2)cc1
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride (106 mg; 2.43 mmol; 7.4 eq.) was added in one portion to a solution of 6-pyridin-4-ylpyridazin-3(2H)-one (176 mg; 1.02 mmol; 3.1 eq.) in DMF (6 mL). After 10 min a solution of tert-butyl 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (565 mg; 0.33 mmol; 1.0 eq.) in DMF (6 mL) was added dropwise over 2 min and the reaction solution stirred for 4 h at RT. The reaction mixture was then poured into saturated solution of NaHCO3 and extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.75-8.62 (m, 3H), 8.30 (d, J=8.8 Hz, 2H), 8.24-8.18 (m, 3H), 8.15 (d, J=9.2 Hz, 1H), 7.93 (dd, J=1.6, 4.6 Hz, 2H), 7.78-7.72 (m, 1H), 7.19 (d, J=9.8 Hz, 1H), 5.59 (s, 2H), 3.92 (s, 3H), 1.68 (s, 9H). MS (ESI+): 605.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)C1(Nc2cccc(OC)c2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(Nc2cccc(OC)c2)CCNCC1

Procedure:
A mixture of 60 parts of methyl 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol, previously saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-[N-(3-methoxyphenyl)amino]-4-piperidinecarboxylate as an oily residue.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O.O>[OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([N+:11]([O-:13])=[O:12])=[CH:6][N:7]=1
Reactant: NC(=O)c1nccnc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)c1nc([N+](=O)[O-])cnc1O
Temperature: 40 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
In 24 mL of concentrated sulfuric acid is suspended 4.00 g of 3-hydroxy-2-pyrazinecarboxamide. To the suspension is added 3.09 g of potassium nitrate under ice-cooling. The resulting mixture is stirred at 40° C. for 3 hours. The reaction mixture is poured into 240 mL of water, and the deposited crystals are collected by filtration. The crystals thus obtained are suspended in 80 mL of water and heated under reflux for 30 minutes. After cooling, the crystals are collected by filtration to obtain 2.45 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide.