Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:16]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Reactant: OB(O)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(-c3ccccc3F)c2)nc1

Procedure:
In a 5 mL microwave vial, 3-bromo-5-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (20 mg, 0.05 mmol), 2-fluorophenylboronic acid (14.16 mg, 0.1012 mmol), cesium carbonate (82.42 mg, 0.2530 mmol), tetra-n-butylammonium iodide (18.69 mg, 0.05060 mmol), and POPd (2.538 mg, 0.005060 mmol) were dissolved in Water (0.04 mL, 2 mmol) and N,N-dimethylformamide (0.2 mL, 2 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH 10. The combined pure fractions were reduced in vacuo to afford the title compound as colorless oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[C:14](OC)=[O:15].Cl>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[CH2:14][OH:15]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
Add a solution of DIBAL-H in toluene (1.0 M, 35 mL) to a solution of methyl 3-chloro-4-hydroxybenzoate (1.9 g, 10 mmol) at 0° C. under nitrogen. Stir the reaction at 0° C. and gradually warm to ambient temperature overnight. Quench the reaction with slow addition of 0.1N aqueous HCl, add more acid to break the gel-like solid to two clear layers. Separate the organic layer, and extract the aqueous layer with EtOAc three times. Combine the organic layers, wash with brine, dry over Na2SO4, filter and concentrate to give a white solid. MS (ES−) m/z 157 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(N)n1
Yield: 90.4 %

Procedure:
To a solution of 4,6-dichloro-2-amino pyrimidine (5.0 g, 30.5 mmol) in MeOH (100 mL) was added 25% sodium methoxide (6.59 g, 30.5 mmol). The solution was refluxed for 20 hours, at which time the methanol was removed in vacuo. The residue was dissolved in EtOAc (350 mL), washed with H2O (100 mL) and with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 4.4 g (90%) of 4-chloro-6-methoxypyrimidine-2-ylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[Cl:11][CH2:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of ortho-nitrophenol (5.0 g, 35.8 mmoles) and 2-chloroethanol (9.5 ml, 143 mmoles) in THF (50 mL), in a round bottom flask, under nitrogen, was stirred at room temperature. Triphenylphosphine (14 g, 53.7 mmoles) was added, followed by diethylazodicarboxylate dropwise (8.5 mL, 53.7 mmoles). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water (1×), brine (1×), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 40% EtOAc/hexane to give the title compound as an off-white solid (5.6 g, 28 mmoles).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:13]([N:15]2[CH2:20][CH2:19][NH:18][C:17](=[O:21])[C:16]2([CH3:23])[CH3:22])=[O:14])=[C:8]([N+:10]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:10][C:8]1[CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:6][C:7]=1[C:13]([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[C:16]1([CH3:22])[CH3:23])=[O:14]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)N2CCNC(=O)C2(C)C)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(N)c(C(=O)N2CCNC(=O)C2(C)C)[nH]1
Yield: 93 %

Procedure:
A mixture of the previously prepared 4-(2-tert-butyl-4-nitro-1H-pyrrole-5-carbonyl)-3,3-dimethylpiperazin-2-one (80 mg, 0.25 mmol) dissolved in methanol (2 mL) and Pd on charcoal (10% w/w, 20 mg) was shaken under hydrogen atmosphere in a Parr shaker at 50 psi for 18 hours. The reaction was filtered through celite, the residue concentrated under vacuum to afford 68 mg of the desired 4-(4-amino-2-tert-butyl-1H-pyrrole-5-carbonyl)-3,3-dimethylpiperazin-2-one as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([O:10][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][N:13]=1)[C:18]#[N:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
Sodium hydride (60% oil, 0.13 g, 3.3 mmol) was suspended in tetrahydrofuran (2 ml), Benzyl alcohol (0.30 g, 3.2 mmol) was added thereto and the mixture was stirred for 30 minutes. A solution of 2-chloro-4-cyanopyridine (0.40 g, 2.9 mmol) in tetrahydrofuran (1 ml) was added to the mixture and the mixture was refluxed for 6 hrs. The reaction mixture was combined with ethyl acetate and water and stirred. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (30 g) column chromatography, eluted with hexane-ethyl acetate (4:1, v/v) to give the titled compound (0.37 g, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.O>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:26]=1[C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Nc2ccc(Cl)nn2)CC(C)(C)N1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(Nc2ccc(-c3ccc4ccccc4c3)nn2)CC(C)(C)N1
Temperature: 120 °C

Procedure:
To a 2 mL microwave vial was added 6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-2 (100 mg, 0.37 mmol), naphthalen-2-ylboronic acid (96 mg, 0.56 mmol), Na2CO3 (118 mg, 1.17 mmol), water (0.25 mL), DME (1 mL), and PdCl2(dppf).CH2Cl2 (30 mg, 0.037 mmol). The reaction vessel was sealed and heated in a microwave at 120° C. for 45 mins. The crude mixture was diluted with EtOAc, then the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified via silica chromatography to give 6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (86 mg). LCMS Rt=1.39 min (condition B); MS (M+1)=361.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.30 (s, 1H), 8.12 (dd, J=8.6, 1.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.76-7.84 (m, 2H), 7.67 (d, J=9.3 Hz, 1H), 7.37-7.48 (m, 2H), 6.69 (d, J=9.1 Hz, 1H), 4.82 (br. m, 1H), 4.31-4.51 (m, 2H), 2.07 (dd, J=12.9, 3.5 Hz, 2H), 1.35 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[N:7]3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(Cl)n12
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2cccc(NCCc3ccc(N)cc3)n12
Yield: 75.5 %

Procedure:
A mixture of 4.07 g (17.1 mmol) of 5-chloro-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine, 3.48 g (25.6 mmol) of 2-(4-aminophenyl)ethylamine and 4.41 g (34.1 mmol) of N,N-diisopropylethylamine in 60 ml of acetonitrile was heated for 64 hours under reflux with stirring. After cooling, the solvent was distilled off. To the residue was added chloroform. The residue was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=30:1) and recrystallized from ethyl acetate-n-hexane to give 4.37 g of the desired compound (75.7%, pale brown crystals).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1I.[CH3:16][Si:17]([CH3:34])([CH3:33])/[CH:18]=[CH:19]/[Sn](CCCC)(CCCC)CCCC>ClC(Cl)C.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1/[CH:19]=[CH:18]/[Si:17]([CH3:34])([CH3:33])[CH3:16]
Reactant: CCc1nc(C(=O)OC)c(I)c(N)c1F
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc(C(=O)OC)c(/C=C/[Si](C)(C)C)c(N)c1F
Temperature: 120 °C
Yield: 57.9 %

Procedure:
Methyl 4-amino-6-ethyl-5-fluoro-3-iodopicolinate (270 mg, 0.833 mmol) and bis(triphenylphosphine)palladium(II) dichloride (58.5 mg, 0.083 mmol) were combined in a microwave reactor vessel. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (649 mg, 1.666 mmol) dissolved in dichloroethane (0.8 mL) was added and the reaction mixture was heated at 120° C. for 30 min a microwave reactor. The cooled reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated on to silica. The product was purifed by flash chromatography (SiO2, 0-30% EtOAc:Hex gradient) to provide the title compound as an off-white solid (143 mg, 0.482 mmol, 57.9% yield): 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 9H), 1.16 (t, J=7.6 Hz, 3H), 2.65 (qd, J=7.6, 2.6 Hz, 2H), 3.71 (s, 3H), 5.99 (d, J=19.3 Hz, 1H), 6.25 (s, 2H), 6.84 (d, J=19.2 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −148.85; ESIMS m/z 297 ([M+H]+), 295 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]#[C:27][NH2:28].Cl>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1)[C:27]([NH2:28])=[NH:26]
Reactant: Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
2.0 g (6.1 mmol) of (Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 1.0 g (23.7 mmol) of cyanamide are dissolved in 100 ml of ethanol and 10 ml of ethereal hydrochloric acid and heated for 24 hours in a glass bomb at 80° C. The solvent is distilled off. Chromatography of the residue on silica gel (ethyl acetate/methanol/glacial acetic acid/water=17:3:5:5) yields the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@@H:23]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:22][C@@H:13]2[O:14]CC2C=CC=CC=2)[CH3:10])[C:4](=[O:39])[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:40])[CH2:3][C:4](=[O:39])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@@H:23]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:22][C@@H:13]2[OH:14])[CH3:10])[C:6](=[O:8])[CH2:7]1
Reactant: CC(=O)OC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 94 %

Procedure:
Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranoside (11) (100 mg, 0.17 mmol) was dissolved in MeOH (5 ml) and hydrogenated over Pd/C (10%) (20 mg) overnight. The suspension was filtered, and the filtrate was evaporated to give 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (12) (75 mg, 90%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:20](OCC)=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1.ClCCl.O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:20](=[O:21])[C:15]=3[N:16]([CH3:19])[C:17]=2[CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
4 ml (40.6 mmol) of phenylhydrazine are added at room temperature to a solution of 4.6 g (13.6 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate in 120 ml of acetic acid. The reaction mixture is stirred for 30 min at room temperature and then for 4 hours at reflux. The mixture is cooled and 350 ml of dichloromethane and 100 ml of water are added. The organic phase is separated by settling, washed with a saturated aqueous sodium hydrogencarbonate solution and then with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 4.1 g (10.7 mmol) of product are isolated.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:34].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH2:34])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (41 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.02 ml) and 1 drop of N,N-dimethylformamide. After stirring at room temperature for 15 minutes, ammonia solution (28%, 1 ml) was added to the mixture and stirred at room temperature for 15 minutes. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-benzyl-4-(3-carbamoylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (139 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH2:24])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.[NH4+].[Cl-]>[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH:24][C:27](=[O:28])[CH2:26][Cl:25])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)(c1cccc(Br)c1)c1cc[nH]n1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)CCl)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
DIPEA (1.18 mL, 6.77 mmol) was added to a solution of rac-1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1.2 g, 4.51 mmol) in DCM (20 mL) and the mixture was cooled in an ice bath. Then chloroacetyl chloride (0.40 mL, 4.96 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The mixture was diluted with NH4Cl (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and NaHCO3 (aq. sat. solution) (1 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and the product extracted with DCM. The combined organic layers were concentrated in vacuo to yield rac-N-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-2-chloro-acetamide (1.22 g, 79% yield) as a colourless oil, which was used in the next step without further purification.
Reaction SMILES: CC1[CH2:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH:8](C)[CH:7]([CH3:15])[C:6]([CH3:17])([CH3:16])[C:5]=2C(=O)C1.CC1(C)C(C)C(C)[C:27](C)(C)[C:26]2[CH2:25][C:24](=[O:34])[CH2:23]C[C:21]1=2>>[CH3:15][CH:7]1[C:6]([CH3:17])([CH3:16])[C:5]2[CH:21]=[C:26]([CH3:27])[C:25]([C:24]([CH3:23])=[O:34])=[CH:11][C:10]=2[C:9]([CH3:12])([CH3:13])[CH2:8]1
Reactant: CC1C(C)C(C)(C)C2=C(CCC(=O)C2)C1(C)C
Reactant: CC1CC(=O)C2=C(C1)C(C)(C)C(C)C(C)C2(C)C
Product: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C

Procedure:
However, if there was added to the base the same amount of (6RS,7RS)-3,5,5,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one or (6RS,7RS)-5,5,6,7,8,8-hexamethyl-3,4,5,6,7,8-hexahydronaphthalen-2(1H)-one the whole olfactif effect was closer to the one provided by Tonalide®. The effect obtained by the addition of (6RS,7RS) -5,5,6,7,8,8-hexamethyl-3,4,5,6,7,8-hexahydronaphthalen-2(1H)-one was also slightly more ambrette than the one imparted by (6RS,7RS)-3,5,5,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][CH2:25][O:26][CH3:27])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COCCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COCCN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-bromo-2-methoxyethane. MS 362 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.59 μM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][C:20]=3[F:31])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:31][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][C:19]=1[CH2:18][NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)=[CH:33][CH:32]=2)[CH2:10][CH2:11]1)=[O:16])[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1
Product: O=C(O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Yield: 27.5 %

Procedure:
Methyl 2-(4-{[({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}-3-fluorophenoxy)acetate (0.605 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.477 g, 1.2 mmol) according to Procedure G to furnish the title compound (0.280 g, 0.33 mmol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Cl:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19](B(O)O)=[CH:18][CH:17]=1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:2]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Reactant: Cc1nc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1nc(Cl)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 140 °C
Yield: 605.6 %

Procedure:
The reaction was carried out in eight microwave vials. To each vial were added 4-bromo-6-(trifluoromethyl)-1H-indazole (0.5 g, 1.886 mmol), (6-chloro-2-methylpyridin-3-yl)boronic acid (0.3875 g, 2.264 mmol) and PdCl2(dppf) (0.069 g, 0.0944 mmol) in dioxane (12 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light-brown suspensions were each heated at 140° C. for 60 minutes in a microwave reactor. The reaction mixtures were combined and concentrated and the crude residue was diluted with EtOAc and washed with water. The volatiles were removed via rotary evaporation and the product purified by CombiFlash® chromatography, eluting with a gradient of 0-100% EtOAc in heptane over a period of 180 minutes. The product-containing fractions were combined and the volatiles removed via rotary evaporation to give the title compound (3.56 g, 76%). ESI-MS m/z [M+H]+ calc'd for C14H9ClF3N3, 312.05. found 311.89.