Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]>CC(N(C)C)=O.C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27]([CH2:4][CH:5]3[CH2:7][CH2:6]3)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: BrCC1CC1
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: II
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(CC3CC3)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 70 °C
Yield: 7.6 %

Procedure:
Under nitrogen protection, zinc suspension (1.76 mL, 1.338 mmol) was added to a solution of diiodine (4.5 mg, 0.018 mmol) in DMA at room temperature. After several minutes, (bromomethyl)cyclopropane (120 mg, 0.892 mmol) was added. The reaction mixture was heated at 70° C. for 3 h, cooled down to room temperature, then transferred to a flask containing (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (70 mg, 0.178 mmol) and bis(tri-t-butylphosphine)palladium (0) (9.1 mg, 0.018 mmol) in THF (1 mL). The whole reaction mixture was heated at reflux overnight, cooled down and quenched with saturated sodium bicarbonate. The solid was filtered, and the filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (5 mg) as white solid. LCMS m/z=368.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.3 Hz, 1H), 1.22-1.28 (m, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 1.95-2.04 (m, 1H), 2.09-2.16 (m 1H), 2.26-2.32 (m, 1H), 2.37-2.41 (m, 4H), 2.68-2.74 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.5 and 6.2 Hz, 1H), 3.69 (d, J=6.3 Hz, 2H), 3.72-3.77 (m, 1H), 4.78 (br, 1H), 6.97 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 9.15 (d, J=1.3 Hz, 1H).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[N:37]=[C:36]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=3)(=[O:41])=[O:40])[C:35]([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])=[C:34]([O:58][CH3:59])[N:33]=2)[CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH3:59][O:58][C:34]1[C:35]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])=[C:36]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=2)(=[O:41])=[O:40])[N:37]=[C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:25][NH:24][C:1](=[O:4])[CH3:2])[CH:31]=2)[N:33]=1
Reactant: CC(=O)O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CNC(C)=O)c2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.6 mg of acetic acid and 22.3 mg of 4-methylmorpholin in DMF (5 ml) were added under ice-cooling 22.3 g of 2-Chloro-4,6-dimethoxy-1,3,5,-triazine and the solution was then stirred for 90 minutes at RT. Then 60 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride were added and stirring was continued for 12 h at RT. The mixture was partitioned between cold diluted HCl and EtOAc. The layers were separated the organic layer washed with water, dried over Na2SO4 and the solvent removed in vacuo to give N-{4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridin-2-ylmethyl}-acetamide as a light yellow crystalline solid. ISN mass spectrum, m/e 549.1 (M−1 calculated for C26H26N6O6S: 549).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][N:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:32]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Reactant: Clc1cc(Br)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(Cl)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 2-Chloro-4-bromopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white amorphous, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Commercially available methyl 3-amino-pyrazine-2-carboxylate (available from Aldrich Chemical Company) was brominated using a procedure similar to that of Russ, T., Ried, W., Ullrich, F., and Mutschler, E. Arch. Pharm. (Weinheim) 1992, 325, 761-767. To a solution of methyl 3-amino-2-pyrazine carboxylate (30.0 g, 200 mmol) in acetic acid (200 mL), bromine (11 mL) was added slowly via addition funnel. After complete addition of bromine, sodium carbonate powder was added slowly until precipitation occurred. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was reduced to half-volume in vacuo and then diluted with water (500 mL). The reaction mixture was shaken vigorously and the resulting solid was collected using vacuum filtration. The solid was washed with ether to afford a pure yellow solid (91% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]4[CH2:36][O:35]C(C)(C)[O:33]4)=[O:31])[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:31])[C@@H:32]([OH:33])[CH2:36][OH:35])[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:15])([CH3:16])[CH3:14])=[N:11][N:12]=1
Reactant: CCn1nc(C2CCN(C(=O)[C@@H]3COC(C)(C)O3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(C2CCN(C(=O)[C@@H](O)CO)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reaction time: 16 h
Yield: 48 %

Procedure:
To a mixture of 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (257 mg, 0.50 mmol, TFA salt), potassium (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (101 mg, 0.55 mmol) and EDCI (105 mg, 0.55 mmol) in DCM (5 mL) were added 1-hydroxy-1H-benzotriazol hydrate (85 mg, 0.56 mmol) and DIPEA (194 mg, 1.50 mmol). The mixture was stirred for 16 hours at room temperature. Water was added to the mixture and the mixture was extracted with DCM. The organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to give (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg). Mass Spectrum [M+H]+=526. To a mixture of (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg) in DCM (10 mL) at r.t was added dropwise TFA (1.6 ml, 20.77 mmol). The mixture was stirred for 16 h at r.t, concentrated and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as the eluant. The fractions containing the desired compound were evaporated to dryness to afford the title compound (142 mg, 48%) as a white solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.56 (1H, m), 1.70 (1H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.C(O)(C)C>[S:11]([N:1]=[N+:2]=[N-:3])([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Tosyl azide was prepared as follows. A solution of sodium azide (58.5 g, 0.90 tool) in distilled water (170 mL) was quickly added to a stirred suspension (partly in solution) of p-toluenesulfonyl chloride (143.0 g, 0.75 tool) in isopropanol (850 mL) contained in a beaker at room temperature. The mixture was stirred for one hour, then poured into 3 L of distilled water and stirred for one more hour. The separated oily tosyl azide was washed three times with water, dried over anhydrous magnesium sulfate, then dried by stirring under vacuum. It is important for its use as a reagent in the lithiation reaction that tosyl azide is substantially pure (free of impurities) and contains a negligible amount of water (measured by proton NMR). 114 g of colourless tosyl azide oil was obtained (yield 77%). A 95% yield could be obtained by extracting the drying agent with chloroform. 1HNMR: δ=7.84 H-ortho-sulfonyl (2H d, J≈8.3); δ=7.41 H-orthomethyl (2H d, J≈8.3); δ=2.49 Me (3H s).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=O)[C:10]=2[CH:29]=1)(=[O:4])=[O:3].Cl.[NH2:31][OH:32].N1CCCCC1>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[N:31][OH:32])[C:10]=2[CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Reactant: NO
Agent: Cl
Solvent: C1CCNCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=NO)CC1(CCN(CCc3ccccc3)CC1)O2

Procedure:
In the manner of Example 427, 3,4-dihydro-6-methane-sulfonamido-1'-(2-phenylethyl)-spiro [(2H)-benzopyran-2,4'-piperidine]-4-one was treated with hydroxylamine hydrochloride to give, after chromatography, the piperidine as a solid, m.p. 95°-99° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16](O)[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7].N1C=CC=CC=1>C(Cl)Cl>[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([Cl:3])[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1Cl
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of thionyl chloride (72 parts) in methylene chloride (270 parts) was added dropwise over a period of 30 minutes to a mixture of 2,3-dihydro-2-hydroxy-3,3-dimethyl-5-benzofuranyl methanesulphonate (130 parts) and pyridine (48 parts) in methylene chloride (1,300 parts) cooled in an ice bath. After stirring for three hours, the solution was washed twice with water, dried over sodium sulphate and the solvent distilled off under reduced pressure. The brown liquid which remained solidified to form 2-chloro-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulphonate (135 parts, 97% yield), melting point 59°-61° C, confirmed by its elemental analysis:
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5](C(O)=O)=[C:4](C)[CH:3]=1.[C:16](OC)([O:20][CH3:21])([O:18]C)[CH3:17]>CN1C(=O)CCC1>[CH3:14][S:11]([C:10]1[C:9]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:5][C:17]([C:16]([O:20][CH3:21])=[O:18])=[C:3]([CH3:4])[CH:2]=1)(=[O:13])=[O:12]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: COC(C)(OC)OC
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 100.0 g of 4-chloro-5-methanesulfonyl-2-methylbenzoic acid and 68.1 g of trimethyl orthoacetate in 322 ml of NMP was refluxed until the acid had reacted completely. After the excess orthoester had been distilled off, 96.5 g of sodium methanesulfinate were added, and the mixture was stirred at 90° C. for 18 h. Conventional work-up gave methyl 4,5-bis-methanesulfonyl-2-methylbenzoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21](=[O:25])([O:22][CH2:23][CH3:24])[O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 127.9 %

Procedure:
To a mixture of tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (53.93 g) obtained above and ethyl acetate (350 mL) were added pyridine (53.78 mL) and ethyl chlorocarbonate (70.57 g) under ice-cooling, and stirred at room temperature for 96 hrs. To the reaction solution was added ethyl acetate (500 mL), and washed with water (500 mL), aqueous solution of copper sulfate (200 mL), water (300 mL) and saturated brine (300 mL), followed by drying over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate as colorless oil (93.19 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C.CCOC(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.[Cu]I>[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CCC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.0 g, 10.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.03 g, 1.07 mmol) and CuI (203 mg, 1.07 mmol) in triethylamine (30 mL), was added 4-methylpent-1-yne (2.23 g, 27.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound (2.2 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.90-3.86 (m, 1H), 3.77-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.33 (d, 2H), 2.05-1.94 (m, 2H), 1.86 (m, 1H), 1.76-1.71 (m, 1H), 1.60-1.54 (m, 2H), 1.02 (d, 6H); LCMS: 283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCI
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A suspension of 2-methyl-5-phenyl-3-furancarboxylic acid (5.0 g), ethyl iodide (4.7 g) and potassium carbonate (3.5 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.7 g, 100%) as an oil.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
p-Toluoyl chloride (0.48 ml, 3.63 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (1 g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylene chloride under nitrogen atmosphere. After 1 h, the product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes/ethyl acetate (1:2) gave N-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as an oil. The free amine was dissolved in ether and 3.5 equivalents of 1N ethereal HCl solution (10.7 ml) was added. Filtration of the resulting solid provided N-{(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as the bis hydrochloride salt, mp 227.8-228.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]>N1CCCCC1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:16]([C:15]([CH:14]([O:13][CH2:11][CH3:12])[O:23][CH2:24][CH3:25])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1OC)C(=O)C(OCC)OCC

Procedure:
A solution of 2-methoxybenzaldehyde (2.7228 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 or 5 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed with water and dried. The solvent was removed from the extract to give oily ethyl 2-(2-methoxybenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.5832 g) was heated in an oil bath (about 100° C.) for 7 hours. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water twice and dried over magnesium sulfate. The solvent was removed to give a red oil. The oil was purified by a column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0779 g). The product was recrystallized from n-hexane to give pale yellowish prisms, m.p. 105° to 107° C.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[CH2:22](Br)[CH3:23]>C1(C)C=CC=CC=1>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: CCBr
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3
Temperature: 130 °C
Yield: 98.6 %

Procedure:
A mixture containing 25 ml of toluene, 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate and 5.67 g of ethyl bromide was placed in a sealed tube and heated at 130°C (bath temperature) for 30 hours. The reaction mixture was worked up as described in Example 9 and 4.93 g of ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate was obtained.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Under an argon atmosphere, a suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (232 mg), 3-thienylboronic acid (138 mg), tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 189 mg, 81%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].C(N(CC)CC)C>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:9][C:6]1[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: C#Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cnc(N)cn1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a stirred solution of 5-ethynyl-2-aminopyrazine (18 mg; 0.151 mmol), in ethyl acetate (500 μL) was added triethylamine (63 μL; 0.45 mmol) and Pd(OH)2 (0.01 mmol; 20% wt on carbon). The reaction was placed under a hydrogen atmosphere at 45 psi and shook for 6 hours. The reaction was filtered and concentrated under reduced pressure to yield an off white solid (84% yield).