Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]2[C:15]=1[CH2:16][O:17][C:18]2=[O:24].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:13]/[C:14]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]3[C:15]=2[CH2:16][O:17][C:18]3=[O:24])=[CH:7][CH:6]=1)[CH3:3]
Reactant: Nc1cc(F)cc2c1COC2=O
Reactant: CN(C)Cc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Yield: 60.1 %

Procedure:
A solution of 4-((dimethylamino)methyl)benzaldehyde (1.0 g, 6.13 mmol), 4-amino-6-fluoroisobenzofuran-1(3H)-one (1.024 g, 6.13 mmol) and anhydrous magnesium sulfate (7.356 g, 61.3 mmol) in acetonitrile (50 ml) was heated at reflux for 2 days. The solution was filtered and concentrated in vacuum. The crude product was re-crystallized with isopropanol to obtain the title compound (1.15 g, yield 60%). LC-MS (ESI) m/z: 313 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.28 (s, 6H), 3.52 (s, 2H), 5.38-5.38 (m, 2H), 7.09-7.12 (m, 1H), 7.42-7.44 (m, 1H), 7.46-7.48 (d, J=8 Hz, 2H), 7.87-7.89 (d, J=8 Hz, 2H), 8.51 (s, 1H).
Reaction SMILES: [CH3:1]OC1C=C(C=CC=1)C=O.COC(OC)CN.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[CH:23]=[N:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].C[Mg]I>CCOCC.O.C1(C)C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[CH:23]([NH:24][CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[CH3:1]
Reactant: COc1cccc(C=O)c1
Reactant: COc1cccc(C=NCC(OC)OC)c1
Agent: COC(CN)OC
Agent: C[Mg]I
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cccc(C(C)NCC(OC)OC)c1
Reaction time: 1 h

Procedure:
A solution of 13.6 g. (0.1 mole) of 3-methoxy-benzaldehyde and 10.5 g. (0.1 mole) of aminoacetaldehyde dimethyl acetal in 250 ml. of toluene is refluxed for one hour and water produced in the reaction is collected in a Dean-Stark trap. The resulting solution of 3-methoxy-N-(2,2-dimethoxyethyl)benzylidenamine is added to a solution of (0.2 mole) of methylmagnesium iodide in 250 ml. of ether over 1.5 hours. The mixture is stirred for one hour, cooled and quenched by careful addition of 250 ml. of water. The aqueous phase was filtered through Celite, extracted with 150 ml. of ether and the combined organic phases washed, dried and evaporated to yield 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)benzylamine.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(CCCc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and phenylpropylbromide (0.183 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.015 g (4.0%); MS m/z: 372.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.84-1.90 (m, 2H); 2.62 (t, 2H, 3J=7.6 Hz); 3.39 (t, 2H, 3J=7.6 Hz); 3.39 (s, 3H); 4.45 (s, 2H); 6.71 (br s, 1H); 6.73 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.83-6.85 (m, 2H); 7.12-7.14 (m, 2H); 7.16-7.19 (m, 3H); 7.24-7.27 (m, 2H); 7.36 (d, 1H, 3J=8.9 Hz); 8.08 (s, 1H); HPLC (METHOD [A]): rt 16.97 min (93.2%)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 76.8 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis (diphenylphosphino)-ferrocene}dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)[CH3:3].C(O)C.C([O-])([O-])=O.[K+].[K+].[I-].C[N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O>[N:6]1[CH:5]=[C:4]([CH:2]([N:1]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH3:3])[CH:9]=[N:8][CH:7]=1
Reactant: CC(N)c1cncnc1
Reactant: C[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(c1cncnc1)N1CCC(=O)CC1
Yield: 26.2 %

Procedure:
To a stirred mixture of 1.1 g of 5-(1-aminoethyl)pyrimidine (O. Cervinska and P. Malon, Coll. Czechoslov. Chem. Commun. 1977, 42, 3464-72.), 17 mL of ethanol and 1.36 g of K2CO3 heated to reflux was added dropwise over 30 min, a solution of 4 g of 1,1-dimethyl-4 -oxopiperidinium iodide in 70 mL of water. When the addition was complete, the mixture was heated under reflux for an additional 2 h, cooled, basified to pH 9 with K2CO3 and extracted with 5 times with 50 mL portions of methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 90:10 CH3CN:MeOH gave 0.48 g of 1-(1-(5-pyrimidinyl)-ethyl)-4-oxopiperidine as an oil: 1H NMR (400 MHz, CDCl3) 9.14 (s, 1H), 8.78 (s, 2H), 3.8 (q, J=7 Hz, 1H), 2.7-2.9 (m, 4H), 2.45 (m, 4H), 1.5 (d, J=7 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=O)#[N:2].C[O-:8].[Na+].[CH3:10][N:11]([CH:13]=NC=[N+](C)C)C.[Cl-]>C(COC)OC>[C:1]([C:3]1[CH:10]=[N:11][C:13]([OH:8])=[N:6][CH:4]=1)#[N:2]
Reactant: CN(C)C=NC=[N+](C)C
Reactant: C[O-]
Reactant: N#CCC(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cnc(O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanoacetamide (8.58 g, 0.10 mol) was added to an initial charge of sodium methoxide (54.02 g, 0.30 mol, 29% in methanol). 150 ml of dimethoxyethane were added. The solid Gold's reagent prepared as in Example 1 (18.08 g, 0.11 mol) was then added using a spatula. The suspension was then stirred overnight at room temperature. The yellow suspension was poured on to an aqueous, ice-cold hydrochloric acid solution (2 eq. of HCl) and adjusted to pH 5.5. After the organic solvents had been evaporated off, the product precipitated out of the aqueous phase. Digestion in water and subsequent filtration gave the title product in a yield of: 9.14 g (75%) in the form a yellow solid.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[C:72]([CH3:73])=[C:71]([CH:74]=O)[C:70]([CH3:76])=[N:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:74]([C:71]3[C:70]([CH3:76])=[N:69][N:68]([CH3:67])[C:72]=3[CH3:73])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: Cc1nn(C)c(C)c1C=O
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Reaction time: 6 h
Yield: 33.9 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 1,3,5-trimethyl-1H-pyrazole-4-carboxaldehyde (1.1 eq, 0.21 mmol, 29 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 34%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.36 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.60 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.64 (t, J=4.2 Hz, 4H, piperazine N(CH2)2), 3.74 (s, 3H, NCH3), 7.38 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.77 (dt, J=7.8, 1.5 Hz, 1H, pyridine H-4), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.55 (d, J=1.5 Hz, 1H, pyridine H-2), 12.67 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([OH:10])=O)=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:40][C@@:41]1([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47])[CH2:45][CH2:44][O:43][CH2:42]1>C1COCC1.CN(C=O)C>[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:40][C@@:41]2([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47])[CH2:45][CH2:44][O:43][CH2:42]2)=[O:10])=[CH:3]1
Reactant: O=C(O)c1cn[nH]c(=O)c1
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cn[nH]c(=O)c2)CCOC1
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid (11.5 g), TBTU (25.3 g), triethylamine (20.9 mL) and 40 mL DMF in 200 mL THF was stirred for 30 minutes at ambient temperature. Then n-butyl (S)-3-amino-tetrahydrofuran-3-carboxylate (14.0 g) was added and the mixture was stirred further overnight. For working up the mixture was evaporated to dryness in vacuo and the residue was stirred with 200 mL of ethyl acetate. This solution was washed twice with 5% sodium hydrogen carbonate solution, then dried and evaporated down. The product was thus obtained in a yield of 90% of theory.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]1[NH:15][C:16](=[O:24])[C:17]([CH2:22][CH3:23])=[C:18]([CH2:20][CH3:21])[N:19]=1)[CH2:2][CH3:3].[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][CH2:32][NH2:33]>>[CH2:20]([C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[C:9]([NH:33][CH2:32][CH2:31][C:27]2[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=2)=[O:11])[NH:15][C:16](=[O:24])[C:17]=1[CH2:22][CH3:23])[CH3:21]
Reactant: CCCOc1ccc(C(=O)O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: Cn1cccc1CCN
Product: CCCOc1ccc(C(=O)NCCc2cccn2C)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
According to the same manner as that of example 89, the compound of example 58 was reacted with 2-(1-methylpyrrol-2-yl)ethylamine to give the compound of example 117. 1H NMR (DMSO-d6) δ: 12.01 (1H, br), 8.50 (1H, t), 8.12 (1H, d), 7.96 (1H, dd), 7.22 (1H, d), 4.08 (2H, t), 3.28 (2H, m), 2.98 (1H, m), 2.58 (2H, q), 2.47 (2H, q), 2.25 (3H, s), 2.13 (2H, m), 1.90 (2H, m), 1.75 (2H, m), 1.64 (2H, m), 1.45 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.96 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.[CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:25]([O:24][C:22]([C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=2)[N:10]=[CH:9][CH:8]=1)=[CH2:23])[CH2:26][CH2:27][CH3:28]
Reactant: COc1cc(F)c2nccc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(OCCCC)c1ccnc2c(F)cc(OC)cc12
Yield: 68.8 %

Procedure:
15.5 g (47.5 mmol) of 1,1,1-Trifluoro-methanesulfonic acid 8-fluoro-6-methoxy-quinolin-4-yl ester, 24.5 mL (0.19 mol) of butyl vinyl ether and 13.3 mL of triethylamine were takent up in 100 mL of DMF. 2.0 g (4.75 mmol) of dppp (1,3-bis(diphenylphosphino)propane) and 1.06 g (4.75 mmol) of Pd(OAc)2 were added and the contents heated to 60 C for 4 hrs. No starting material remained. Contents were rotary-evaporated to remove as much DMF as possible. Crude material was purified by flash chromatography on silica gel using 10% ethyl acetate/hexanes as the eluent to give 9.0 g (69%) of the desired product. 1H NMR (CDCl3, 400 MHz) 8.78 (d, 1H), 7.43 (d, 1H), 7.28 (m, 1H), 7.09 (d, 1H), 4.58 (d, 1H), 4.50 (d, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 1.80 (m, 2H), 1.53 (m, 2H), 0.97 (t, 3H LCMS (M+H)+ 276.
Reaction SMILES: [C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2].O1C=CN=C1[Cl:25]>CN(C)C=O.O1CCCC1>[C:1]([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:25])=[O:12])=[CH:7][C:6]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: Clc1ncco1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C=CC(=O)Cl)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-acetoxy-3,5-dimethoxycinnamic acid (638 mg), dimethylformamide (2 drops) and tetrahydrofuran (8 ml) was added oxazolyl chloride (0.25 ml). The mixture was stirred at room temperature for one hour and then the solvent was distilled off to obtain 4-acetoxy-3,5-dimethoxycinnamic acid chloride as crystals. To a solution of the crystals in dichloromethane (15 ml) were added 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (576 mg) and N,N-dimethylaniline (0.25 ml) with ice cooling. After warming to room temperature, the mixture was stirred for 5 hours, washed in turn with water, aqueous saturated NaHCO3 solution and water, and then dried over MgSO4. The solvent was distilled off and the residue was crystallized from ethanol (729 mg, 67.4%). 5-(4-Acetoxy-3,5-dimethoxycinnamoylamino)-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine was obtained as colorless prisms by recrystallization from acetone, mp: 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[I-].[CH3:18][N+:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(OCC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:24]1[CH:23]=[C:22]([CH3:25])[CH:21]=[CH:20][N:19]1[CH3:18]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Cc1cc[n+](C)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2C=C(C)C=CN2C)c(OC)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5 g, 2.3 mmol) in diethyl ether (10 ml) cooled at −78° C. under nitrogen was added a solution of n-butyl lithium (1.0 ml, 2.5 mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at −78° C. for 2 hours and then 1,4-dimethyl pyridinium iodide (2) (0.54 g, 2.5 mmol) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and extracted with diethyl ether (2×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.5 g, 93%) as a brown oil, 1H NMR CDCl3??1.7 (s, 3H), 2.7 (s, 3H), 3.8 (s, 6H), 4.45 (dd, 1H, J=2.7) 4.85 (m, 1H), 5.4 (d, 1H, J=4), 6.05 (d, 1H, J=7), 6.45 (d, 1H, J=3), 6.55 (m, 1H), 7.5 (d, 1H, J=9).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(Cl)cc3Cl)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)=[O:35])[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]([N:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[O:35])=[CH:37][N:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)nc2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 4 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (205 mg, 0.7 mmol) and 4-(6-amino-pyridine-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (236 mg, 0.8 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (13 mg, 41%). MS(ESI) m/z 463.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.O>[C:15]([O:19][C:20](=[O:21])[NH:22][CH2:26][CH2:25][CH2:24][C:23]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1)=[O:27])([CH3:18])([CH3:16])[CH3:17]
Reactant: CSc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
Cool a solution of 3-bromothioanisole (10.68 g, 52.6 mmol) in tetrahydrofuran (250 mL) to −78° C., and add n-butyllithium (2.5 M in hexanes, 25.9 mL, 64.8 mmol) over 25 min. Stir the reaction at −78° C. for 1.25 h, then slowly add a solution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (7.50 g, 40.5 mmol) in tetrahydrofuran (100 mL). Stir the reaction for 2 h at −78° C., then add saturated aqueous ammonium chloride (100 mL). Upon warming to room temperature, add water (200 mL), and extract the reaction with dichloromethane (3×300 mL). Combine the organic extracts and dry over magnesium sulfate, filter, and evaporate under reduced pressure to afford a crude mixture (14.91 g). Purify the crude mixture by flash chromatography (330 g RediSep silica gel column, gradient from 0:100 to 30:70 ethyl acetate:hexanes) to provide slightly impure product (10.34 g, 83%), which is used without further purification. MS (APCI+): 210 [C16H23NO3S—C5H8O2+H]+; 1H NMR (300 MHz, CDCl3): δ 7.81-7.82 (m, 1H), 7.67-7.71 (m, 1H), 7.41-7.45 (m, 1H), 7.34-7.39 (m, 1H), 4.64 (br s, 1H), 3.17-3.26 (m, 2H), 3.00 (t, J=7.1 Hz, 2H), 2.52 (s, 3H), 1.93 (quintet, J=7.0 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1>>[C:35]([O:34][C:32](=[O:33])[CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:26][CH2:27]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Product: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2ccccc2)CC1
Yield: 60.2 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.5 g, 1.55 mmol) using t-butyl 4-piperidine acetate (0.93 g, 4.66 mmol) to yield an oil of N-4-cyanobenzoyl-β-phenylα,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (470 mg, 60.2%).
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH3:6])[CH3:5])=O.Cl.[N+:8]([C:11]1[CH:12]=[C:13]([NH:17][NH2:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].O.O.O.C([O-])(=O)C.[Na+]>O.CCO>[N+:8]([C:11]1[CH:12]=[C:13]([NH:17]/[N:18]=[C:2](/[CH:4]([CH3:6])[CH3:5])\[CH3:1])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(=N\Nc1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of isopropyl methyl ketone (2.5 g, 29 mol), 3-nitrophenylhydrazine hydrochloride (6.1 g, 32 mmol) and sodium acetate trihydrate (4.8 g, 35 mmol) in H2O (50 mL) and EtOH (50 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (100 mL) and CHCl3 (150 mL). The organic layer was removed and the aqueous phase was further extracted with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=222 (M+1).