Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:16](=[O:29])[CH2:17][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10].[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:46][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)[C:16](=[O:29])[CH2:17][N:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(CCc1ccccc1)C2=O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)C(=O)CN(CCc1ccccc1)C2=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A mixture of hydroxylammonium chloride (0.61 g), sodium hydrogencarbonate (0.89 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[7-ethyl-2,5-dioxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl]methyl}biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.096 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.08 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.13 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42](O)=[O:43])[S:7][C:6]=2[CH:45]=1.CN(C(O[N:54]1N=[N:61][C:56]2C=CC=C[C:55]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)CN>CN(C=O)C>[NH2:54][CH2:55][CH2:56][NH:61][C:42]([C:8]1[S:7][C:6]2[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=3[C:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:36][CH:37]=3)=[N:20]2)[CH2:14][CH2:15]1)=[O:43]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: NCCN
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCN)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A stirred solution of 300 mg (0.43 mmol) 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 5 mL of dry DMF was treated with 812 mg (2.14 mmol) of HBTU and 0.75 mL (4.28 mmol) of DIEA. The solution was stirred for 5 min before the addition of 0.28 mL (4.28 mmol) of ethylenediamine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated sodium bicarbonate (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of (2 N NH3 in MeOH)/CH2Cl2) afforded 200 mg (66%) of a clear oil. MS (electrospray): exact mass calculated for C33H38F4N6O3S2: 706.24; m/z found, 707.2 [M+H]+. 1H NMR (CD3OD, 400 MHz): 8.14 (m, 1H), 7.84 and 7.72 (A and B of AB quartet, J=8.41 Hz, 4H), 7.68 (m, 1H), 7.21 (dt, J=8.81, 2.74 Hz, 1H), 4.54 (s, 2H), 4.27 (t, J=6.26 Hz, 2H), 4.00-3.90 (m, 2H), 3.76-3.61 (m, 8H), 3.28-3.23 (br m, 1H), 3.19-3.09 (br m, 3H), 2.98 (s, 3H), 2.97-2.93 (m, 2H), 2.67 (br m, 2H), 2.52-2.37 (m, 3H), 2.02 (br d, J=13.89 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:16]C(OC(C)(C)C)=O)[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:4]1[CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:16]1)=[O:24]
Reactant: COC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1CCC(c2cccc(F)c2)=N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester (0.57 g, 1.7 mmol) in 1.7 mL of CH2Cl2 at 0° C. was added dropwise 3.8 mL (49 mmol, 29 eq) of TFA. The mixture was stirred at 0° C. for 2 hr. After concentration under vacuum, the residue was dissolved in CH2Cl2 (30 mL), washed with 10% NaHCO3, water, and brine, dried (Na2SO4) and concentrated under vacuum to give (2R)-5-(3-fluoro-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.77–7.70 (2H, m), 7.50 (1H, q), 7.27 (1H, tq), 5.05 (1H, tt), 3.90 (3H, s), 3.30–3.00 (2H, m), 2.55–2.30 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:22])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of 4.45 g (28.9 mmol) of 4-fluorophenylacetic acid in 3.26 g (31.8 mmol) of triethylamine and 275 mL of acetonitrile was added 8.9 g (28.9 mmol) of 2-bromo-4'-(methylsulfonyl)acetophenone (prepared in Step 3) at ambient temperature. The reaction mixture was stirred for 30 minutes, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate/hexane (1:1) gave 6.87 g (68%) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone as a colorless solid: NMR (CDCl3) δ3.08 (s, 3H), 3.79 (s, 2H), 5.35 (s, 2H), 7.06 (s, t, J=9 Hz, 2H), 7.32 (dd, J=6 and 9 Hz, 2H), 8.06 (s, 4H).
Reaction SMILES: [OH:1][C@@H:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=1[C:12]1[NH:13][C:14]2[C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:64][P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[F:64][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:37][C:21]([C:20]2[C:14]3[NH:13][C:12]([C:6]4[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=4[NH:4][CH2:3][C@@H:2]([OH:1])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:16][C:15]=3[CH:17]=[CH:18][CH:19]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12

Procedure:
2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid4-fluoro-benzylamide was synthesized from 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 4-fluoro-benzylamide. LC/MS calcd for C28H24FN5O3 (m/e) 497.0, obsd 498 (M+H). 1H NMR (DMSO-d6): 13.35-13.53 (m, 1H), 11.13-11.38 (m, 1H), 10.35-11.03 (m, 1H), 9.19-9.42 (m, 1H), 7.68-7.97 (m, 2H), 7.24-7.58 (m, 9H), 7.08-7.22 (m, 2H), 6.13-6.30 (m, 1H), 5.74-6.02 (m, 1H), 4.49-4.98 (m, 3H), 3.49-3.29 (m, 2H).
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH2:35][CH2:36]O)[CH3:34]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CN(C)CCO
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1)C(OC(B(OCCN(C)C)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (45 mg) was obtained by allowing 41 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 19 mg of dimethylaminoethanol to act in 1 mL of ethanol.
Reaction SMILES: N#N.[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:23])[C:10]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][C:14]=2[N:15]=1)(=[O:5])[CH3:4].[C:24]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([O-:27])(=[O:26])[CH3:25].[C:33]([O:32][CH2:31][CH2:30][O:29][CH2:28][N:13]1[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:9](=[O:23])[NH2+:8][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[N:15][C:14]1=2)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reactant: CC(=O)OCCOCOC(C)=O
Agent: N#N
Solvent: CN(C)C=O
Product: CC(=O)NC1=NC2=C(C(=O)[NH2+]1)N(Cc1ccccc1)CN2COCCOC(C)=O
Product: CC(=O)[O-]
Temperature: 80 °C

Procedure:
To a mixed solution containing 100 mg (0.35 mmol) of N2 -acetyl-7-benzylguanine and 1 ml of DMF was added 64 mg (0.37 mmol) of (2-acetoxyethoxy)methyl acetate [prepared by the method described in M. J. Robins et al., Can. J. Chem., 60, 547 (1982)]. The mixture was heated at 80° C. for 20 h, and then allowed to cool. The reaction solution was concentrated, and purified by silica-gel column chromatography to yield 9-(2-acetoxyethoxy)methyl-7-benzyl-N2 -acetylguaninium acetate.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.BrCC1CC1>C1COCC1>[CH:9]1([CH2:10][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:7][CH2:8]1
Reactant: [Li]CCCC
Reactant: C#C[Si](C)(C)C
Agent: BrCC1CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)C#CCC1CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 500 mL three-necked round bottom flask was charged with (trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0° C. for 10 minutes and then re-cooled to −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, the reaction mixture was washed with water (4×100 mL) and brine (2×100 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate. Hexane and THF was distilled off at 75110° C. then distillation at 138142° C. afforded the title compound (12 g). 1H NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H), 0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:35]2[CH2:34][CH2:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:36]2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 58.7 %

Procedure:
2.0 g (0.0093 mol) of 4-bromo-2-methylbenzoic acid were boiled under reflux in 15 ml (0.175 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 10 ml of toluene each time. The residue was dissolved in 15 ml of toluene, treated with 2.33 ml (0.01675 mol) of triethylamine and 2.67 g (0.01395 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 2.12 g (59%) of 1-benzyl-piperidin-4-yl 4-bromo-2-methyl-benzoate were obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.44 mmol), K2CO3 (124 mg, 1.89 mmol) in DMF (5 mL) was stirred at RT and CH3I (182 mg, 1.32 mmol) was added dropwise. The reaction was stirred at RT for 3 h. The reaction was concentrated, washed with H2O and filtered to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 5.88 (s, 1H), 3.34 (s, 3H), 3.10 (s, 3H), 3.05 (d, J=5.2 Hz, 3H). MS (M+H)+: 462/464.
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:13](O)([CH3:15])[CH3:14].[C:21](=[O:24])([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:13]([NH:2][CH:21]=[O:24])([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)c1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(NC=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To 7 ml of acetic acid, 2.83 g (57.8 mmol) of sodium cyanide was gradually added at a temperature not higher than 20° C. To the suspension thereby obtained, 7 ml of an acetic acid solution of 7 ml of concentrated sulfuric acid was dropwise added at not higher than 20° C., and the mixture was stirred at room temperature for one hour. Then, 10.3 g (50 mmol) of 3,5-dichloro-α,α-dimethylbenzyl alcohol was dropwise added thereto at not higher than 20° C. The reaction mixture was stirred at room temperature for two days, and then poured into ice water. The mixture was alkalified with potassium carbonate and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried and then concentrated. The solid thereby obtained was washed with n-hexane and collected by filtration to obtain 8.2 g (yield: 70.7%) of N-(3,5-dichloro-α,α-dimethylbenzyl)formamide as white needle-like crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:34])[F:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:33])[F:34])=[O:20]
Reactant: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(O)ccc12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
The material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2,-b]pyridine 1e with 6-hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid methylamide 76 h and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ8.51 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.78 (1H, s), 7.72 (1H, d, J=8.6 Hz), 7.41 (1H, s), 7.18 (1H, d, J=9.8 Hz), 7.03 (1H, s), 6.66 (1H, d, J=5.4 Hz), 3.99 (3H, s), 3.86 (3H, s), 2.81 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 486, found 486.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=O.C1N2[CH2:16][CH2:17]N(CC2)C1.[CH2:18]([OH:20])C>>[OH:20][CH2:18][CH:16]1[O:3][N:1]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:17]1
Reactant: C1CN2CCN1CC2
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CCO
Product: CCOC(=O)C1=NOC(CO)C1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a mixture of allylic alcohol (0.650 mL; 9.35 mmol) and ethyl 2-nitroacetate (2.65 mL; 23.37 mmol) in ethanol (12 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.189 g; 1.64 mmol). The tube was heated at 80° C. for 48 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 0 to 6% of methanol in dichloromethane) of the residue provided 1.51 g (93%) of ethyl 5-(hydroxymethyl)-4,5-dihydroisoxazole-3-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]2[NH:20][C:19](=[O:21])[CH2:18][S:17]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].O=C1CSC(C[CH2:29][CH2:30][C:31]2[CH:41]=[CH:40][C:34](C(OCC)=O)=[CH:33][CH:32]=2)N1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]2[N:20]([CH2:29][CH2:30][C:31]3[CH2:41][CH2:40][CH2:34][CH2:33][CH:32]=3)[C:19](=[O:21])[CH2:18][S:17]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(CCCC2NC(=O)CS2)cc1
Reactant: CCOC(=O)c1ccc(CCCC2NC(=O)CS2)cc1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1Cl

Procedure:
This compound is prepared by the method described in Example 4, Step B, except that an equivalent quantity of ethyl 2-chloro-4-[3-(4-oxo-2-thiazolidinyl)propyl]benzoate is substituted for the ethyl 4-[3-(4-oxo-2-thiazolidinyl)propyl]benzoate of Example 4, Step B. The title compound is obtained as an oil by column chromatography on silica gel with 2% methanol in chloroform as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[CH2:39]=O>C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[C:10]([CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 60 °C

Procedure:
A solution of 1-[4-(4-amino-6-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea (120 mg, 0.7 mmol) in acetic acid (2 mL) was treated with a mixture of morpholine (240 μL, 2.72 mmol) and formaldehyde (37%, 204 μL, 2.72 mmol) in acetic acid (1 mL). The reaction was heated to 60° C. overnight. The reaction was then diluted with EtOAc and washed with NaHCO3. The organic layer was dried (MgSO4) and concentrated. The pale orange solid was then triturated with ether. The desired product was collected by vacuum filtration (30 mg, 20%). 1H-NMR (DMSO-d6) δ 9.95 (bs, 1H), 9.82 (bs, 1H), 8.55 (d, J=4.1 Hz, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.64 (d, J=6.8 Hz, 2H), 7.38-7.32 (m, 3H), 3.82 (s, 2H), 3.53-3.50 (m, 4H), 2.54-2.49 (m, 2H), 2.44-2.41 (m, 4H), 0.97 (t, J=7.5 Hz, 3H). MS [M+H]+=541.1; LCMS RT=2.86.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14]Cl.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:11][CH2:12][CH2:13][CH2:14][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCCBr
Product: N#Cc1ccc(OCCCCN2CCOCC2)cc1
Yield: 86 %

Procedure:
According to a similar manner as that in Reference Example 78 except that 4-cyanophenol, 1-bromo-4-chlorobutane, and morpholine were used, 4-(4-morpholinobutoxy)benzonitrile (86%) was obtained as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=C[NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][C:23]2([NH2:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1.C([N:34](CC)CC)C>C(O)CCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]2[CH2:25][CH2:24][C:23]([NH2:29])([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:31][CH:30]=3)[CH2:28][CH2:27]2)=[C:8]2[CH:14]=[N:34][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reactant: NC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(Cl)cc2)CC1
Yield: 87 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (Example 68A) (50 mg, 0.22 mmol), 4-(4-chlorobenzyl)-piperidin-4-ylamine hydrochloride (65 mg, 0.22 mmol) and triethylamine (150μ) in n-butanol (1.5 mL) was irradiated in a microwave reactor (200W) for 1 hr at 100° C. After cooling, the solvent was evaporated. The solids obtained were dissolved in ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate, brine and then dried (Na2SO4). Evaporation of the organic solution gave 4-[4-amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester as an off-white solid (80 mg, 87%). LC-MS (LCT2) m/z 415 [M+H+], Rt 3.99 min.