Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CN(C(O[N:28]1N=N[C:30]2[CH:31]=CC=C[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)CC>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:28][CH2:29][CH2:30][CH3:31])=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (524 mg, 2 mmol, 1 eq) was added HBTU (642 mg, 2 mmol, 1 eq) in DMF (5 mL). DIPEA (700 uL, 4 mmol, 2 eq) was then added in 100 uL portions. After 10 min propylamine (328 uL, 4 mmol, 2 eq) was then added and the mixture was stirred overnight at room temperature. The solvent was then removed in vacuo. The residue was then dissolved in chloroform and purified by aminopropyl SPE: LC-MS m/z 304 (M+H)+, 3.37 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:11].[BH3-]C#N.[Na+]>CC(O)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc2cc[nH]c2cc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(cc1Br)NCC2
Temperature: -10 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 6-bromo-5-methylindole (1.00 g, 4.75 mmol) in AcOH (150 mL) was treated with NaBH3CN (0.897 g, 14.3 mmol) while maintaining a temperature of −10° C. The mixture was then stirred at RT overnight and concentrated. The resulting residue was treated with aqueous K2CO3, and extracted with DCM (3×100 mL). The combined organic layers were dried over MgSO4, concentrated and purified by column chromatography (0-75% EtOAc/hexanes) to afford 6-bromo-5-methylindoline (13A, 716 mg).
Reaction SMILES: BrC(Br)C.C[Si](Cl)(C)C.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)C.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1>C1COCC1.[Zn]>[OH:17][C:18]1([CH2:14][C:13]([O:12][CH3:10])=[O:16])[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:22][CH2:23]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a round-bottom flask containing Zn dust (2.3 g, 36 mmol) was added dibromoethane (585 mg, 3.11 mmol). The resulting mixture was warmed to 60° C. and allowed to cool for 1 min. This heating-cooling process was repeated three more times, and then the flask was allowed to cool for an additional 3 min. Trimethylsilylchloride (456 mg, 4.2 mmol) in THF (5 mL) was added, followed by addition of ethyl-2-bromoacetate (2 g, 12 mmol) in THF (8 mL). The reaction was warmed to 60° C. for an additional two hours until a dark grey suspension was obtained. The mixture was cooled to room temperature; benzyl 4-oxopiperidine-1-carboxylate (1.9 g, 8.2 mmol) in THF (20 mL) was then added. The resulting mixture was stirred for 3 days, and then quenched with water. The solid was filtered off, and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. Purification by a standard method gave the desired product. 1H NMR (CHLOROFORM-d) δ: 7.33-7.43 (m, 5H), 5.14 (s, 2H), 3.89-4.05 (m, 2H), 3.68-3.79 (m, 3H), 3.22-3.36 (m, 2H), 2.49 (s, 2H), 2.19 (s, 1H), 1.71 (d, J=12.6 Hz, 2H), 1.53 (dd, J=12.5, 4.2 Hz, 2H). LCMS (m/z): 308.1 (M+1)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1cnc(N2CCNCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred, warm (approximately 50°) solution of anhydrous piperazine (100 g, 1.16 mole) and sodium carbonate (58 g, 0.47 mole) in 465 mL water was added 2-chloropyrimidine (53 g, 0.46 mole) in portions over about 1 hour. External cooling was required to maintain the temperature in the 50°-65° range. After the addition, the stirred reaction mixture was kept in the temperature range of 50°-65° for one hour and then allowed to slowly cool to 35° over a 2 hour period. The mixture was filtered, removing 1,4-dipyrimidinylpiperazine, and the filtrate was extracted with 350 mL portions of chloroform. The chloroform extracts were dried (MgSO4) and concentrated to 62 g (82%) of an oily solid which can be purified by distillation (b.p. 118°-120°/2 Torr.) or converted to a salt form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:13])[C:11]#[N:12].[CH3:14]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12]
Reactant: COc1ccc(C(C)C#N)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19 g, 0.097 mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL) was flushed with argon for 2 min and cooled to 0° C. Sodium hydride (60% oil susp., 4.4 g, 0.11 mol) was added in small portions. The thick suspension was stirred for another 18 h at 25° C. and then poured into water (300 mL) and extracted with Et2O (3×100 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving a yellow oil which was distilled. Bp: 103-106° C./0.06 mbar, clear oil that solidifies on standing. Yield: 17.5 g (83%). GCMS: >99%
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]2[S:8][CH:9]=[C:10]([CH:11]([CH2:25][OH:26])[C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[O:13])[C:6]=2[CH:5]=1.[S:29](Cl)(=[O:32])(=[O:31])[NH2:30]>CN(C=O)C>[Cl:3][C:4]1[CH:28]=[CH:27][C:7]2[S:8][CH:9]=[C:10]([CH:11]([C:12](=[O:13])[NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH2:25][O:26][S:29](=[O:32])(=[O:31])[NH2:30])[C:6]=2[CH:5]=1
Reactant: NS(=O)(=O)Cl
Reactant: O=C(Nc1ccc2ccccc2c1)C(CO)c1csc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)OCC(C(=O)Nc1ccc2ccccc2c1)c1csc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 95% NaH (0.017 g, 0.68 mmol) in DMF (2 mL) at 0° C. was added a solution of Compound 136 (0.10 g, 0.26 mmol) in DMF (2 mL) dropwise. The suspension was stirred at 0° C. for 1 h, then sulfamoyl chloride (0.067 g, 0.58 mmol) was added as a solid. After stirring for 1 h at 0° C., the mixture was treated with excess sulfamoyl chloride. After stirring overnight, the reaction was, quenched with water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure at rt. The residue was purified by flash column chromatography (silica, 0-40% EtOAc/hexanes) to yield Compound 120 (0.1.0 g) as a white foam: HPLC: 4.12 min; MS (ES) m/z 461 (MH+); 1H NMR (DMSO-d6) δ 4.29-4.34 (m, 1H), 4.65-4.75 (m, 2H), 7.39-7.50 (m, 3H), 7.57-7.64 (m, 1H), 7.81-7.90 (m, 4H), 8.09 (d, 1H, J=8.5 Hz), 8.215 (d, 1H, J=2 Hz), 8.34 (s, 1H), 10.55 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:10]([C:18](O)=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOCC>[NH:9]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:10]([C:18]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14]
Reactant: NCc1ccccc1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1
Yield: 97.9 %

Procedure:
Benzylamine (0.270 g, 2.52 mmol) was coupled to Fmoc-Thr(tBu)-OH(S29, 1.00 g, 2.52 mmol) using the standard HATU coupling procedure. The reaction was diluted with Et2O (150 mL), and washed with 10% citric acid solution (60 mL), water (3×60 mL), and brine (60 mL). The organic layer was dried (MgSO4), filtered, and concentrated by rotary evaporation. The crude product was purified using flash chromatography (15% EtOAc/hexanes) to afford S30 as a white solid (1.20 g, 98% yield). Rf 0.53 (1:1 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.61 (d, J=7.4 Hz, 2H), 7.44-7.27 (m, 9H), 6.06 (d, J=4.6 Hz, 2H), 4.50 (dd, J=7.8, 5.7 Hz, 2H), 4.44-4.37 (m, 2H), 4.27-4.14 (m, 3H), 1.24 (s, 9H), 1.04 (d, J=6.5 Hz, 3H); HRMS m/z calcd for C30H34N2NaO4 [MNa+] 509.2416. found 509.2226.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[C:10]([N:17]([CH3:23])[C@H:18]([C:20](O)=[O:21])[CH3:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:8]([C:4]1[N:3]=[C:2]([NH:1][C:20](=[O:21])[CH:18]([N:17]([CH3:23])[C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH3:19])[CH:7]=[CH:6][CH:5]=1)#[CH:9]
Reactant: C#Cc1cccc(N)n1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)n1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 2-amino-6-ethynylpyridine (G55, 203 mg) synthesized according to the method described in WO2012/052451 A1, N-Boc-N-methyl-L-alanine (524 mg), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.31 g), N,N-diisopropylethylamine (1.2 mL) and N,N-dimethylformamide (4.5 mL) were added at room temperature, and the mixture was stirred at 45° C. for 12 hours. The reaction mixture was cooled on ice, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (1-((6-ethynylpyridin-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (G56, 180 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: COc1cc(C)c2nc(Cl)cc(Cl)c2c1
Product: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Yield: 58 %

Procedure:
2-Chloro-6-methoxy-4-(4-methoxybenzyloxy)-8-methyl-quinoline 221f was synthesized from compound 220f as a white solid in 58% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.68 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 5.11 (s, 2H), 6.72 (s, 1H), 6.97 (d, J=9.03 Hz, 2H), 7.15 (dd, J=3.01 Hz and J=0.96 Hz, 1H), 7.20 (d, J=3.00 Hz, 1H), 7.40 (d, J=9.03 Hz, 2H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][SH:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:16][CH3:17])[C:8]=1F.O>CN(C)C=O>[CH3:17][S:16][C:9]1[C:8]([S:5][CH3:4])=[C:7]([Cl:6])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CSc1c(C(=O)O)ccc(Cl)c1F
Reactant: CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Cl)ccc(C(=O)O)c1SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
Lithium hydroxide monohydrate (4.95 g) was added to a solution of methyl mercaptan (4.4 g) in N,N-dimethyl formamide, and 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (5.5 g) was added to the resultant mixture. It was stirred at room temperature for 1 hour and heated to 80° C. overnight. It was cooled, poured into water, extracted with ether, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of acetic acid, ether and hexane (1:10:89) to give 2,3-bis(methylsulphenyl)-4-chlorobenzoic acid (3.24 g) as an off white solid, m.p. 130°-131° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([I:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: N#CCc1cc(I)cc(CC#N)c1
Agent: Cl
Product: N#CCc1cc(I)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 36.3 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-iodobenzene (420 mg, 1.49 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (321 mg, 1.49 mmol) and the resultant product was crystallized from ethyl acetate-hexane to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-iodophenylacetonitrile (240 mg, 36%) as a colorless powder.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
Next, 1.09 g (2.01 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(3-nitrophenyl)phosphono]butanoate and 1.30 g (12.0 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.80 g (6.00 mmol) of aluminum trichloride and reaction was carried out at room temperature for 3 hours. Thereafter, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was removed, and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, 30 mL of the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out from water to obtain 2-amino-4-[methyl(3-nitrophenyl)phosphono]butanoic acid (0.40 g, yield 63%) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]#[N:12])=[N:4][N:5]([CH2:9][CH3:10])[C:6]=1[CH2:7][CH3:8].[CH3:13][C:14]([CH3:30])([CH3:29])[C:15]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1B(O)O)=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:3]1[C:2]([C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[NH:17][C:15](=[O:16])[C:14]([CH3:29])([CH3:13])[CH3:30])=[C:6]([CH2:7][CH3:8])[N:5]([CH2:9][CH3:10])[N:4]=1)#[N:12]
Reactant: COc1ccc(B(O)O)c(NC(=O)C(C)(C)C)c1
Reactant: CCc1c(Br)c(C#N)nn1CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCc1c(-c2ccc(OC)cc2NC(=O)C(C)(C)C)c(C#N)nn1CC
Temperature: 100 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A 50 mL round bottom flask containing a mixture of 4-bromo-1,5-diethyl-1H-pyrazole-3-carbonitrile (prepared as described in Part E of Example 11, 1.12 g, 4.91 mmol) and 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid (1.36 g, 5.40 mmol) in 1-propanol (25 mL) was evacuated and backfilled with nitrogen. To the flask was added triphenylphosphine (38.6 mg, 0.147 mmol), 2 M aqueous sodium carbonate (7.4 mL), water (5 mL), and palladium (II) acetate (11 mg, 0.048 mmol). The yellow suspension was heated at 100° C. After 3 hours, the reaction mixture was allowed to cool to room temperature, water (10 mL) was added, and the 1-propanol was removed under reduced pressure. The water layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, washed with 2 M aqueous sodium carbonate (50 mL), water (50 mL), and brine (50 mL), then dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-40% ethyl acetate in hexanes) to provide 0.54 g of N-[2-(3-cyano-1,5-diethyl-1H-pyrazol-4-yl)-5-methoxyphenyl]-2,2-dimethylpropanamide as a colorless liquid. MS (ESI) m/z 355.28 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([NH2:24])[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1.C(OCC)(=O)C>C(#N)C.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:23][CH:19]1[CH2:20][CH2:21][CH2:22][CH:17]([NH2:24])[CH2:18]1)([O-:10])=[O:9]
Reactant: NC1CCCC(N)C1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: NC1CCCC(Nc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a suspension of 2-fluoronitrobenzene (197 mg) and potassium carbonate (193 mg) in acetonitrile (4 mL), 1,3-cyclohexanediamine (480 mg) was added at room temperature, and the mixture was stirred for 10 hours and 30 minutes under reflux by heating. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol) to obtain N1-(2-nitrophenyl)cyclohexane-1,3-diamine (C41, 162 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]#[N:13])[N:9]([CH3:11])[CH:10]=1)(=[O:4])=[O:3].[H][H]>[Pd].CO>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][NH2:13])[N:9]([CH3:11])[CH:10]=1)(=[O:3])=[O:4]
Reactant: Cn1cc(NS(C)(=O)=O)cc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1cc(NS(C)(=O)=O)cc1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 22-7 (150 mg) and 10% palladium/carbon (catalytic amount), together with methanol (10 ml), were poured into reactor and the reactor was filled with hydrogen gas, followed by stirring at room temperature for 24 hours. After the completion of the reaction, the resulting mixture was filtered through celite and concentrated under reduced pressure. The following procedure was carried out using the obtained residue which was not purified.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)=[O:33])[CH2:28][CH2:27]1>>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([CH:37]2[CH2:38][CH2:39][N:34]([C:32]([CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:33])[CH2:35][CH2:36]2)=[CH:41][CH:42]=1
Reactant: CN1CCC(C(=O)N2CCC(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: CN1CCC(C(=O)N2CCC(c3ccc(N)cc3)CC2)CC1

Procedure:
[4-(4-Amino-phenyl)-piperidin-1-yl]-(1-methyl-piperidin-4-yl)-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (1-Methyl-piperidin-4-yl)-[4-(4-nitro-phenyl)-piperidin-1-yl]-methanone. LC/MS (E/I+) 302.15 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCOC(=O)C(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(C)O[Si](C)(C)C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
7.69 g (60 mmol) of 2-propenyl 2-hydroxypropionate and 7.29 g (72 mmol) of triethylamine were dissolved in 130 ml of toluene, and 7.17 g (66 mmol) of trimethylsilyl chloride was dropwise added thereto at 5 to 10° C., taking 10 minutes. This was reacted at room temperature for 4 hours, the reaction liquid was washed twice with water, and the organic layer was separated and concentrated. The concentrate was purified through reduced pressure distillation to give 6.24 g (yield 52%) of 2-propenyl 2-(trimethylsilyloxy)propionate.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15]N[CH2:13][CH2:12]1.O>CN1CCCC1=O>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([N:1]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:3]1
Reactant: C1CNCCN1
Reactant: Nc1csc2ccccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(N3CCNCC3)csc2c1

Procedure:
To a solution of methyl 3-aminobenzothiophene-2-carboxylate [prepared by the method of J. R. Beck, J. Org. Chem. 1972, 37, 3224] (6.5 g, 31.4 mmol) in N-methylpyrrolidinone (30 ml) was added 1-methylpiperazine and the reaction mixture was heated to 178° C. for 4 h. After cooling the mixture was poured into water and the product extracted with diethyl ether (3×100 ml), the extracts were washed with water (1×100 ml) and brine (1×100 ml), combined and dried (MgSO4). Concentration of the extracts yielded 3-aminobenzothiophene (5.9 g), which was used without purification. To a solution of 3-aminobenzothiophene (5 g, 32 mmol) in N-methylpyrrolidinone (50 ml) was added piperazine (8.7 g, 102 mmol) and the mixture heated to reflux under nitrogen for 14h. Cooled and poured into water and extracted with dichloromethane (4×100 ml). The extracts were washed with brine (50 ml), combined and dried (MgSO4). On concentration of the extracts a white solid came out of solution which was collected by filtration to yield the title compound (0.78 g, more product left in solution); δH (DMSO-d6 +TFA), 3.3 (8H, m, 4×piperazinyl CH2), 7.08 (1H, s, 3-H), 7.39 (2H, m, 2×ArH), 7.83 (1H, m, ArH), 7.95 (1H, m, ArH), and 9.30 (1H, br s, NH).