Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12](=O)[CH:11]=1)C>CCOCC>[CH3:16][C:14]1([CH3:17])[CH2:15][C:10](=[O:9])[CH:11]=[CH:12][CH2:13]1
Reactant: CCOC1=CC(=O)CC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)CC=CC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flame-dried 100 mL round-bottomed flask containing lithium aluminum hydride (0.95 g, 24.4 mmol, 0.5 mol equiv) in 35 mL anhydrous ether under nitrogen atmosphere at 0° C. was added 8.20 g (48.7 mmol) 3-ethoxy-5,5-dimethylcyclohex-2-en-1-one (7) portionwise through a syringe as a solution in 10 ml anhydrous ether. The reaction mixture was allowed to warm to room temperature, and after 4 h, TLC analysis indicated complete consumption of starting material. The reaction mixture was then cooled to 0° C. before the cautious addition of 50 mL water, and the contents of the flask were then poured into a 500 mL Erlenmeyer flask containing 150 mL ice-cold 10% H2SO4. The mixture was then extracted with ether (2×200 mL), and the combined organics were washed successively with water (100 mL), and saturated aqueous NaHCO3 (100 mL), dried over Na2SO4, and concentrated under diminished pressure to give 6.05 g (quantitative) of the dimethylenone (Rf 0.55, 2:1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 6H, geminal-CH3 's), 2.23 (dd, 2H, CHCH2), 2.28 (s, 2H, COCH2), 6.03 (ddd, 1H, 2-H), 6.87 ppm (ddd, 1H, 3-H).
Reaction SMILES: [CH3:1][C:2]([NH2:8])([C:6]#[N:7])[CH:3]([CH3:5])[CH3:4].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:23])[C:18]=1[O:19][CH2:20][C:21]#[CH:22])[C:13](Cl)=[O:14]>>[CH3:1][C:2]([NH:8][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([F:23])[C:18]([O:19][CH2:20][C:21]#[CH:22])=[C:10]([F:9])[CH:11]=1)([C:6]#[N:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(C)(N)C#N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Product: C#CCOc1c(F)cc(C(=O)NC(C)(C#N)C(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,2-dimethyl-1-cyanopropylamine was used in place of 2,2-dimethylpropylamine, 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,2-dimethyl-1-cyanopropyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 53 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C[O-].[K+]>C(O)(C)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Fe]
Agent: C[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(O)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (3.8 mg, 4 μmol, 0.5 mol %) and a chiral ligand (M=Fe, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.33 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, m-chloroacetophenone (0.8 mmol), i-propanol (2 mL) and a solution of potassium methoxide in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (50 atm) at 10° C. The solvent was removed under reduced pressure, the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(m-chlorophenyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][OH:14])=[C:8](C)[CH:9]=1)=[O:4]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(OCCO)s1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCCO)s1

Procedure:
4-Methyl-5-(2-hydroxy-1-ethoxy)-thiophene-2-carboxylic acid methyl ester, melting point (benzene) 70°-72° C. (90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13](NCCCN3CCCCC3)=[O:14])[N:12]=2)=[C:4]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:3]=1.C(#N)C.[OH2:32]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:14])=[O:32])[N:12]=2)=[C:4]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)NCCCN2CCCCC2)co1
Reactant: O
Solvent: CC#N
Product: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)O)co1
Reaction time: 0.03 h

Procedure:
[2-(6-Chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)oxazole-4-carboxamide (40b)]: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.622 min; LCMS (ES-API), m/z 406.2 (M+H).
Reaction SMILES: C([N:4]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:16]=2)[C:6]2([CH2:9][S:8](=[O:11])(=[O:10])[CH2:7]2)[CH2:5]1)(=O)C.Cl.C([O-])(O)=O.[Na+]>CO>[N:18]1([C:15]2[CH:16]=[C:17]3[NH:4][CH2:5][C:6]4([CH2:9][S:8](=[O:10])(=[O:11])[CH2:7]4)[C:12]3=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC(=O)N1CC2(CS(=O)(=O)C2)c2ccc(N3CCOCC3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=S1(=O)CC2(CNc3cc(N4CCOCC4)ccc32)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 1-acetyl-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide (0.046 g, 0.137 mmol) in MeOH (1.367 mL) was added 5.0N HCl solution (0.27 mL, 1.37 mmol). The solution was stirred at 60° C. for 3 h and then it was cooled to rt and poured into saturated aqueous NaHCO3 and extracted with DCM. The organic extracts were dried over MgSO4 and evaporated in vacuo to give 6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide as a brown solid. Mass Spectrum (ESI) m/e=295.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][CH:18]4[CH2:20][CH:19]4[C:21]([O:23][CH3:24])=[O:22])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[Si:25]([O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CC=CC=1.CC1C=CC(S(OCC23CCC(C4SC(C)=NC=4C4C=CC=CC=4)(CC2)OC3)(=O)=O)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Si:25]([O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][CH:18]4[CH2:20][CH:19]4[C:21]([O:23][CH3:24])=[O:22])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)C1CC1CCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CC1CCC12CCC(c3cccc(Oc4cccc(O[Si](C)(C)C(C)(C)C)c4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.2 %

Procedure:
A mixture of methyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropane-carboxylate (65B; 360 mg, 1.09 mmol), (3-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (340 mg, 1.348 mmol), Cu(OAc)2 (237 mg, 1.31 mmol), TEA (1.52 mL, 10.9 mmol), pyridine (0.88 mL, 10.9 mmol), and 4A molecular sieves (5 g) in DCM (10 mL) was stirred under air at rt for 3 days. The reaction was then filtered, and the filtrate was concentrated in vacuo. The residual crude oil was dissolved in EtOAc (15 mL) and washed with 1N aq. HCl and water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 30% over 10 min EtOAc/hexane) to give the title compound (570 mg, 1.06 mmol, 97% yield) as a clear oil. LCMS [M+H]+=537.3; 1H NMR (CDCl3) δ: 7.26 (t, J=7.9 Hz, 1H), 7.18-7.11 (m, 2H), 7.09 (dd, J=2.5, 1.7 Hz, 1H), 6.85 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 6.58 (dd, J=8.2, 2.3 Hz, 2H), 6.49 (t, J=2.3 Hz, 1H), 3.78 (d, J=1.1 Hz, 2H), 3.68 (s, 3H), 2.00 (dt, J=11.4, 4.1 Hz, 4H), 1.62 (dtd, J=8.1, 4.1, 3.5, 2.0 Hz, 4H), 1.41-1.14 (m, 7H), 0.97 (s, 9H), 0.71 (ddd, J=8.1, 6.3, 4.1 Hz, 1H), 0.18 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(O)C(Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenol (Example 59) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: [a]25/D=+31.791° (9.940 mg/mL CHCl3); NMR (CDCl3); δ8.23 (ddd, J=8, 1, 1 Hz), 7.81 (ddd, J=8, 1, 1 Hz, 1 H), 7.64 (ddd, J=8,7, 1 Hz, 1 H), 7.58 (dd, J=9, 2Hz, 2 H), 7.52-7.39 (m, 7 H), 7.37-7.28 (m, 2 H), 6.68 (ddd, J=8,1, 1 Hz, 1 H), 5.48 (t, J=7 Hz, 1 H, -CH), 3.5 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 2 bromine isotope pattern, 756 (65%), 758 (100%), 760 (90%); Anal. calc. for C31H19Br2IO3S: C, 49.10, H, 2.53, N, 0.00. Found: C, 50.75, H, 3.00, N, 0.09.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirring solution of N-t-butyloxycarbonyl-L-serine (2.26 g) in N,N-dimethylformamide (15 mL) under argon at −20° C. was slowly added sodium hydride (60% oil dispersion, 0.88 g gross weight). The resulting mixture was warmed to 0° C. for 1 h, then recooled to −20° C. before a solution of 2-chloro-3-nitropyridine (1.6 g) in N,N-dimethylformamide (10 mL) was added over 10 min. The resulting red solution was stirred at −20° C. for 1 h. Water (100 mL) was then added, and the mixture was washed with diethyl ether (30 mL twice). The aqueous layer was adjusted to pH 7 with 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate (30 mL three times). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:2) to obtain N-t-butyloxycarbonyl-O-(3-nitro-2-pyridyl)-L-serine (2.46 g).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:21]([OH:23])=O)[CH3:20].C(OC([N:31]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH-:40])=[CH:37][CH:36]=1)[C:32]([NH2:34])=[NH:33])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([S:8]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH:31]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:21](=[O:23])[C@H:19]([CH3:20])[NH2:18])=[CH:37][CH:36]=1)[C:32]([NH2:34])=[NH:33]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=N)N)c1ccc(C[NH-])cc1
Agent: O=C(O)[C@@H](CO)NS(=O)(=O)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NCc1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution benzylsulfonyl-D-serine-L-alanine-(4-(N-tert-butoxycarbonylguanidino) benzylamide (7-5) (9.0 mg, 0.016 mmol), in a mixture of CH2Cl2/TFA (1:1, 600 μl) was stirred at room temperature for 90 minutes. The solvent was removed in vacuo to give a transparent oil. HPLC purification (CH3CN, H2O, 0.1% TFA) gave a fluffy white solid as the title compound (5.0 mg, 66%), MS (electrospray) 477 (M+1).
Reaction SMILES: CC(O/N=C(/C(NCC=O)=O)\C1N=C(N)SC=1)(C(O)=O)C.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[N:39]=[C:38]([CH2:47][OH:48])[C:37]=2[Br:49])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:40]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[N:39]=[C:38]([CH:47]=[O:48])[C:37]=2[Br:49])=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Agent: CC(C)(O/N=C(/C(=O)NCC=O)c1csc(N)n1)C(=O)O
Product: O=Cc1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Yield: 82.5 %

Procedure:
Aldehyde 8.3 was prepared from 8.2 according to the procedure described above for the preparation aldehyde 2.2. In this example, 8.2 (295 mg, 0.668 mmol) was oxidized to yield 242 mg (82%) of 8.3. MS (ESI) 439.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:9]5[N:8]6[C:4]([S:5][CH:6]=[CH:7]6)=[N:3][C:2]=5[CH3:1])=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1nc2sccn2c1C(=O)O
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc2sccn2c1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 20 h
Yield: 19 %

Procedure:
A mixture of 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61 mg, 0.33 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (77 mg 0.39 mmol) and HOAt (54 mg, 0.39 mmol) was stirred in DMF (3 ml) at 80° C. for 1 h then at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified by preparative LC/MS to give 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (LC/MS Basic: Rt 2.56 [M+H]+ 463).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH2:9]>C(C1C=CC=CC=1C)C>[CH2:8]([C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1)[CH3:9]
Reactant: Cc1ccccc1
Reactant: C=C
Agent: CCc1ccccc1C
Product: CCc1ccc(C)cc1

Procedure:
Toluene and ethylene were reacted over the Ba-Modified ZSM-11 at 400° C. The feed WHSV for toluene was 7.0 and for ethylene was 0.5. Conversion of toluene was 5.3% and the yield of para-ethyltoluene in the ethyltoluene produced was 89.0%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:26][N:25]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2I)cc1
Reactant: Ic1n[nH]c2ncccc12
Agent: C[Sn](C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2n[nH]c3ncccc23)cc1
Temperature: 100 °C

Procedure:
4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (100 mg, 0.22 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (71 mg, 0.29 mmol), bis(triphenylphosphine)Pd(II)dichloride (20 mg, 0.03 mmol), and hexamethylditin (70 L, 0.33 mmol) were suspended in 0.7 mL of dioxane and heated to 100° C. for 24 hours in a sealed 4 mL scintillation vial. The black crude residue obtained was purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 441.1, found 441.0.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][C:23]([C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=4)[CH2:13][CH2:12]2)[N:2]=1.[OH-].[Na+].Cl>CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][C:23]([C:27]([OH:29])=[O:28])=[CH:22][CH:21]=4)[CH2:13][CH2:12]2)[N:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cc5ccccc5cn4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cc5ccccc5cn4)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-(isoquinolin-3-yl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (216.6 mg, 0.46 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (91.2 mg, 2.28 mmol, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 56 mg (26%) of 3-(4-(isoquinolin-3-yl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)C.[CH3:19][CH:20]([NH:28][NH2:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C(O)C>[CH3:8][C:6]1[NH:29][N:28]([CH:20]([CH3:19])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:4](=[O:18])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(C)NN)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Solvent: CCO
Product: COc1ccc(Cc2c(C)[nH]n(C(C)c3ccc(C)cc3)c2=O)cc1
Reaction time: 8 h

Procedure:
31 g of α-(4-methoxybenzyl)-acetoacetic acid ethyl ester were added to a solution of 15 g of α-methyl-4-methylbenzylhydrazine in 30 ml of absolute ethanol in an inert gas atmosphere, during which the temperature of the reaction mixture rose to 60° C. After heating for 2 hours under reflux and standing overnight, the product crystallized out and was recrystallized from a mixture of ethanol and a little dimethylformamide.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:43])[CH2:14][N:15]1[CH2:34][C@@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[C@:17]2([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:18]2=[O:32])[CH2:16]1)(C)(C)C>C(Cl)Cl>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C@H:33]2[C@:17]3([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:18]3=[O:32])[CH2:16][N:15]([CH2:14][C:13]([OH:43])=[O:12])[CH2:34]2)=[CH:40][CH:39]=1)#[N:42]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)OC(C)(C)C)C[C@H]2c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1

Procedure:
Trifluoroacetic acid (4.8 ml, 59 mmol) was added to a solution of Example 63 (1.56 g, 2.95 mmol) in DCM (40 ml). The solution was refluxed for 3 h. It was then concentrated in vacuo and partitioned between EtOAc/aqueous NH4OH . The aqueous layer was acidified to pH=2 with SO2. The white precipitate was separated by filtration. The aqueous layer was extracted with DCM and concentrated to give white crystals which where combined with the precipitated solid to give, after drying, the above-titled compound (1.04 g), mp=220° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[F:14])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][C:12]=1[F:13])[CH3:2]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CCOc1c(F)cc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1c(F)cc(-c2nc(-c3cccc4cnccc34)no2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 5.8 %

Procedure:
A mixture of 4-(ethyloxy)-3,5-difluorobenzoic acid (JRD Fluorochemicals Ltd; 130 mg, 0.641 mmol), HATU (244 mg, 0.641 mmol), Hunig's base (0.3 mL, 1.718 mmol) in N,N-dimethylformamide (DMF) (1 ml) was stirred at room temperature for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 100 mg, 0.534 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was stirred at room temperature for 2-3 hrs and then heated in a microwave at 140° C. for 1.5 hr. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Waters Atlantis column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)) to give the title compound (11 mg)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]>>[CH:1]1([NH:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1ccccc1NC1CC1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To cyclopropylamine (27.3 g, 33.1 mL, 0.48 mol, 2.25 equiv; [CAS RN 765-30-0]) was added dropwise 2-fluoronitrobenzene (30.0 g, 0.21 mol, 1.0 equiv; [CAS RN 1493-27-2]) over 1 hours at 30° C. and stirring of the reaction mixture continued at room temperature for 18 h. The reaction mixture was extracted from a saturated aqueous solution of sodium bicarbonate (500 mL) with ethyl acetate (three times 300 mL) and the combined organic phases were dried over magnesium sulfate. Purification by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a mixture of n-heptane:ethyl acetate (9:1) afforded 32.4 g (86%) of the title compound as a yellow oil. MS (ISP): m/z=178.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2].Cl[CH2:17][C:18]([CH3:20])=[CH2:19]>C(Cl)(Cl)Cl.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:9]=[CH:8][C:7]=2[CH3:14])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CCc1cc2c(O)ccc(C)c2[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: C=C(C)COc1ccc(C)c2[nH]c(=O)c(CC)cc12
Yield: 75 %

Procedure:
Using 3-ethyl-5-hydroxy-8-methylcarbostyril (0.91 g, 4.87 mmol) and 3-chloro-2-methyl-1-propene (0.485 g, 5.36 mmol), the procedure of Reference Example 31 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 0.94 g of the title compound as pale brown crystals (75.1%).