Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:16]([C:18]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCCl>CCOCC>[CH3:24][C:21]1([CH3:25])[O:20][CH2:19][C:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:16][NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:23][O:22]1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Yield: 71.3 %

Procedure:
To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Ooii et al, J. Org. Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc)3 (0.3 g; 1.4 mmol) in 1,2-dichloroethane (3.5 ml) AcOH (0.06 ml; 1 mmol) was added at room temperature with stirring under N2. After stirring for 2 h, the mixture was diluted to 20 ml with Et2O, washed with 1.M NaOH (2×5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexane (5 ml) and kept in the freezer (−18° C.) overnight. The crystals formed were filtered off, washed with small volume of hexane and dried to give the title compound (0.32 g; 71%), as colourless crystals. 1H-NMR (CDCl3) 6.96 (d, 2H, J=8.4 Hz); 6.58 (d, 2H, J=8.4 Hz); 4.84 (broad s, 1H); 4.01 (d, 2H, J=11.9); 3.85 (broad s, 1H); 3.8 (d, 2H, J=11.9 Hz); 3.44 (s, 2H); 2.46 (t, 2H, J=7.9 Hz); 1.5 (m, 2H); 1.45 (s, 3H); 1.43 (s, 9H); 1.42 (s, 3H); 1.26 (m, 10H); 0.86 (t, 2H, J=6.95 Hz).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.Cl.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1)#[N:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:3](=[O:5])[C@@H:2]2[CH2:13][CH2:14][CH2:15][N:1]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reaction time: 48 h
Yield: 90 %

Procedure:
276 g of Boc-Pro-OSu (0.88 mol) were introduced into 2 l of methylene chloride at 0° C. To this solution were added successively 163.9 g of 4-cyanobenzylamine hydrochloride (0.97 mol) and 230 ml of diisopropylethylamine (1.34 mol). The suspension was stirred in a melting ice bath for 48 h and then filtered. The filtrate was extracted with 20% strength NaHSO4 solution (4×), saturated NaHCO3 solution (3×) and saturated sodium chloride solution (2×), dried and evaporated in a rotary evaporator. Recrystallization of the residue from methyl tert-butyl ether resulted in isolation of 261 g (90%) of white crystals, m.p. 124°-125° C.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>ClCCl>[N:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:31][CH:32]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Triethylamine (0.41 ml) was added to a stirred suspension of 4-[2-[4-(4-pyridyl)piperazin-1-yl]ethyl]benzylamine, trihydrochloride (300 mg) in dry dichloromethane (20 ml). After 5 minutes, 1-butanesulphonyl chloride (0.10 ml) was added and the mixture stirred overnight. Dichloromethane (80 ml) was added and the solution washed with water (2×25 ml), dried (MgSO4) and the solvent removed in vacuo. Trituration of the residue with a small volume of ethyl acetate gave the title compound, 50 mg, as an off-white solid: m.p. 154°-156° C.; NMR (d6DMSO) δ8.16 (2H, d), 7.53 (1H, t), 7.22 (4H, m), 6.37 (2H, d), 4.10 (2H, d), 3.35 (6H, m+H2O), 2.81 (4H, m), 2.54 (4H, m+DMSO), 1.56 (2H, m) 1.29 (2H, m) 0.82 (3H, t); m/e 417 (M+H)+ ; calculated for C22H32N4O2S.0.75H2O: C, 61.5; H, 7.8; N, 13.0. found: C, 61.5; H, 7.6; N, 12.7%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=C(C=CC=1)C(OO)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:17])=[N:4][CH:3]=1
Reactant: Ic1cnc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc2ncc(I)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 3-iodo-1,5-naphthyridine (D-14) (2.750 g, 10.7 mmol, 1.0 eq) in CH2Cl2 (30 mL), 3-chloroperoxybenzoic acid (2.780 g, 16.1 mmol, 1.5 eq) was added. After the resulting mixture was stirred at RT for 2 h, saturated sodium carbonate solution (50 mL) was added, and extracted with CH2Cl2 (10×30 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (50% EA-PE) to afford the desired product 7-iodo-1,5-naphthyridine 1-oxide (D-15) (1.574 g, 54% yield) as a solid. 1H NMR (400 MHz, CDCl3-d6) δ: 9.45 (dd, J=2.0 Hz, J=0.8 Hz, 1H), 9.18 (d, J=2.5 Hz, 1H), 8.54 (d, J=6.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.59-7.55 (m, 1H); ESI-MS m/z: 272.95 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]>ClCCl>[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:10]3[O:14][CH:13]=[N:12][CH:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc(C#N)c2)ccc1-c1cnco1
Yield: 89 %

Procedure:
3-Methoxy-4-(5-oxazolyl)aniline, 1D (1.00 g, 5.26 mmol) and 3-cyanophenyl isocyanate (1.17 g, 7.89 mmol) in dichloromethane (40 mL) were stirred at rt for 20 h. The precipitate formed was collected by filtration, followed by washing with dichlorometnane to provide 1E (1.57 g, 89% yield) as a yellow solid. (LC/MS retention time=3.67 min.; M+=335. Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)=[N:1]2
Reactant: O=Cc1ccccn1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added 2-pyridine carboxaldehyde (0.082 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.15 g, 0.84 mmol), and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. overnight. The mixture was cooled to room temperature. Water (40 mL) was added and the reaction mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 1% methanol in CH2Cl2 as eluent) to give 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (0.077 g, 36%) as a white solid. 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one was converted to the corresponding hydrochloride. Selected data: MS (m/z): 284.0; MP 215-217° C. (hydrochloride).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1)=[O:11]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
A mixture of N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (9.80 g, 39.3 mmol), 5-bromo-2-nitropyridine (7.14 g, 35.1 mmol), cesium carbonate (14.8 g, 45.3 mmol) and N,N-dimethylformamide (80 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10→0/100) to give N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 59%) as a white solid. To a solution of N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.68 g, 20.7 mmol) thus-obtained in methanol (50 mL) was added palladium carbon (50% water-containing product, 700 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (6.20 g, 88%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:14])([CH3:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CN(c2ncc(Br)cc2N)CCO1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine (2.22 g, 7.03 mmol) in EtOAc (30 mL) was added tin(II) chloride dihydrate (8.94 g, 39.6 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 1 h, the reaction was cooled to rt, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (0-35% EtOAc in hexanes) to provide a colorless film as 5-bromo-2-(2,2-dimethylmorpholino)-pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (1H, d, J=2.2 Hz), 7.13 (1H, d, J=2.3 Hz), 5.10 (2H, s), 3.83 (2H, m), 2.90 (2H, m), 2.77 (2H, s), 1.24 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[C:16]2[O:17]CC(C)(C)N=2)=[CH:4][CH:3]=1.Cl.[OH2:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[C:16]([OH:17])=[O:24])=[CH:6][CH:7]=1
Reactant: CC1(C)COC(c2c(F)cccc2Sc2ccc(F)cc2)=N1
Reactant: O
Agent: Cl
Product: O=C(O)c1c(F)cccc1Sc1ccc(F)cc1

Procedure:
The compound 2-[2-(4-fluorophenylthio)-6-fluorophenyl]-4,4-dimethyloxazoline (5.0 g, 15.66 mmol) is added to 310 ml of a 4.5N HCl solution in water and is refluxed overnight. The cooled reaction mixture is extracted twice with ethyl acetate. The extracts are washed with water and then brine and dried over MgSO4 to afford the subtitle compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Si:49]([O:56][CH2:57][C@@H:58](O)[CH3:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>O>[Si:49]([O:56][CH2:57][C@H:58]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:59])([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:51])[CH3:50]
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution of 2-methylquinolin-8-ol (0.40 g, 2.5 mmol) in tetrahydrofuran (2.1 mL, 2.5 mmol) was added triphenylphosphine (1.6 g, 6.3 mmol), diethyl azodicarboxylate (0.63 mL, 4.0 mmol), and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (0.62 g, 3.3 mmol). The resultant mixture was allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.33 g, 40%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[S:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:9])=[O:8])/[CH3:28])[CH:26]=1
Reactant: NNC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccccc1S(=O)(=O)N1CCOCC1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 21 %

Procedure:
2-(morpholinosulfonyl)benzohydrazide (30 mg, 0.105 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (17.94 mg, 0.105 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-2-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 21.28% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 7.95 (d, 1H, J=8.0 Hz), 7.95-7.70 (m, 2H), 7.66 (d, 1H, J=7.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.25 (dd, 1H, J=2.8 & 8.8 Hz), 6.91 (d, 1H, J=8.4 Hz), 3.66 (m, 4H), 3.2 (m, 4H), 2.36 (s, 3H). Mass [M+H]+: 438.1
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH3:33]>CC(O)C>[NH2:33][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(CO)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 110 °C

Procedure:
A solution of {3-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol (compound of Formula II-B where Z=cyclobutyl and Q1=2-phenylquinolin-7-yl) (265 mg, 0.6 mmol) in 5 mL of iPrOH was cooled to −78° C. and charged with NH3 gas for 1 min. This sealed tube was equipped with a teflon O-ring, sealed and heated at 110° C. for 3 days. The mixture was cooled to −78° C. and the cap was removed. The salt was filtered off and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluting with 100% ethyl acetate→EtOAc:MeOH=90:10) to obtain the title compound as a light yellow solid, a mixture of cis and trans isomers in the ratio of 5:1; MS (ES+): m/z 422 [MH+]; 1H NMR (CDCl3, 400 MHz): δ=2.42-2.48 (m, 2H), 2.66-2.74 (m, 3H), 3.71-3.85 (m, 3H), 5.25 (br s, 2H), 7.10-7.19 (m, 2H), 7.46-7.57 (m, 3H), 7.91-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J=8.6 Hz, 1H), 8.42, 8.44 (2×s, 1H, 5:1 ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([NH2:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[C:16]([Cl:15])[CH:25]=[CH:24]3)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 22.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (0.86 g, 3.37 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26) (0.5 g, 2.80 mmol), DMAP (cat), pyridine (0.68 ml, 8.42 mmol) and DCM (10 ml) gave the title compound (0.25 g, 23%) after purification by column chromatography DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:28][C:25]1[CH:26]=[N:27][C:22]([O:21][CH2:20][CH2:19][N:18]([CH3:29])[CH3:17])=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)CCOc1ccc(N)cn1
Product: CN(C)CCOc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cn1
Yield: 70.2 %

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.54 mmol) was reacted with 6-[2-(dimethylamino)ethoxy]pyridin-3-amine (120 mg, 0.65 mmol) to afford the desired product (160 mg, 70%) as a light yellow solid; 1H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.46 (t, J=5.5 Hz, 2H), 3.20 (s, 3H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s, 6H); ESI MS m/z 422 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:25][CH:24]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:36].ClN1C(=O)CCC1=O>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:27][CH:28]=2)=[C:16]([Cl:36])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCOc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethylene (3.5 g, 7.5 mmol) and chloroform 935 mL). Add N-chlorosuccinimide (1.99 g, 14.9 mmol). Heat a t reflux. After 18 hours, cool the reaction mixture and extract with water, aqueous saturated sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and dry in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[C:3](=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=2)[CH2:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH2:1]1[CH2:10][O:9][C:8]2[C:3](=[C:4]([CH:11]=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: OCc1cccc2c1CCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc2c1CCCO2
Yield: 100 %

Procedure:
(2H-3,4-Dihydrobenzopyran-5-yl)methanol was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (100%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[S-:10][C:11]#[N:12].[K+].C(O)C>CCCCC>[S:10]([CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[C:11]#[N:12]
Reactant: N#C[S-]
Reactant: O=C(CCl)N1CCCC1
Agent: [K+]
Solvent: CCO
Solvent: CCCCC
Product: N#CSCC(=O)N1CCCC1
Reaction time: 4 h

Procedure:
1-(α-Chloroacetyl pyrrolidine (14.7 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.2 mol) and ethanol (50 ml) were charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 4 hours. The mixture was then cooled and filtered. The filtrate was stripped of solvent to yield a solid product. The solid was extracted with three 200 ml portions of boiling benzene, and the benzene extracts were combined and evaporated under reduced pressure to yield an oil. The oil was poured into pentane wherein it solidified. The solid was recrystallized from a benzene-pentane mixture to yield 1-(α-thiocyanoacetyl) pyrrolidine having a melting point of 95° to 96° C. and having the following elemental analysis; calculated for C7H10N2OS.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:8]=1[CH3:28])C.FC(F)(F)C(O)=O.[NH:39]([C:41]1[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[N:45][CH:46]=1)[NH2:40].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:47]([C:44]1[N:45]=[CH:46][C:41]([N:39]2[C:6]([C:7]3[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[C:8]=3[CH3:28])=[CH:5][CH:4]=[N:40]2)=[CH:42][CH:43]=1)#[N:48]
Reactant: N#Cc1ccc(NN)cn1
Reactant: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)nc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 28.2 %

Procedure:
Methyl 6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.073 g, 0.17 mmol) and 5-hydrazinopyridine-2-carbonitrile trifluoroacetate (0.050 g, 0.20 mmol) in dioxane (3 ml) were placed in a vial. 2M HCl (0.188 ml) was added and the mixture was stirred at 55° C. for 15 min. After cooling, NaHCO3 (0.048 g) was added and the mixture was extracted with DCM and water. The combined organic phases were washed with water, brine, dried (Na2SO4) and evaporated. The residue was dissolved in acetic acid (10 ml) and the vial was sealed. The solution was stirred at 90° C. for 10 h. After evaporation, the residue was purified by preparative HPLC to give 0.023 g (28%) of the title compound.