Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([NH2:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[N:22]=[C:18]3[CH3:17])[CH3:31])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)n1c(N)cnc1-c1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnc(-c2ccc(Cl)cc2)n1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3-isopropyl-imidazol-4-amine (0.10 g, 0.43 mmol), 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.09 g, 0.43 mmol), HATU (0.16 g, 0.43 mmol), and Et3N (200 μL, 1.4 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 30 min. The reaction mixture was then diluted with 10 mL of saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was subsequently washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography (SiO2, 100% EtOAc-30% MeOH/EtOAc) to afford the titled compound as a white solid (0.046 g, 0.10 mmol, 23% yield). 1H NMR (400 MHz, CDCl3) 7.52 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.07 (s, 1H), 5.18 (q, J=7.1 Hz, 1H), 4.36 (q, J=7.0 Hz, 1H), 2.42 (s, 3H), 1.78 (d, J=7.1 Hz, 3H), 1.33 (d, J=7.0 Hz, 6H). MS: (ES) m/z calculated for C20H21ClF3N5O [M+H]+ 440.1, found 440.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=[CH:10][C:5]2=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2c(Cl)nc(N)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2c(-c3ccco3)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A solution of tert-butyl 6-amino-4-chloro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate (269 mg, 1 mmol) in DMF (2 mL) was treated with PdCl2(PPh3)2 (35 mg, 0.05 mmol) and 2-(tributylstannyl)furan (315 μL, 1 mmol), stirred at room temperature for 16 h and the resulting solid filtered and washed with EtOAc to give the title compound (298 mg, 99%) as a cream solid.
Reaction SMILES: OC1CCCN(C2N=C3C=C(OCC4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(OC(C)(C)C)=O)C1.[CH2:38]([C:40]1[CH:41]=[C:42]([CH2:45][CH2:46][C:47]2[CH:72]=[CH:71][N:50]3[C:51](=[O:70])[C:52](/[CH:61]=[CH:62]/[C:63]([O:65]C(C)(C)C)=[O:64])=[C:53]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:54]=[C:49]3[CH:48]=2)[S:43][CH:44]=1)[CH3:39]>>[CH2:38]([C:40]1[CH:41]=[C:42]([CH2:45][CH2:46][C:47]2[CH:72]=[CH:71][N:50]3[C:51](=[O:70])[C:52](/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64])=[C:53]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:54]=[C:49]3[CH:48]=2)[S:43][CH:44]=1)[CH3:39]
Reactant: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)c1
Agent: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Product: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)c1
Yield: 56 %

Procedure:
Reactions were performed in the same manner as in Example 1, (L) by using tert-butyl (E)-3-{8-[2-(4-ethyl-2-thienyl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]-pyrimidin-3-yl}-2-propenoate (65 mg, 0.13 mmol) as a starting material. As a result, 32 mg (56%) of yellow crystals were obtained.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]1[S:10][C@H:11]2[O:17][C@H:16]([CH2:18][CH2:19][C:20](OCC)=[O:21])[C@@H:15]([O:25]CC3C=CC(OC)=CC=3)[C@H:14]([O:35]CC3C=CC(OC)=CC=3)[C@H:12]2[N:13]=1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].ClCCl.[C:55]([OH:61])([C:57]([F:60])([F:59])[F:58])=[O:56]>C1COCC1>[F:58][C:57]([F:60])([F:59])[C:55]([OH:61])=[O:56].[OH:21][CH2:20][CH2:19][CH2:18][C@H:16]1[O:17][C@H:11]2[C@H:12]([N:13]=[C:9]([NH:8][CH3:6])[S:10]2)[C@@H:14]([OH:35])[C@@H:15]1[OH:25]
Reactant: CCOC(=O)CC[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CCCO)O[C@@H]2S1
Yield: 23 %

Procedure:
A solution of compound 77 (150 mg, 0.23 mmol) in THF (10 mL) was treated with LiAlH4 (26.6 mg, 0.70 mmol) for 3 h at room temperature. The reaction mixture was then quenched by addition of saturated aqueous NH4Cl (20 mL), extracted with dichloromethane (3×30 mL), and dried over anhydrous magnesium sulfate. The filtrate was concentrated under vacuum to give crude compound 78 as a yellow oil (90 mg), which was dissolved into dichloromethane (10 mL) and treated with TFA (1 mL) overnight at room temperature. Removal of volatiles gave a residue, which was purified by Prep-HPLC with the following conditions: [(Agilent 1200 prep HPLC: Column, Sun fire prep. C18; mobile phase, water with 0.03% trifluoroacetic acid and CH3CN (10% up to 20% in time 10); Detector, 220 nm.)] to give the title compound 79 (Example 143) as a white solid (10.8 mg, 23%). (ES, m/z) [M+H]+ 263.1; 1H NMR (300 MHz, D2O) δ 6.18-6.20 (d, J=6.3 Hz, 1H), 4.08-4.12 (m, 1H), 3.89-3.93 (m, 1H), 3.36-3.51 (m, 4H), 2.74-2.76 (m, 3H), 1.68-1.76 (m, 1H), 1.33-1.62 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[Cl:11])[NH:4][CH:3]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[Cl:11])[N:4]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1c(-c2ccccc2)cnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)c(-c3ccccc3)cnc21
Reaction time: 0.33 h
Yield: 95 %

Procedure:
3-Bromo-4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.30 g, 4.23 mmol) was placed in DMF (10 mL) at 0° C. NaH (0.203 g, 5.07 mmol) was then added, and the reaction was stirred for 20 minutes. Benzenesulfonyl chloride (0.595 mL, 4.65 mmol) was then added, and the reaction was stirred for 30 minutes at 0° C. The reaction was then poured into water and extracted with EtOAc. The combined organic fractions were dried, filtered, concentrated and purified (2:1 D CM: hexanes) to give 3-bromo-4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (1.80 g, 95.1% yield).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([O:20]C)=[C:14]([O:22]C)[CH:13]=2)=[N:7][C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>>[CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[C:14]([OH:22])[CH:13]=2)=[N:7][C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1sc(NC(=O)c2cc(OC)c(OC)c(OC)c2)nc1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Product: CCCCc1sc(NC(=O)c2cc(O)c(O)c(O)c2)nc1-c1ccc(O)cc1
Yield: 47.5 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-n-butyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,4,5-trimethoxy-benzamide prepared in Example 64 and boron tribromide were used as starting materials, the crude product was purified by recrystallization with acetone to give a product as a white solid in a yield of 47.5%, mp: 119-120 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.88 (3H, t, J=7.2 Hz, CH3), 1.35 (2H, sextuple, J=7.20 Hz, CH2), 1.63 (2H, quintuple, J=7.20 Hz, CH2), 2.82 (2H, t, J=7.2 Hz, CH3), 6.83 (2H, d, J=8.80 Hz, ArH), 7.08 (2H, s, ArH), 7.40 (2H, d, J=8.80 Hz, ArH), 8.80 (4H, br, OH), 12.12 (1H, br, CONH); EI-MS m/e (%): 400.1 (M+, 14), 248.2 (55), 205.1 (100), 163.1 (38); HREI-MS Calcd. for C20H20N2O5S: 400.1093. found: 400.1091.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(Cl)Cl>CN(C)C=O.O.CCOCC.CO>[CH:19]1([O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 100 °C
Yield: 99.6 %

Procedure:
To a suspension of 2-methoxy-5-nitrophenol (525 g, 3.104 mol) and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 L), under N2 protection, was added cyclopentyl bromide (499.2 mL, 4.66 mmol). The suspension was heated to 100° C. for 6 h. Potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100° C. for 4 h. TLC indicated the reaction was complete (9:1 DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3 L) and ether (3 L). The layers were separated and the aqueous layer was re-extracted with ether (2 L). The combined organic layers were washed with 1N NaOH (2 L), water (2 L), and brine (2 L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2×300 mL) to obtain 736.7 g (99.6% yield) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][C@@H:10]1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C:12](=[N:27][O:26][CH3:25])[CH2:11][C@@H:10]1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.1 %

Procedure:
cis-N1,N2-Bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (1.5 g) was dissolved in methanol (30 ml), and O-methylhydroxylamine hydrochloride (572 mg) and pyridine (737 ml) were added to stir the mixture at room temperature for 17 hours. After the reaction mixture was concentrated, water was added to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (1.52 g) as a colorless solid.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[H-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:8])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1CCCC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
Cyclopentanecarboxylic acid (10.0 g, 87.7 mmol) was heated under reflux with thionyl chloride (13 mL, 176 mmol). After 2 hrs the thionyl chloride was distilled under reduced pressure to give the crude acid chloride (9.8 g, 74.2 mmol) as a liquid. In another vessel, 50% sodium hydride (4.28 g, 89.09 mmol) was taken up in THF (100 mL) and diethyl malonate (11.88 g, 74.24 mmol) was added dropwise at 0° C. Into this mixture the previously-prepared acid chloride (9.8 g, 74.2 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at r.t. for an hour. The reaction was quenched with cold water and extracted with ethyl acetate. The combined organic layer was washed with water, sodium bicarbonate solution, brine solution, dried over sodium sulfate, filtered and concentrated to afford 2-cyclopentanecarbonyl malonic acid diethyl ester (19.2 g, 85.5%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH3:25])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 60 °C
Yield: 100.1 %

Procedure:
To a solution of the 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.28 mmol), prepared as described in Example 1, in DMF (3 mL) at RT was added K2CO3 (116 mg, 0.84 mmol), followed by iodomethane (79 mg, 0.56 mmol). The reaction was heated at 60° C. for overnight. The reaction was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (20 mL×3). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound, 7,8-bis(4-chlorophenyl)-2-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (104 mg, 100%) as a yellow oil. HPLC retention time: 3.67 min; MS [M+H]+: found 371.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][O:25]C)[N:14]([CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][OH:25])[N:14]([CH2:15][C:16]3([OH:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCOCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CCO)n2CC1(O)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A suspension of 4-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin 1-yl]methyl}tetrahydro-2H-pyran-4-ol (0.95 g, 2.67 mmol) in dichloromethane (15 mL) was cooled to 0° C. Boron tribromide (8 mL, 8.00 mmol) was added and the reaction mixture was allowed to stir overnight while slowly warming to ambient temperature. The reaction mixture was concentrated. The residue was taken up in a mixture of methanol (15 mL) and 6M hydrochloric acid (10 mL) and refluxed for 2.5 hours. The reaction mixture was cooled to ambient temperature and the pH was adjusted to 8 with 2M sodium hydroxide. The mixture was extracted with chloroform (12×20 mL). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material purified by HPFC eluting with a gradient of 0 to 45% CMA in chloroform to provide an off white solid. The solid was triturated with acetonitrile, isolated by filtration, and dried in a vacuum oven at 140° C. to provide 0.536 g of 4-{[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol as a white solid, mp 237-238° C. MS (ESI) m/z 343 (M+H)+; Anal. calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.04; H, 6.57; N, 16.19.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]=[CH:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]=[CH:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH3:23])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccncc1I
Reactant: O=c1[nH]ccn1-c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1-n1ccn(-c2ccc3ncsc3c2)c1=O
Yield: 6.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (I-142b: 170 mg, 0.7834 mmol) was reacted with 3-iodo-4-methyl-pyridine (172 mg, 0.7834 mmol), 1,4-dioxane (10 mL), copper iodide (17 mg), trans-1,2-diamino cyclohexane (34 mg) and potassium phosphate (499 mg, 2.3502 mmol) to afford the crude product. Purification by column chromatography on silica gel (2-3% MeOH in CHCl3), followed by preparative HPLC afforded 16 mg of the product (6.63% yield).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH:22]2[CH2:25][N:24](C([O-])=O)[CH2:23]2)[CH2:6][CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH:24]1[CH2:25][CH:22]([C:11]2[N:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]3)[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=2)[CH2:23]1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CN(C(=O)[O-])C3)nc3cnc4ccsc4c32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1

Procedure:
3-{1-[trans-4-(Cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}azetidine-1-carboxylate (14 mg, 0.031 mmol) was treated with trifluoroacetic acid (1 mL) in methylene chloride (1 mL) at room temperature for 1 h. The mixture was stripped to dryness, diluted with MeOH and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C19H22N5S (M+H)+: m/z=352.2. Found: 352.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([O:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(N)ccc1OCc1cccc(F)c1
Temperature: 70 °C
Yield: 84.9 %

Procedure:
A mixture of 14A (162 mg, 0.56 mmol) and Fe powder (249 mg, 4.46 mmol) in HOAc/EtOAc (1/1) (2.4 ml) was heated at 70° C. for 2.5 h. The mixture was cooled to rt, filtered through a 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (25 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 14B (123.8 mg, 67% pure).
Reaction SMILES: Cl.C([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)=[CH:14][S:15][CH2:16][CH2:17][CH3:18])CCC>>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:19]1[NH:23][CH:22]=[CH:21][N:20]=1)=[CH:14][S:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccccc1C(=CSCCC)c1ncc[nH]1
Agent: Cl
Product: CCCSC=C(c1ncc[nH]1)c1ccccc1O

Procedure:
After adding an equivalent amount of hydrogen chloride to 200 mg of an oily substance which was Isomer B of 1-(2-n-butyloxyphenyl)-1-imidazolyl-2-n-propylthioethylene obtained from Compound 19 in the same manner as in Example 6, the resultant precipitate was recrystallized from ethyl acetate/acetone to obtain 140 mg of Isomer B (Compound 21) of 1-(2-n-butyloxyphenyl)-1-imidazolyl-2-n-propylthioethylene hydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([C:8]1([NH2:11])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C1O[N:15]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)Cl>[CH2:1]([C:8]1([NH:11][NH:15][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.6 g (72.0 mmol) of 1-benzylcyclopropanamine was dissolved in 90 mL of methylene chloride, mixed with 14.3 g (54.5 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice, and stirred at room temperature for 30 minutes. After completion of the reaction, methylene chloride was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 350 g, ethyl acetate:hexane=1:20) to give 4.6 g of the desired product as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([O:19][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 10 °C

Procedure:
Suspend N5 -benzyloxycarbonyl-ornithine (80 g, 0.3 mol) in t-butyl acetate (250 mL) and cool to 10° C. Add p-toluenesulfonic acid (57 g, 0.3 mol) and add, by dropwise addition, concentrated sulfuric acid (80 mL). Stir at 10° C. until the reaction is complete, basify to pH 8 by adding a suspension of sodium bicarbonate in water. Extract with ethyl acetate, dry (MgSO4), and evaporate to give N5 -benzyloxycarbonyl-ornithine, t-butyl ester.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2-].[Li+].[SH:21][CH2:22][CH2:23][C:24](OC)=[O:25]>C1(C)C=CC=CC=1>[SH:21][CH2:22][CH2:23][C:24]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)=[O:25]
Reactant: COC(=O)CCS
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CCS)CC(C)(C)N1OC1CCCCC1

Procedure:
The general procedure of Example 1 is followed using 2.00 grams (7.8 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.18 gram of lithium amide and 0.94 gram (7.8 mmol) of methyl 3-mercaptopropionate in 50 ml of toluene to afford the title compound after purification by silical gel chromatography.