Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:47](=[O:48])[CH2:46][O:45][CH3:44])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.1 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (1200 mg, 2.344 mmol) in THF (15 ml) was added Et3N (471 mg, 4.668 mmol) followed by 2-methoxyacetyl chloride (254 mg, 2.344 mmol). The reaction was stirred at room temperature for 20 min. After this time, the reaction was diluted with EtOAc (100 ml) and the resulting solution was wash with water (2×50 ml) and saturated NaCl (50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (120 g silica gel, 20-60% EtOAc/CH2Cl2) to the give product N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methoxyacetohydrazide as a light yellow solid 780 mg (57% yield). HPLC retention time 2.858 min (Method A); LCMS (M+H)=583.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CN1CCN(CCCN)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.4 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described in Example 278), and 1-(3-aminopropyl)-4-methylpiperazine (132 mg, 0.84 mmol) in DMF (5 ml) was heated to 70° C. for 3 hours. The solvents were removed in vacuo and the residue taken up in dichloromethane. This was washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-(4-methylpiperazin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (44 mg, 31%).
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[F:16][C:17]([F:28])([F:27])[CH2:18][I+]C1C=CC(F)=CC=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:29][N+:30]1[CH:34]=[CH:33][N:32]([CH2:18][C:17]([F:16])([F:27])[F:28])[CH:31]=1
Reactant: Fc1ccc([I+]CC(F)(F)F)cc1
Reactant: Cn1ccnc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
(2,2,2-Trifluoroethyl)(4-fluorophenyl)iodonium bis(trifluoromethanesulfonyl)-imide (17.6 g, 30 mmol) and methylene chloride (60 ml) were placed in a reaction vessel to convert the inside of the reaction vessel to a nitrogen atmosphere. While stirring and cooling in an ice bath, 1-methylimidazole (2.46 g, 30 mmol) was added dropwise thereto. After the dropwise addition thereof, the ice bath was removed, and the mixture was allowed to react at room temperature for 3 hours. After the completion of the reaction, the solvent was removed by distillation. The resulting liquid product was washed with hexane (or pentane), water, and then hexane (or pentane). Subsequently, this liquid product was dissolved in a small amount of ethyl acetate, and a large amount of ether was added thereto to separate the liquid product. The liquid product was separated from the solvent and then dried at 110° C. for 6 hours under reduced pressure using a vacuum pump. Thus, pure 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium bis(trifluoromethanesulfonyl)imide (compound 9) was obtained as a liquid substance (yield 11.5 g, 86%). When the product is colored, it may be subjected to decolorization with active carbon. Separately, p-fluoroiodobenzene was obtained from the aforementioned hexane (or pentane) wash in a substantially quantitative manner.
Reaction SMILES: C=O.CO.[NH:5]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[C:18]([C:30]([NH:32][C:33]4[S:37][N:36]=[C:35]([CH3:38])[N:34]=4)=[O:31])=[N:19][C:20]([S:23][C:24]4[N:28]([CH3:29])[CH:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:6]1.[C:39](=O)([O-])O.[Na+]>[Cl-].[Zn+2].[Cl-].[B-]C#N.[Na+].CO.O>[CH3:39][N:5]1[CH2:6][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[C:18]([C:30]([NH:32][C:33]4[S:37][N:36]=[C:35]([CH3:38])[N:34]=4)=[O:31])=[N:19][C:20]([S:23][C:24]4[N:28]([CH3:29])[CH:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:8]1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CNC3)cc2)n1
Reactant: O=C([O-])O
Agent: C=O
Agent: [B-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CN(C)C3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.20 ml of aqueous 37% formaldehyde solution and 0.10 ml of 0.3 M zinc chloride-sodium cyanotrihydroborate/methanol solution (J. Org. Chem. 1985, 50, 1927-1932) were added to a methanol (0.40 ml) solution of 13 mg of 3-{[4-(azetidin-3-yloxy)phenyl]thio}-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in the step 2, and stirred at room temperature for 30 minutes. Aqueous saturated sodium hydrogencarbonate solution and saturated saline water were added to it, and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (NH-PLC05 (by Fuji Silicia Chemical), chloroform/methanol=95/5) to obtain 12 mg of the entitled compound as a yellow solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][N:6]=1>O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:2][NH2:3])=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(Br)nc1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 32.8 %

Procedure:
To hydrazine monohydrate (5.51 mL, 114 mmol) was added 2-bromo-5-fluoropyridine (1.00 g, 5.68 mmol). The mixture was heated under microwave irradiation in a sealed, thick-walled glass tube for 1 h at 110° C. The thick, white suspension was poured into 60 mL water and stirred vigorously for 5 min. The precipitate was collected by filtration, rinsed with water, and then dried under reduced pressure to provide the title compound (0.35 g) as a white solid. LCMS m/z=188.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13 (s, 2H), 7.09 (dd, J=8.7, 3.2 Hz, 1H), 7.11 (bs, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.87 (d, J=2.9 Hz, 1H).
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:19]I)[C:15]([O:17][CH3:18])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].FC(F)(F)S(O[C:27]1[CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>CN(C=O)C.[Cl-].[Na+].O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:27]1[CH2:31][CH2:30][CH2:29][CH:28]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
To a suspension of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSCl (46 mL) dropwise. The mixture was stirred at ambient temperature for 45 min. The upper clear liquid was removed and the residue was washed with DMF (200 mL×2). The resulting solid was re-suspended in DMF (200 mL) and the mixture was cooled to 0° C. A solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (104 g, 0.320 mol) in DMF (300 mL) was added. The mixture was stirred at 0° C. under nitrogen for 20 min. The upper clear liquid was removed and added to a solution of cyclopent-1-en-1-yl trifluoromethanesulfonate (90 g, 0.37 mol) and Pd(dppf)Cl2 (3.9 g, 4.7 mmol) in DMF (500 mL) dropwise. After addition, the reaction mixture was stirred at 50° C. under nitrogen overnight then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with MTBE (300 mL×3). The organics were combined, washed with brine, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1 to 40:1) to afford (S)-Methyl 2-(tert-butoxycarbonylamino)-3-cyclopentenylpropanoate as viscous oil (62 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 5.48 (br s, 1H), 4.97 (d, J=6.6 Hz, 1H), 4.40-4.43 (m, 1H), 3.74 (s, 3H), 2.46-2.63 (m, 2H), 2.23-2.34 (m, 4H), 1.82-1.93 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([OH:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)cc(F)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylphenol (1.26 g, 6.15 mmol) in acetic acid (4 mL) and chloroform (2 mL) was added concentrated nitric acid (0.392 mL, 6.15 mmol) at −10° C. and the mixture was stirred at room temperature for 18 hours and then at 50° C. for 20 minutes (−50% desired product). The reaction mixture was diluted with ethyl acetate, then washed with water and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated and purified on silica gel (0-15% ethyl acetate/n-hexane) to afford 4-bromo-6-fluoro-3-methyl-2-nitrophenol (0.69 g, 2.76 mmol, 44.9% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.57 (d, 1 H), 2.54 (d, J=1.2 Hz, 3 H); LC/MS (m/z) ES−: 247.96 (M−1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:36]([O:28][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([O:26][CH3:27])=[O:25])[CH3:37]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: C[C@H](O)c1ccccc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Br

Procedure:
In a similar manner as described for example B31, 1.68 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 960 mg of (1S)-1-(2-bromophenyl)ethanol, 2.67 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.842 g of di-tert-butyl azodicarboxylate in 50 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][C:11]([CH3:14])=[CH:12][CH:13]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][C:11]([CH3:14])=[CH:12][CH:13]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Cl)cc3o2)s1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cc(Cl)cc3o2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
A mixture of 6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (41 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (35 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.08 mL, 0.56 mmol) was added. The resulting reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide (30 mg, 55%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.4 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 6.90 (dd, J=3.7, 0.9 Hz, 1H), 4.33-4.29 (m, 1H), 3.54-3.47 (m, 1H), 3.15-3.03 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.79 (m, 1H), 2.61 (s, 3H), 2.15-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.75-1.65 (m, 1H); MS (ESI+) m/z 402 (M+H); HPLC>99% (AUC), tR=12.99 min.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][CH2:36][CH3:37])[C:15](=[O:17])[CH3:16].[OH-].[NH4+:39].C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:39][C:26]1[C:25]2[N:24]=[C:23]([CH2:35][CH2:36][CH3:37])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:14]([O:13][CH3:12])[C:15](=[O:17])[CH3:16])[C:34]=2[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Chloroperoxybenzoic acid (77% pure, 0.44 g, 1.95 mmol) (mCPBA) was added to a solution of N-methoxy-N-[4(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide (1.0 mmol) in dichloromethane (25 mL) cooled to 0° C. and stirred for 10 minutes, and then the reaction was stirred for one hour at ambient temperature. Concentrated ammonium hydroxide (10 mL) and phenylsulfonyl chloride (0.22 mL, 1.75 mmol) were sequentially added and the reaction mixture was stirred for 1 hour and then diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (2×50 mL) containing 5% sodium hydroxide (5 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL) and the combined organic solutions were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide a brown oil. The material was purified by flash column chromatography on silica gel (eluting with 5% methanol and concentrated ammonium hydroxide (2 mL) in dichloromethane). The resulting crystalline solid was recrystallized twice from acetonitrile and water and dried overnight under vacuum at 70° C. to afford 0.26 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxyacetamide as light yellow needles, mp 138-140° C. MS (APCI) m/z 370 (M+H+); Anal. calcd for C20H27N5O2: C, 65.02; H, 7.37; N, 18.96. Found: C, 64.97; H, 7.04; N, 18.80.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1>N1CCCCC1.C(O)C>[CH3:17][C:15]1[S:16][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C=O)s1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.42 mg of the 5-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 237.8 mg (99%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[Si](C)(C)C)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1.[Br:22]Br.C[O-].[Na+].CCOC(C)=O>C(Cl)Cl.CO>[Br:22]/[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[C:9](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[CH2:10][CH3:11]
Reactant: CC/C(=C(\c1ccc(F)cc1)[Si](C)(C)C)c1ccccc1
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC/C(=C(/Br)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.6 %

Procedure:
To a solution of (2) (3.93 g, 13.2 mmol) in CH2Cl2 (25 mL) at −78° C. was added bromine (2.5 g, 15.8 mmol) in 11 mL CH2Cl2 dropwise over 0.5 h. A solution of NaOMe (26.2 mmol) in methanol (36 mL) was added and the mixture was allowed to warm to rt. After stirring 3.5 h, EtOAc was added and the solution was washed with water, brine, and was dried (MgSO4) . The solvent was removed under reduced pressure and the resulting solid was recrystallized (methanol) to give the bromide (3) as a white solid (2.36 g, 59%): 1 H NMR (CDCl3) δ 7.33 (m, 7 H), 7.08 (m, 2 H), 2.33 (q, J=7.7 Hz, 2 H), 0.86 (t, J=7.7 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)cc1

Procedure:
Prepared from compound 1 and 4-methoxybenzylchloride as described for compound 78. Crystallized from diethyl ether. M.p. 77°-78° C.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C@:7]([CH2:14][CH3:15])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8]O>ClC(Cl)C>[CH2:10]([C@:7]1([CH2:14][CH3:15])[CH2:8][NH:6]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@](N)(CC)CO
Agent: O=S(=O)(O)Cl
Solvent: CC(Cl)Cl
Product: CCCC[C@]1(CC)CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Chlorosulphonic acid (1 molar equivalent) was added to a solution of the product from step (f) (15 g) in dichloroethane (90 ml) at a temperature of <16° C. When addition was complete, the mixture was stirred for 2 hours at room temperature and then evaporated i vacuo. Water (60 ml) and 50% w/v aqu. NaOH (41 ml) were added and the mixture distilled at atmospheric pressure. The organic phase of the distillate was separated and dried over KOH to give a solution of the desired product (77% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCOc1ccc(-c2ccncc2)cc1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A mixture of 4-[4-(3-chloropropoxy)phenyl]pyridine (1.22 g) and metachloroperbenzoic acid (1.82 g) in chloroform (25 mL) is stirred at room temperature for four hours, then concentrated under reduced pressure and purified by column chromatography over silica gel using a gradient dichloromethane/methanol from 100/0 to 95/5. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 1.09 g of 4-[4-(3-chloropropoxy)phenyl]pyridine 1-oxide as a pale yellow solid used without further purification.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH:16]=[C:15]([CH3:31])[C:14]=2[C@H:32]([OH:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[C:10]([O:38][C@@H:32]([C:14]1[C:15]([CH3:31])=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[C:19]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:18]=2)[C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:13])([CH3:11])[CH3:9]
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 116.3 %

Procedure:
Perchloric acid (70%, 0.28 mL, 3.2 mmol) was added to a solution of (S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate (0.82 g, 1.6 mmol) in tert-butyl acetate (5 mL) at room temperature. After 3 h, solid NaHCO3 was added and the slurry stirred vigorously for 30 min. Saturated NaHCO3 was added slowly until the mixture was pH ˜8. Following extraction of the organic layer with EtOAc, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-35% EtOAc/Hex) to produce 0.52 g (57%) of the title compound as an amorphous solid. 1H-NMR: 400 MHz, (CDCl3) δ: 7.69 (s, 1H); 7.66 (d, J=2.4 Hz, 1H); 7.51 (m, 2H); 7.44 (m, 1H); 7.34 (d, J=9.4 Hz, 1H); 7.27 (m, 1H); 7.15 (dd, J=9.4, 2.4 Hz, 1H); 5.12 (s, 1H); 4.17 (m, 2H); 2.63 (s, 3H); 1.23 (t, J=7.2 Hz, 3H); 1.01 (s, 9H).