Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])/[CH2:18][CH2:19][CH2:20][C:21]2[C:26]/1=[CH:25][CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C1\CCCc2ccccc21
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.112 ml, 8.26 mmol) and ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate (1.785 g, 8.26 mmol) in CH2Cl2 (33.3 ml) at 0° C. was added TFA (0.064 ml, 0.826 mmol) dropwise. Removed the ice bath and stirred at room temperature for 4 hours. Dilute with CH2Cl2 and wash twice with saturated NaHCO3. The organics were dried over sodium sulfate, concentrated, and purified on silica gel 20% EtOAc/Hex.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:13][C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2].[H-].[Na+].[CH2:16]([N:18]1[C:22]([CH3:23])=[CH:21][CH2:20][C:19]1([C:26]1[CH:31]=[CH:30][C:29]([CH2:32]OS(C)(=O)=O)=[CH:28][CH:27]=1)C#N)[CH3:17].O.[CH3:39][N:40](C)C=O>>[C:39]([C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:16][CH3:17])[C:19]=1[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:13]2[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:30][CH:31]=1)#[N:40]
Reactant: CCSc1nc2c(C)ccnc2[nH]1
Reactant: CN(C)C=O
Reactant: CCN1C(C)=CCC1(C#N)c1ccc(COS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2c(C#N)cc(C)n2CC)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (3.00 g) in dimethylformamide (30 ml) was added sodium hydride (627 mg) portionwise at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for an hour. To the mixture was added a solution of 1-ethyl-2-(4-methanesulfonyloxymethyl phenyl)-5-methylpyrrole-2-carbonitrile (4.94 g) in dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 3 hours. Water was added therein, and extracted twice with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography eluted by n-hexane/ethyl acetate (1/1) to give 3-[4-(3-cyano-1-ethyl-5-methyl-2-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.52 g) as colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)[C:8]([CH3:20])=[C:7]([C:21]([N:23]=[C:24]([NH2:26])[NH2:25])=[O:22])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27]CCl.B(Br)(Br)Br.CO.C(OCC)(=O)C>ClCCl>[ClH:27].[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[C:8]([CH3:20])=[C:7]([C:21]([N:23]=[C:24]([NH2:25])[NH2:26])=[O:22])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CCn1c(C(C)(C)C)cc(C(=O)N=C(N)N)c1C
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N=C(N)N)cc(C(C)(C)C)n1CCc1ccccc1O
Product: Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 330 mg portion of 5-tert-butyl-N-(diaminomethylene)-1-[2-(2-methoxyphenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide was dissolved in 10 ml of dichloromethane, and 2.78 ml of a 1 M boron tribromide dichloromethane solution was added dropwise thereto at −70° C. under an atmosphere of argon, followed by stirring at room temperature for 14 hours. Under ice-cooling, 5 ml of methanol was added to the reaction liquid, and the reaction liquid was concentrated under a reduced pressure. The residue was subjected to three times of azeotropy with methanol, and a saturated sodium bicarbonate aqueous solution and saturated brine were added to the residue, followed by extraction with 20% methanol/chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), methanol:chloroform=10:90). The resulting product was dissolved in 3 ml of ethanol and, under ice-cooling, 0.263 ml of 4 M hydrogen chloride/ethyl acetate was added, followed by stirring at room temperature for 15 hours. Then, the solid formed by adding ethyl acetate was collected by filtration to obtain 206 mg of 5-tert-butyl-N-(diaminomethylene)-1-[2-(2-hydroxyphenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide hydrochloride as a light brown solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C.CCOC(C)=O.O>[CH3:29][O:28][N:27]([CH3:26])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2ncccc2c1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of quinoline-6-carboxylic acid (10 g, 57.75 mmol) in DMF (200 mL) was added carbonyl diimidazole (10.3 g, 62.5 mmol) under nitrogen. The reaction was stirred for 1 hour. To the solution was added N,O-dimethyl hydroxylamine (5.6 g, 57.75 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc (150 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (5×100 mL). The organics were combined and washed with water (3×100 mL), brine (2×100 mL), dried over Na2SO4, filtered and concentrated to give quinoline-6-carboxylic acid methoxy-methyl-amide (11.97 g, 97% yield).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[O:9])=[CH:6][N:5]=1)[NH2:3].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(=O)([O-])[O-].[K+:37].[K+]>O.C(O)C>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[N:3][N:2]([C:4]2[CH:17]=[CH:16][C:7]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][N:5]=2)[C:21]=1[O-:20])=[O:24])[CH3:27].[K+:37]
Reactant: COCCCNC(=O)c1ccc(NN)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A mixture of 6-hydrazinyl-N-(3-methoxypropyl)nicotinamide hydrochloride (7.5 g, 28.8 mmol), diethyl 2-(ethoxymethylene)malonate (14 mL, 69 mmol), and potassium carbonate (9.94 g, 71.9 mmol) in water (150 mL) and ethanol (25 mL) and stirred at 25° C. for 3 h and then at 60° C. for 18 h. The mixture was cooled to 20° C. to give a precipitate which was collected by filtration and washed with water to give the title compound (8.14 g, 73.2% yield) as a yellow solid. MS m/z 349 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.1 Hz, 3H) 1.77 (quin, J=6.7 Hz, 2H) 3.25 (s, 3H) 3.27-3.34 (m, 2H) 3.38 (t, J=6.3 Hz, 2H) 4.02 (q, J=7.1 Hz, 2H) 7.52 (s, 1H) 8.10 (dd, J=8.8, 2.5 Hz, 1H) 8.42 (dd, J=8.8, 0.5 Hz, 1H) 8.48 (t, J=5.6 Hz, 1H) 8.78 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[C:29]([OH:33])(=[O:32])[CH2:30][SH:31]>>[C:29]([CH2:30][S:31][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:16][C:3]1=2)([OH:33])=[O:32]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: O=C(O)CS
Product: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and thioglycolic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].[N:14]([O-])=O.[Na+].NC(N)=O>O>[S:9]([O-:13])([OH:12])(=[O:11])=[O:10].[F:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]#[N:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(F)cc1
Product: O=S(=O)([O-])O
Reaction time: 0.25 h

Procedure:
4-Fluoroaniline (11.2 g; 0.1 mol) was added dropwise into a solution of sulphuric acid (25 g) in water (60 ml) over 10 min. A smooth paste was formed. The mixture was cooled to <5° and a solution of sodium nitrite (7.8 g; 0.11 mol) in water (25 ml) was added dropwise over 0.5 hours while maintaining the temperature at <5° with external cooling. A clear red solution was obtained. The solution was stirred for 0.25 hours to complete the reaction and urea (1.0 g) was added to destroy the excess nitrous acid. The resulting solution was used directly in the next stage.
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4](=[O:53])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41]([C@H:43]6[C:52]7[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=7)[CH2:46][CH2:45][NH:44]6)=[O:42])=[N:33][CH:32]=5)=[CH:27][CH:26]=4)[CH:21]=3)[CH:16]=2)=[CH:13][N:14]=1.[CH2:60]=O>[Zn].C(O)(=O)C>[CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41]([C@H:43]6[C:52]7[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=7)[CH2:46][CH2:45][N:44]6[CH3:60])=[O:42])=[N:33][CH:32]=5)=[CH:27][CH:26]=4)[CH:21]=3)[CH:16]=2)=[CH:13][N:14]=1)=[O:53]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H]6NCCc7ccccc76)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H]6c7ccccc7CCN6C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (135 mg, 0.17 mmol), acetic acid (1.7 mL), zinc dust (111 mg, 1.7 mmol), and formaldehyde were all mixed in round bottom flask and stirred at room temperature overnight. The crude mixture was filtered through a celite plug and the filtrate was concentrated down to dryness on rotovap. The residue was then taken up in EtOAc and washed with 10% Na2CO3 and brine and dried over MgSO4. The filtrate was then concentrated down and the residue was purified on reverse phase HPLC. (13 mg, 10%). MS (ESI) m/z 805.77 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]([OH:30])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>C(OCC)C.C1(C)C(C)=CC=CC=1>[C:20]([OH:30])(=[O:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CNCCC(Oc1ccccc1C)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 33.69 g (0.132 mol) of (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine dissolved in 50 ml of diethyl ether was added a solution of 9.89 g (0.067 mol) of L-(+)-mandelic acid in 20 ml of warm xylene. The resulting mixture was refluxed gently for about 5 minutes and an additional 30 ml of diethyl ether was added thereto. The mixture was stirred at room temperature overnight and the resulting slurry was chilled in an ice bath. The mixture was filtered and the resulting solid was rinsed with 50 ml of diethyl ether. The solid was dissolved in 25 ml of methylene chloride and 50 ml of ethyl acetate and the resulting mixture was heated to reflux. The methylene chloride was removed by vacuum and 50 ml of diethyl ether was added to the residue. The mixture was seeded with a crystal of desired product and the resulting mixture was stirred for 2 hours while being chilled in an ice bath. The precipitated solid was collected by filtration and rinsed with 30 ml of a 1:1 (v:v) ethyl acetate/diethyl ether solvent solution. The resulting solid was dried overnight at 55° C. in a vacuum oven to provide 15.7 g of (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine mandelic acid as an off white solid. mp =119°-122° C. The resulting solid was recrystallized with 50 ml of methanol employing 3 g of decolorizing carbon. The resulting mixture was filtered through Celite and the filtrate was concentrated under vacuum to provide a white solid. This solid was dissolved in 50 ml of ethyl acetate with heating and the solution was allowed to cool. An additional 50 ml of diethyl ether was added and the precipitated solid was collected by filtration and rinsed with 50 ml of 1:1 (v:v) ethyl acetate/diethyl ether. The solid was dried in a vacuum oven at 50° C. for 1 hour to provide 13.2 g of (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine mandelic acid. mp=122°-123° C. Yield 49%.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])[CH3:2]>CC(C)=O>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Solvent: CC(C)=O
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
66 g of (Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 700 ml of acetone in which nitrogen had been preliminarily bubbled, and 43 ml of concentrated hydrochloric acid was gradually added while stirring at room temperature in a stream of nitrogen under light-shielded conditions. After stirring at room temperature for 1.5 hours, the reaction mixture was gradually poured into water to crystalize. The crystals were filtered, washed with water and dried to obtain 50.0 g of the titled compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[C:11]([C:13](O)=[O:14])[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:31].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[CH3:29][N:30]([CH3:31])[C:13]([C:11]1[O:12][C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:9]=2[CH:10]=1)=[O:14]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)O)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)N(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 6-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-2-carboxylic acid (450 mg, 1.11 mmol) in DMF (10 mL) was added HATU (846 mg, 2.23 mmol), DIEA (719 mg, 5.56 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (136 mg, 1.67 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added and the product was extracted with CHCl3. The combined organic layers were washed with water (2×), brine, dried over Na2SO4, and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (460 mg, 96%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 3.13 (s, 3 H) 3.33 (s, 3 H) 4.40 (q, J=7.16 Hz, 2 H) 7.07-7.15 (m, 2 H) 7.16 (d, J=0.75 Hz, 1 H) 7.65 (d, J=0.94 Hz, 1 H) 7.87-7.94 (m, 2H) 8.10-8.15 (d, J=0.94 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17]I>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:17])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: CI
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (510 mg) was reacted with methyl iodide via General Procedure C to give 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine. 4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (100 mg) was cooled in 1.5 mL of anhydrous THF to −78° C. before adding 2 eq of a 2.5 M solution of n-butyl lithium. The reaction was stirred for 1 hour at −78° C. upon which 3 eq of DMF were added. The reaction was subsequently warmed to 0° C. after 30 minutes. The reaction was quenched into a cold 0.25 M aqueous solution of HCl and the orange solid was filtered, collected and dried to give 48 mg crude intermediate 2-chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29].C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Reactant: NCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCCN

Procedure:
1,5-Di-(3,3-dimethylnorborn-2-yl)-3-pentanone (6.04 g., 0.02 mole) and 1,3-diaminopropane (0.10 mole) in 150 ml. toluene is heated at reflux overnight with a Dean-Stark water separator. The cooled solution is concentrated under reduced pressure. The residue is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under vacuum. The residue is dissolved in ether and the ether solution washed several times with water to remove the excess 1,3-diaminopropane. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave the diamine product, 1-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentyl]-1,5-diazapentane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].S(Cl)(Cl)=O.[CH3:26]O.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([O:20][CH3:26])=[O:19])[C:5]2=[O:21]
Reactant: CO
Reactant: Cc1cc(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cn(CC(F)(F)F)c2c(C)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.3 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid in 25 ml of pyridine, at 0°, was added 1.1 ml of thionyl chloride. The resulting slurry was stirred at room temperature for 0.5 hour and subsequently treated with 5 ml of methanol. After 1 hour, the reaction mixture was poured into 200 ml of water; the resulting white solid was filtered, washed with water, and dried to give 2.0 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, methyl ester, m.p. 168°-171°.
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]3[CH:21]=[CH:22][C:9]([CH2:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:2])[CH3:3])=[CH:10][CH:11]=3)[CH2:16][CH2:17]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: CC(C)N(Cc1ccc(C(=O)N2CCNCC2)cc1)C(C)C
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Br)ccc4c3)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a mixture of 1-(4-diisopropylaminomethylbenzoyl)piperazine (200 mg) in 10% sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml), was added 6-bromonaphthalene-2-sulfonylchloride (179 mg), and the solution was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated. The residue was crystallized with ether to give the title compound (201 mg), as colorless crystals.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[O:6]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7]1.[OH-].[K+].O.[C:16](#[N:18])C>>[O:6]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[CH2:2][NH:18][CH3:16])=[CH:7]1
Reactant: O=Cc1ccoc1
Reactant: C[S+](C)C
Reactant: CC#N
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNCC(O)c1ccoc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
Trimethylsulfonium iodide (20.4 g) and 3-furaldehyde (8.65 mL) are added to potassium hydroxide (11.2 g) and H2O (0.45 mL) in acetonitrile (150 mL). The reaction mixture is heated to 60° C. for 2.5 h. The reaction mixture is allowed to cool to room temperature. The precipitate is filtered off, and the filtrate is concentrated in vacuo. The resulting crude epoxide (10.747 g) is dissolved in methanol (50 mL) and added to a 2.0 M solution of methylamine in methanol (100 mL). The reaction mixture is stirred at room temperature for 3 d and then heated to reflux for 30 min. The reaction mixture is allowed to cool to room temperature and is concentrated in vacuo. The resulting brown oil was purified via column chromatography (CHCl3/methanol, 95/5, 90/10; CHCl3/methanol/NH4OH, 90/10/1) to yield 2.703 g (19%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
5-Bromosalicylic acid (434 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-bromosalicylate (299 mg, yield 61%).