Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:24][O:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=[CH:24][O:25][CH3:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Product: COC=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The title compound is prepared in a manner analogous to that described in Example 137b) starting from 4.8 g of N-benzyloxycarbonyl-3(R,S)-formyl-1,2,3,4-tetrahydroquinoline, 7.2 g of methoxymethyl-triphenylphosphonium chloride and 5.4 g of sodium-bis(trimethylsilyl)amide: Rf (A)=0.67.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:50])[CH:7]([C:31]([CH:35]([NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH:36]([CH3:38])[CH3:37])([OH:34])[PH2:32]=[O:33])[CH2:8][C:9]1[CH:10]=[N:11][C:12]([N:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([CH3:15])[CH:14]=1)C.CO>C(#N)C>[CH2:43]([O:42][C:40]([NH:39][CH:35]([C:31]([OH:34])([PH2:32]=[O:33])[CH:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[C:13]([CH3:15])[CH:14]=1)[C:6]([OH:50])=[O:5])[CH:36]([CH3:38])[CH3:37])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(O)([PH2]=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(CC(C(=O)O)C(O)([PH2]=O)C(NC(=O)OCc2ccccc2)C(C)C)cnc1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
1 M LiOH (2 mL) was added dropwise to a solution of 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphinoylmethyl]-3-(6-bis(tert-butoxycarbonyl)amino-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (100 mg, 0.145 mmol) in acetonitrile (2 mL). The mixture was stirred overnight and concentrated under reduced pressure. The mixture was purified by column chromatography (isopropanol/concentrated aqueous NH3/water, 4:2:1) to give impure product. The impure product was stirred with MeOH, filtered and concentrated under reduced pressure. The crude product was stirred with EtOH, filtered and concentrated under reduced pressure. The crude product was stirred with ethylacetate/ethanol, filtered and concentrated under reduced pressure to give 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphinoylmethyl]-3-(6-tert-butoxycarbonylamino-5-methyl-pyridin-3-yl)-propionic acid (52 mg, 63.8%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:41])[C:17]([CH2:39][CH3:40])=[C:18]([C:37]#[N:38])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26](O)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[CH:22][CH:21]=1)=[O:14])[CH3:11].O>C(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:41])[C:17]([CH2:39][CH3:40])=[C:18]([C:37]#[N:38])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([F:7])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[CH:22][CH:21]=1)=[O:14])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1c(-c2ccc(C(O)Cc3cccc(C#N)c3)cc2)c(C#N)c(CC)n1C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(F)Cc3cccc(C#N)c3)cc2)c(C#N)c(CC)n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add (diethylamino)sulfur trifluoride (145 uL, 1.1 mmol) to 4-cyano-3-{4-[2-(3-cyano-phenyl)-1-hydroxy-ethyl]-phenyl}-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.427 g, 1.0 mmol, prepared in example E-163) in methylene chloride with stirring at −78° C. After 30 minutes, gradually allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 430.0 (M+1).
Reaction SMILES: [Na][Na].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[C:9]([O:26][CH2:27]C(O)=O)[CH:8]=1)[CH:4]=[CH2:5]>CCOCC>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[C:9]([O:26][CH2:27][CH2:18][C:22]([OH:24])=[O:23])[CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(C(=O)C=Cc2cccc(C(=O)O)c2)c(OCC(=O)O)c1
Agent: [Na][Na]
Solvent: CCOCC
Product: C=CCOc1ccc(C(=O)C=Cc2cccc(C(=O)O)c2)c(OCCC(=O)O)c1

Procedure:
6.30 g. of the above diacid were slurried with 12.60 ml. methanol and a solution of 1.30 g. sodium hydroxide in 25.80 ml. water added dropwise thereto. with occasional warming, to give a solution with a pH of 7.0. This solution was filtered and poured, while stirring vigorously, into 300 ml. analytically pure acetone at ambient temperature. The precipitated solid was filtered off, well washed with acetone and dried to constant weight in a vacuum oven at 80° C. The yield was 6.24 g. A thin layer chromatogram, using the above-mentioned elution agent, indicated the material to be of better than 99% purity. The disodium salt thus obtained had a melting point of >300° C. and the infra-red spectrum had major bands at 1645 (sh., enone), 1605 (broad, CO2Na), 1500 (aromatic) and 1255 (ether cm-1. A 10% aqueous solution had a pH of 6.50. The NMR spectrum (D2O) confirmed the structure of the disodium salt of 1-[4-(prop-2-enyloxy)-2-carboxymethoxyphenyl]-3-(3-carboxyphenyl)-prop-2-en-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[C:48]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][N:53]=1)(=[O:50])[CH3:49]>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[C:48]([NH:51][C:52]1[N:53]=[CH:54][C:55]([NH:58][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:21])=[CH:56][CH:57]=1)(=[O:50])[CH3:49]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution, stirred at 20° C. under an inert atmosphere, of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in step 1.1, in 40 mL of DMF are added 1.72 g (8.35 mmol) of dicyclohexylcarbodiimide (DCC) and 1.13 g (8.35 mmol) of 1-hydroxybenzotriazole hydrate (HOBT). The reaction mixture is stirred at room temperature for 30 minutes. 2.1 g (13.92 mmol) of 2-acetamido-5-aminopyridine and 20 mg of dimethylaminopyridine (DMAP) are then added to the reaction mixture. After stirring for 24 hours at 20° C., the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHCO3 solution and 200 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. A solid is collected, and is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 2.6 g of the expected product are thus obtained.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: Nc1ccccc1F
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccccc2F)CC1
Temperature: 25 °C
Yield: 54 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved in tetrahydrofuran (25 ml) under a nitrogen atmosphere, triethylamine (2.68 ml) was added dropwise thereto while stirring in an ice water bath. After stirring at the same temperature for 30 min, thionyl chloride (1.4 ml) was added dropwise while stirring in an ice water bath. After stirring at the same temperature for 30 min, a solution of 2-fluoroaniline (2.04 ml) in tetrahydrofuran (15 ml) was added while stirring in an ice water bath, and the reaction mixture was allowed to gradually warm up to room temperature and stirred overnight. To the reaction mixture was added a 2N aqueous solution of sodium hydroxide (75 ml), and tetrahydrofuran was removed under reduced pressure. To the resultant aqueous solution was added tert-butyl methyl ether (25 ml) and stirred. The organic layer and aqueous layer were separated. The aqueous layer was cooled in an ice water bath, 5N hydrochloric acid (30 ml) was added and stirred. The precipitated solid was collected by filtration and washed with water. Drying under aeration and hot-air drying at 60° C. for 8 hr provided the titled compound as white powder (2.294 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:17][CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23]C)=[O:22].[OH-].[Li+].O1CCCC1.Cl>O.CO>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:17][CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1ccccc1CNc1ccc(C(C)C(=O)OC(C)(C)C)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)OC(C)(C)C)c1ccc(NCc2ccccc2C(=O)O)c(Br)c1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A mixture of methyl 2-((2-bromo-4-(1-tert-butoxy-1-oxopropan-2-yl)phenylamino)methyl)benzoate (4.57 g, 10.2 mmol), lithium hydroxide (0.733 g, 30.6 mmol), tetrahydrofuran (100 mL), methanol (20 mL), and water (30 mL) was stirred overnight. The mixture was poured into water (200 mL) and the whole was acidified with 2 N HCl. The mixture was then extracted with ethyl acetate (150 mL) and the organic layer was washed with brine (100 mL), dried over sodium sulfate, and filtered. Evaporation of the solvents and drying under reduced pressure gave 2-((2-bromo-4-(1-tert-butoxy-1-oxopropan-2-yl)phenylamino)methyl)benzoic acid (4.40 g, 99%) as a thick oil: 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=7.6 Hz, 1H), 7.53 (m, 2H), 7.38 (m, 2H), 7.03 (dd, J=8.4,2.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 4.80 (s, 2H), 3.44 (q, J=7.1 Hz, 1H), 1.39 (s, 9H), 1.38 (d, J=7.2 Hz, 3H).
Reaction SMILES: O[CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)[Cl:26]>>[Cl:26][CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CC(c1ccccc1)N1c2ccccc2Oc2c(CO)cccc21
Product: CC(c1ccccc1)N1c2ccccc2Oc2c(CCl)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-hydroxymethyl-N-(α-phenylethyl)phenoxazine (Example 4) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature under anhydrous conditions for 1 hour and the solvent removed under vacuo, to yield a solution of
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH3:26])([C:21](OCC)=[O:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1>[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH3:26])([CH2:21][OH:22])[CH2:17][CH2:16]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1(C)CCN(CCc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CO)CCN(CCc2ccccc2)CC1
Yield: 95 %

Procedure:
To a suspension of 0.51 g (13.4 mmol) of lithium aluminum hydride in 20 mL of THF under nitrogen was added dropwise a solution of 3.70 g (13.4 mmol) of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine in 15 mL of THF. The solution was heated at reflux for 3 hours. To the cooled reaction mixture (ice bath) was slowly added 0.5 mL of water, followed by 0.5 mL of 15% sodium hydroxide followed by 1.5 mL of water. The precipitated lithium salts were removed by filtration. The filtrate was evaporated to dryness. The residue was reconstituted in methylene chloride, washed with a small amount of water, dried and evaporated to afford 2.97 g of 1-(2-phenylethyl)-4-methyl-4-hydroxymethyl-piperidine as a yellow oil. NMR (CDCl3) δ7.16-7.23 (m, 5H); 3.40 (s, 2H); 2.79-2.87 (m, 2H); 2.57-2.71 (m, 4H); 2.31-2.42 (m, 2H); 1.57-1.63 (m, 5H); 0.97 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].Br.CS(C)=[O:18]>>[F:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C(C)=O)cc1F
Agent: Br
Product: COC(=O)c1ccc(C(=O)C=O)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-acetyl-2-fluorobenzoate (1.6 g, 0.0082 mol), 48% of hydrogen bromide aqueous solution (2.8 mL) in dimethyl sulfoxide (20 mL) was stirred at 60° C. overnight. After cooling, the mixture was poured into ice-water. The product was extracted with ethyl ether. The combined extracts were washed with brine; dried over Na2SO4, filtered concentrated to yield 1.60 g of the product which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:27](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)C1CCCCC1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-cyclohexyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light pink solid, MS (ESI+): m/z=402.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8](NC)=[N:9][C:10]=2[N:14]([CH3:16])[CH3:15].NC1N=C2C(N=CN2CC2C=CC=CC=2[Cl:40])=C(N(C)C)N=1.C(NC1N=C2C(N=CN2CC2C=CC=CC=2Cl)=C(N(C)C)N=1)C.ClC1C=CC=CC=1CN1C=NC2C1=NC(NC)=NC=2.ClC1C=CC=CC=1CN1C=NC2C1=NC(N(C)C)=NC=2.CN(C1N=C2C(N=CN2CC2C=CC=CC=2Cl)=C(N(C)C)N=1)C.NC1N=C2C(N=CN2CC2C=CC=CC=2Cl)=C(NC)N=1.ClC1C=CC=CC=1CN1C=NC2C1=NC(N(C)C)=NC=2NC.NC1N=C2C(N=CN2CC2C=CC=CC=2Cl)=C(N)N=1.NC1N=C(NC)N=C2C=1N=CN2CC1C=CC=CC=1Cl.NC1N=C(N(C)C)N=C2C=1N=CN2CC1C=CC=CC=1Cl.C(NC1N=C2C(N=CN2CC2C=CC=CC=2Cl)=C(N)N=1)C.ClC1N=C2C(N=CN2CC2C=CC=CC=2Cl)=CN=1>>[Cl:40][C:8]1[N:7]=[C:6]2[C:11]([N:12]=[CH:13][N:5]2[CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[Cl:1])=[C:10]([N:14]([CH3:16])[CH3:15])[N:9]=1
Reactant: CNc1nc(N(C)C)c2ncn(Cc3ccccc3Cl)c2n1
Reactant: CN(C)c1nc(N)nc2c1ncn2Cc1ccccc1Cl
Agent: CCNc1nc(N(C)C)c2ncn(Cc3ccccc3Cl)c2n1
Agent: CCNc1nc(N)c2ncn(Cc3ccccc3Cl)c2n1
Agent: CN(C)c1nc(N(C)C)c2ncn(Cc3ccccc3Cl)c2n1
Product: CN(C)c1nc(Cl)nc2c1ncn2Cc1ccccc1Cl

Procedure:
9-(2-chlorobenzyl)-6-(N,N-dimethylamino)-2-(N-methylamino)-9H-purine; 2-amino-9-(2-chlorobenzyl)-6-(N,N-dimethylamino)-9H-purine; 2-(N-ethylamino)-9-(2-chlorobenzyl)-6-(N,N-dimethylamino)-9H-purine; 9-(2-chlorobenzyl)-2-(N-methylamino)-9H-purine; 9-(2-chlorobenzyl)-2-(N,N-dimethylamino)-9H-purine; 2,6-bis(N,N-dimethylamino)-9-(2-chlorobenzyl)-9H-purine; 2-amino-9-(2-chlorobenzyl)-6-(N-methylamino)-9H-purine; 9-(2-chlorobenzyl)-2-(N,N-dimethylamino)-6-(N-methylamino)-9H-purine; 2,6-diamino-9-(2-chlorobenzyl)-9H-purine; 6-amino-9-(2-chlorobenzyl)-2-(N-methylamino)-9H-purine; 6-amino-9-(2-chlorobenzyl)-2-(N,N-dimethylamino)-9H-purine; 2-(N-ethylamino)-6-amino-9-(2-chlorobenzyl)-9H-purine and 2-chloro-9-(2-chlorobenzyl)-9H-purine.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.[H-].[Na+].CCOC(C)=O>O1CCOCC1>[NH:18]1[CH2:22][CH2:21][CH:20]([O:23][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:19]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: OC1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(OCCOc2nccnc2OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
2-Chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) was added to a stirred mixture of 3-pyrrolidinol (260 mg, 2.99 mmol) and NaH (55% dispersion in mineral oil; 110 mg, 2.50 mmol) in dioxane (2 mL), and the reaction was stirred at room temperature for 2 h. EtOAc was added and the mixture was washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using EtOAc/MeOH/HOAc/H2O (50:40:9:1) as eluent to give 38 mg (22%) of the title compound. Anal. (C16H19N3O3) H; C: calcd, 63.77; found, 62.20; N: calcd, 13.94; found, 13.0.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]([F:27])([F:26])[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[N+:23]([O-])=O)[CH2:10]1)=[O:8]>[Pd].CO>[NH2:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]([F:27])([F:5])[F:26])[CH2:10]1
Reactant: Cc1ccc([N+](=O)[O-])c(O[C@H]2CCCN(C(=O)C(F)(F)F)C2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(N)c(O[C@H]2CCCN(C(=O)C(F)(F)F)C2)c1

Procedure:
Amoniumformiate (0.238 g) was added into a suspension of (S)-2,2,2-trifluoro-1-(3-(5-methyl-2-nitrophenoxy)piperidin-1-yl)ethanone and palladium on charcoal (50.0 mg) in MeOH (6.0 ml) at room temperature. The mixture was heated at reflux for 40 mins. The mixture was filtered through a pad of celite and the filtercake was washed with dichloromethane. The filtrate was washed with water and. The residue was purfied by chromatography.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1)=[CH2:6])C.[OH-].[Na+]>C(O)C>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5](=[CH2:6])[C:4]([OH:25])=[O:3])=[CH:12][CH:11]=1
Reactant: C=C(C(=O)OCC)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(C(=O)O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution in hot ethanol of 3,3-bis((4-(2-quinolylmethoxy)phenyl)-propenoic acid ethyl ester (560 mg, 1 mmol), prepared as in step 1, was added aqueous 1N NaOH (8 mL) and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (25 mL), and neutralized with 10% citric acid solution. The resulting precipitate was collected by filtration, washed with water, slurried in warm EtOH (20 mL), collected by filtration, and dried in vacuo to obtain 3,3-bis((4-(2-quinolyl-methoxy)phenyl)propenoic acid (265 mg): mp 127°-130° C.; 1H NMR (300 MHz, DMSO-d6)δ5.40 (s, 4H), 6.20 (s, 1H), 7.08 (m, 6H), 7.21 (d, 2H, J=9 Hz), 7.73 (m, 6H), 8.03 (m, 4H), 8.44 (t, 2H, J=9 Hz), 11.97 (bs, 1H); MS (DCI/NH3) m/e 538 (M+H)+. Anal. Calcd. for C35H26 N3O5 ×3H2O: C, 70.95; H, 5.41; N, 4.73. Found: C, 70.53; H, 5.24; N, 4.61.
Reaction SMILES: [CH:1]([N:4]([CH:8]=[N:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[OH:16])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].CO>CCOCC.C(Cl)Cl>[CH3:24][N:25]([CH3:29])[C:26]([O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:9]=[CH:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:2])[CH3:3])=[O:27]
Reactant: CC(C)N(C=Nc1ccncc1O)C(C)C
Reactant: CN(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C=Nc1ccncc1OC(=O)N(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4-[[(diisopropylamino)methylene]amino]-3-pyridinol (1.06 g) and triethylamine (1.0 ml) in 25 ml dry Et2O was added dimethyl carbamyl chloride (0.53 ml). The mixture was stirred at room temperature for 2 hours, after which no starting material remained as seen by TLC (silica, 10:90 CH3OH:CH2Cl2). The mixture was diluted with 25 ml Et2O, filtered, washed with Et2O, and the filtrate concentrated in vacuo and chromatography on silica using EtOAc eluent. The fractions containing desired product were combined and concentrated to provide 500 mg of pure product. Another run was carried out in the same manner as above using 740 mg of starting material. The products from both runs were combined. Recrystallization attempts failed, and the product was dried in vacuo to provide 790 mg of a white solid, m.p. 76°-79° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.S(OC)(O[CH3:15])(=O)=O.[OH-].[Na+]>>[CH3:15][S:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][Cl:1])=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: Sc1ccc(CCCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(CCCl)cc1
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: (a) 64.3 g of 4-chloroethylthiophenol are placed in a vessel with 13.3 g of dimethyl sulfate; with external cooling (IT<10°), 41 ml of NaOH (25%) are then slowly added dropwise. After approximately one hour, the external cooling is removed and the mixture is heated carefully and kept at 125° for 30 minutes. The cooled solution is extracted with ether and distilled, yielding 4-methylmercaptophenylethyl chloride; b.p. 94°-95°/0.1 mbar.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:27]2[C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[O:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:11]12[O:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][N:9]([C:4]1[C:3]([CH2:2][O:17][C:18]3[C:27]4[C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:10]2
Reactant: ClCc1cccnc1N1CC2CCC(C1)O2
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(OCc3cccnc3N3CC4CCC(C3)O4)cccc2O1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.080 g, 0.35 mmol) and 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (0.061 g, 0.31 mmol) in DMF was added cesium carbonate (0.307 g, 0.94 mmol) and the reaction mixture was heated (60° C.). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer was extracted two times with EtOAc. Combined organic layers were washed with brine, dried over MGSO4 and concentrated in vacuo. Purification by silica gel chromatography yielded 5-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (112 mg, 90% yield). MS (ES) for C22H24N2O5: 397 (MH+).