Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].CN(CC(CC1C=CC=CC=1)COC1C=CC(SC)=CC=1)C.C(O)(=O)C(O)=O.[CH3:35][N:36]([CH2:38][CH:39]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=1)C>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:35][NH:36][CH2:38][CH:39]([CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=1
Reactant: CN(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1
Agent: CSc1ccc(OCC(Cc2ccccc2)CN(C)C)cc1
Agent: O=C(O)C(=O)O
Product: CNCC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1

Procedure:
Illustrative of the invention, N,N-dimethyl-2-benzyl-3-(4-methylmercaptophenoxy)-propylamine oxalate and N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)-propylamine oxalate at an oral dose of 30 mg/kg p.o. show about 80% and 60% inhibition respectively of 3H-5HT uptake. N-Methyl-2-benzyl-3-(4-trifluoromethylphenoxy)-propylamine oxalate gives about a 50% inhibition of 3H-5HT uptake at a dose of 10 mg/kg p.o.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].[Pd]>[CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(Cc2ccccc2)N1
Reaction time: 4 h
Yield: 79 %

Procedure:
190 g (1 mole) of 5-benzylidene-hydantoin are dissolved in 2 l of a N sodium hydroxide solution and 40 g of 5% palladium/charcoal catalyst are added. The mixture is hydrogenated at room temperature under atmospheric pressure and under shaking for 4 hours. The reaction mixture is worked up according to Example 6. Thus 150.2 g of the desired compound are obtained, yield 79%. Mp.: 187°-189° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)([OH:3])=[O:2].C(O)COCCO.[OH-].[Na+].O.NN>O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)C1=CC=C2C(=Cc3ccccc32)C1=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 125 °C
Reaction time: 3 h

Procedure:
2-Carboxyfluorenone (12.3 g, 0.05 mole) and diethylene glycol were added to a 500 mL round bottom flask. Sodium hydroxide (7.65 g, 0.19 mole) and hydrazine hydrate (9.16 mL, 0.23 mole) were added to the solution. The temperature of the reaction was increased to 125° C. Heating was continued for three hours and then the vessel was cooled to room temperature. Distilled water (1.5 L) was added. The product was precipitated with concentrated hydrochloric acid. The product was filtered and rinsed with distilled water (2 L). The solids were dissolved in 0.5 M sodium hydroxide (2.8 L) and heated to 70° C. The product was precipitated with concentrated hydrochloric acid (pH approximately 2). The product was filtered and washed with distilled water (1.5 L). The 2-carboxyfluorene was dried overnight under reduced pressure with phosphorus pentoxide present. NMR confirmed the structure by the appearance of two new protons at δ4.01 ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].[H-].[Na+].O>O1CCCC1>[C:8]1([C:6]2[CH:7]=[C:2]([O:17][CH2:14][C:15]#[CH:16])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCO
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 194 mg of 4-chloro-6-phenylpyrimidine and 68 mg of 2-propyn-1-ol, to which 50 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (37)), m.p.: 65.1° C.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.Cl[CH2:14][C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[O:21]=[C:15]([CH2:14][S:12][C:9]1[N:10]=[CH:11][NH:7][N:8]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(=O)CCl
Reactant: Sc1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1nc[nH]n1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Add dropwise potassium tert-butoxide (11.4 g, 101.8 mmol) in 30 ml N,N-dimethylformamide (30 ml) to a solution of [1,2,4]triazole-3-thiol (10.3 gm, 101.8 mmol) in N,N-dimethylformamide (50 ml). Add dropwise methyl 4-chloroacetoacetate (15.3 gm, 101.8 mmol) in N,N-dimethylformamide (15 ml) and stir for 3 hours. Concentrate under reduced pressure, dilute with ethyl acetate (500 ml), filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography to provide the desired compound (18.3 gm, 83%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[CH3:16]N(C=O)C>CO>[CH3:2][NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CN(C)C=O
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
HCl was bubbled through a mixture of 4-methylamino-3-nitrobenzoic acid (7.41 g, 37.8 mmol), DMF (60 mL) and MeOH (250 mL) at reflux for 10 h. The mixture was allowed to cool, filtered and concentrated. NaHCO3 (aq, sat) was added to the residue which was extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to give the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:46]([OH:52])[CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>COCCOC.O.[Pd].[Cu]I>[OH:52][CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[C:51][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#CCCCCO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 5-bromo-3-(1-tert-butoxycarbonyl-2(S) -azetidinylmethoxy)pyridine (720 mg, 2.1 mmol), K2CO3 (725 mg, 5.25 mmol), PPh3 (50 mg) in DME (5 mL) and H2O (5 mL) was added 10% Pd/C (50 mg) and CuI (50 mg). The mixture was stirred at room temperature for 30 min under argon, then 5-hexyn-1-ol (0.8 mL) was added. The reaction mixture was refluxed for 72 h. After cooled, the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by chromatography with hexane-EtOAc (1:2) and then EtOAc to give an oil (630 mg, 83%), [α]D−37.1 (c 1.9, CHCl3). 1H NMR (CDCl3) δ 8.22 (d, 2H, J=2.1 Hz), 7.24 (t, 1H, J=2.1 Hz), 4.50 (m, 1H), 4.32 (m, 1M), 4.11 (dd, 1H, J=10.2, 3.0 Hz), 3.88 (t, 2H, J=7.5 Hz), 3.75-3.65 (m, 2H), 2.47 (t, 2H, J=6.9 Hz), 2.41-2.20 (m, 2H), 1.95 (s, 1H), 1.80-1.64 (m, 4H), 1.42 (s, 9H); 13C NMR (CDCl3) δ 156.13, 154.40, 144.75, 137.13, 123.26, 121.18, 93.48, 79.76, 77.45, 68.68, 62.20, 60.00, 47.06, 31.82, 28.36, 24.80, 19.18, 19.01.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].Cl[C:5]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:18])(=[O:17])[N:6]=1>ClCCl>[CH2:1]([O:3][C:5]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:17])(=[O:18])[N:6]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc2c1C(Cl)=NS2(=O)=O
Reactant: CCO
Solvent: ClCCl
Product: CCOC1=NS(=O)(=O)c2cccc([N+](=O)[O-])c21
Reaction time: 8 h

Procedure:
Ethanol (100 ml) was added to a solution of 3-chloro-4-nitro-benzoisothiazole-1,1-dioxide (0.86 g) in dichloromethane (110 ml). The resulting solution was allowed to stand overnight at room temperature. Removal of the solvent in vacuo gave an amorphous brown solid, which was triturated under ether (100 ml) to give the title compound as a white solid (0.82 g), mpt 190°-191° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[F:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]2)=[CH:15][CH:14]=1>>[CH3:29][N:28]([CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:31][CH:30]=2)[CH2:27][CH2:26]1)[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: S=C=Nc1ccccc1
Reactant: CNC1CCN(CCCCOc2ccc(F)cc2)CC1
Agent: Cl
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCCCOc2ccc(F)cc2)CC1

Procedure:
The condensation of 2 g (14.8 mmol) of phenyl isothiocyanate with 5.25 g (14.8 mmol) of 1-[4-(4-fluorophenoxy)butyl]-4-methylaminopiperidine dihydrochloride (cf. WO 97/05134) according to the protocol of Example 1.1 provides 5.5 g (Yd: 90%) of white crystals of formula 7.1:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl-].[C:44]([O:48][C:49](=[O:52])[CH2:50][Zn+])([CH3:47])([CH3:46])[CH3:45]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:50][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:52])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cnc(N)nc1
Temperature: 60 °C

Procedure:
A 1 L RB flask was charged with 2-amino-5-bromopyrimidine (8.75 g, 50.3 mmol). THF (262 ml) was added followed by tris(dibenzylideneacetone)dipalladium(0) (0.94 g, 1.027 mmol), X—PHOS (0.978 g, 2.05 mmol) and 2-(tert-butoxy)-2-oxoethylzinc chloride (262 mL, 131 mmol). It was heated at 60° C. (oil bath temperature) overnight. An additional tris(dibenzylideneacetone)dipalladium(0) (500 mg, 0.546 mmol) was added followed by X—PHOS (520 mg, 1.09 mmol). The reaction mixture was heated at reflux for 42 hours. The reaction mixture was then cooled to RT and quenched by addition of saturated NH4Cl solution and the layers separated. The aqueous phase was extracted with EtOAc(2×200 mL). The organic extracts were combined, washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by flash chromatography on silica using a gradient from EtOAc: Hex. 3:2 to EtOAc to afford the title compound.
Reaction SMILES: O[C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][C@H:2]1[CH2:3][CH2:4][C:5]2([CH2:7][CH2:6]2)[O:8]1
Reactant: O[C@@H](CCC1(O)CC1)COC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C1CCC(OC[C@H]2CCC3(CC3)O2)OC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a solution of 1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)-cyclopropanol (1.73 g, 0.0075 mol) and PPh3 (2.95 g, 0.0113 mol, Richjoint) in 32 mL of anhydrous THF at rt under N2 was added DEAD (1.96 g, 0.0113 mol, Aladdin) dropwise via a syringe. The reaction was stirred at 60° C. for 12 hours. The solvent was concentrated in vacuo. The red oil was purified by a silica gel column chromatography (8:1 (v/v) n-hexane/EtOAc) to give the title compound as colorless oil (1.1 g, 64%)2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:17](=O)[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][NH:14][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: NCc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CCCC=O
Product: CCCCNCc1cccc(Oc2ccc(Cl)cc2)c1
Yield: 31.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (3-(4-chlorophenoxy)phenyl)methanamine (ASDI, 533 mg, 2.28 mmol) and butyraldehyde (210 μL, 2.28 mmol) were converted to the title compound (211 mg, 32%). 1H NMR (CDCl3) δ 7.41-7.19 (m, 4H), 7.14-7.06 (m, 1H), 6.99-6.87 (m, 3H), 3.98-3.86 (m, 2H), 2.80-2.66 (m, 2H), 1.66 (quin, J=7.5 Hz, 2H), 1.42-1.24 (m, 2H), 1.00-0.81 (m, 3H); MS (ESI+) m/z 290.1 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([NH:13][OH:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1.CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:29][C@@H:26]1[C:27](=[O:28])[N:24]2[C@@H:25]1[S:30][CH2:31][C:22]([CH2:21][S:1][C:2]1[N:7]3[N:8]=[C:9]([C:11](=[O:12])[NH:13][OH:14])[N:10]=[C:6]3[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1)=[C:23]2[C:32]([OH:34])=[O:33]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(NO)c1nc2nc(CO)cc(S)n2n1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(C(=O)NO)nn34)CS[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
7-Mercapto-N-hydroxy-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine-2-carboxamide (300 mg) (1.24 mmol) and 305 mg (1.12 mmol) of 7-aminocephalosporanic acid are suspended in 50 ml of sulpholane/dichloromethane (1:1 v/v). 5 ml of boron trifluoride diethyl etherate are added thereto at 0° C. The reaction mixture is stirred at 0° C. for 21/2 hours and at room temperature for 24 hours. After the addition of 30 ml of dichloromethane the mixture is stirred for 15 minutes and subsequently filtered. The suction filter material is dissolved in water and adjusted to pH 5 with saturated aqueous sodium hydrogen carbonate solution. The precipitated product is filtered off under suction and washed in succession with water, dichloromethane and diethyl ether. There are obtained 340 mg of (6R,7R)-7-amino-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27]([NH:33][CH3:34])([C:30](N)=[O:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:35][OH:36]>>[CH3:35][O:36][C:30]([C:27]1([NH:33][CH3:34])[CH2:28][CH2:29][N:24]([C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:8]3[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:25][CH2:26]1)=[O:31]
Reactant: CO
Reactant: CNC1(C(N)=O)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Product: CNC1(C(=O)OC)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 60 °C

Procedure:
1-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-methylaminopiperidine-4-carboxylic acid amide 7A-87 (Example 164; 53 mg, 0.093 mmol) and Amberlyst 15 (0.8 g) in methanol (5 ml) was sealed in a tube and then heated to 60° C. for 20 h. The resin was removed by filtration and washed with 2:1 methanol/triethylamine and then 10% NH4OH in methanol. The combined organic layers were concentrated and then purified on a Biotage™ Flash 12S column using 0–2–4% methanol in methylene chloride as eluant to give title compound 21A-1 as a light brown solid (26 mg, 55%): +ESI MS (M+1) 511.1; 1H NMR (400 MHz, CD2Cl2) δ 8.28 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.44–7.32 (m, 5H), 7.21 (d, J=8.7 Hz, 2H), 5.55 (v br s, 1H), 4.65 (v br s, 2H), 4.13 (v br s, 2H), 3.71 (s, 3H), 2.28 (s, 3H), 2.07 (ddd, J=13.7, 9.6, 3.7 Hz, 2H), 1.79 (dt, J=13.7, 3.9 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH3:13])=[C:7]([N+:14]([O-])=O)[CH:6]=1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][CH2+:37]1SC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][C:37]1=[N:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH2:12][CH3:13])[C:4]([NH:3][CH2:1][CH3:2])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNC(=O)c1ccc(NCC)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNC(=O)c1ccc(NCC)c(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c1

Procedure:
In a manner similar to Example 30, intermediate N-ethyl-4-ethylamino-3-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 544 (MH+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:32])[CH2:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1>C(Cl)(Cl)Cl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:32])[CH2:29][CH2:30][CH2:31]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1
Reactant: OC1(Cn2c(CCl)nc3cnc4ccccc4c32)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc(CCl)n(CC3(O)CCC3)c2c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (9.15 g of 70% pure material, 37.1 mmol) was added to a suspension of 1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (8.00 g, 26.5 mmol) in chloroform (100 mL) under a nitrogen atmosphere, and the reaction was stirred at room temperature overnight. Additional chloroform (200 mL) was added, and the solution was washed sequentially with saturated aqueous sodium bicarbonate (2×80 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:4].CCN(CC)CC.[NH2:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30](O)=[O:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)Cl>[NH2:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30]([NH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)=[O:4])=[O:31]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A solution of 4-{(glycylamino}methyl)-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol) in CH2Cl2 (25 mL) was treated with Et3N (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol). After the reaction mixture was stirred at room temperature for 3 h, 2 N aqueous NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 78%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]([F:26])([F:25])[F:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]([F:26])([F:25])[F:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a solution of (R)-methyl 2-(4-fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate (35 mg, crude) in methanol (15 mL) was added a solution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with aqueous hydrochloric acid (1N). The product was collected by filtration and purified by Prep-HPLC under the following conditions: Column, silica gel 19 mm*100 mm; mobile phase, A:B=0.05% TFA:ACN B %=35%˜100% 0˜8 mins; Detector, 5 um. 18.2 mg. (R)-2-(4-Fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid was obtained as a yellow solid (2 steps yield=5.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([OH:12])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:5]=2[C@@H:4]2[CH:18]=[C:19]([CH3:22])[CH2:20][CH2:21][C@@H:3]12
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Yield: 77 %

Procedure:
A mixture of 1.73 g (5.50 mmol) of (6aR-trans)-6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, 10 ml of dimethylsulfoxide, 3 ml of ethyl 4-bromobutyrate and 1.73 g of potassium carbonate was degassed and then heated under reflux under argon over night. The reaction was cooled, diluted with 250 ml of water and extracted with ether. The extracts were passed over a column of silica gel, and the fractions containing the intermediate ester were combined and concentrated under vacuum. The residue was dissolved in 100 ml of methanol, the solution was heated to boiling and 20 ml of water, followed by 2.2 g of sodium carbonate, was added. The mixture was heated under reflux for 3 hrs. The methanol was evaporated under vacuum, and the aqueous residue was acidified with hydrochloric acid and extracted with dichloromethane. The extracts were concentrated, and the residue was dissolved in hexane and adsorbed onto silica gel. Elution with 15% ethyl acetate in benzene, followed by evaporation, gave 1.70 g (77%) of (6aR-trans)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid as a colorless oil: ir (CHCl3) 1710 cm-1 ; uv max (C2H5OH) 225 nm (infl) (ε17,830), 274 (1090), and 282 (1120); nmr (CDCl3) δ11.3 (br, CO2H), 6.29 and 6.20 (two sharp d, H-2 and H-4), 5.41 (m, H-8), 4.01 (t, OCH2C), 3.18 (m, H-10a), 2.59 (t, ArCH2C), 2.48 (t, CCH2CO), 1.69 (s, 9-CH3), 1.34 and 1.06 (two s, 6,6-diCH3), and 0.87 (t, ω-CH3); mass mol wt 400; [α]D25° -195.3° (c 1.104, CHCl3).