Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]([O:18]C)(=O)[CH2:13][C:14]([CH3:16])=O.[NH2:20][NH2:21]>C(OC(=O)C)(=O)C>[CH3:16][C:14]1=[N:20][NH:21][C:12](=[O:18])/[C:13]/1=[C:2]1\[NH:1][C:10]2[C:5]([CH:4]=[CH:3]\1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: NN
Reactant: COC(=O)CC(C)=O
Reactant: [O-][n+]1cccc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CC1=NNC(=O)/C1=C1/C=Cc2ccccc2N1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Commercially available Quinoline N-oxide (Aldrich) (145 mg, 1 mmol) and methyl acetoacetate (0.1 mL, 1 mmol) was dissolved in acetic anhydride (2 mL) and heated at 90° C. for 1-2 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue treated with ether. The resulting precipitate was filtered and dried in vacuo. Then, the crude material was dissolved in a mixture of ethanol and acetic acid (10:1, 2 mL) and treated with hydrazine (0.03 mL, 1 mmol). The mixture was stirred at ambient temperature for 18 hrs, and the resulting solid filtered and washed with a minimum amount of ethanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H), 7.43-7.54 (m, 1H) 7.71 (t, J=7.33 Hz, 2H) 7.89 (d, J=7.83 Hz, 2H) 8.30 (d, J=8.34 Hz, 1H) 11.14 (s, 1H) 11.88 (s, 1H); ESI-MS: m/z calc'd for C13H11N3O 225.09. found 226.2 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]([C:11]1[CH:16]=[CH:15][N+:14]([O-])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[C:5]([C:15]1[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=[CH:13][N:14]=1)#[N:6]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To trimethylsilylcyanide (25.0 ml, 187.5 mmol) was added a solution of 4-tert-butylpyridine-N-oxide (Description 3; 22.68 g, 150 mmol) in anhydrous dichloromethane (200 ml). To this mixture was added dropwise a solution of dimethyl carbamoyl chloride (17.26 ml, 187.5 mmol) in anhydrous dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous K2CO3 (200 ml) was added dropwise and the resulting mixture stirred for 10 minutes. The organic layer was separated and the aqueous layer extracted with 2 further portions of dichloromethane (100 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (24 g, 100%).
Reaction SMILES: NC1C=CC(SC(=O)N)=CC=1[N+]([O-])=O.[C:15]([S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[S:27])=[C:21]([N+:33]([O-])=O)[CH:20]=1)(=[O:17])[NH2:16].NC1C=CC(SC(=O)N)=CC=1N.[CH3:48][O:49][C:50]([N:52]=[C:53]=[S:54])=[O:51]>[Fe].CC(C)=O>[C:15]([S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[S:27])=[C:21]([NH:33][C:53]([NH:52][C:50]([O:49][CH3:48])=[O:51])=[S:54])[CH:20]=1)(=[O:17])[NH2:16]
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]
Reactant: COC(=O)N=C=S
Agent: [Fe]
Agent: NC(=O)Sc1ccc(N)c(N)c1
Agent: NC(=O)Sc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1NC(=S)NC(=O)OC

Procedure:
In a similar manner, substituting 1-amino-4-carbamoylthio-2-nitrobenzene for the 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene in the iron reduction step, 1,2-diamino-4-carbamoylthiobenzene is prepared. 0.5 G. of this latter compound in 30 ml. acetone is treated overnight with 2 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated and the residue triturated with ether. Recrystallization yields 4-carbamoylthio-1,2-bis-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[CH3:9])=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].Cl>O1CCCC1.C([Li])CCC>[F:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[CH:3][CH:4]=1)([F:11])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(C=O)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1-bromo-4-(1,1-difluoroethyl)benzene (1.00 g) in tetrahydrofuran (10.0 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 1.68 mL) was added at −80° C. and the mixture was stirred at that temperature for 5 minutes. Subsequently, N,N-dimethylformamide (0.522 mL) was added at −80° C. and after stirring the mixture at that temperature for 20 minutes, 2 mol/L hydrochloric acid (2.50 mL) was added. After bringing the reaction mixture to room temperature, two extractions were conducted with ethyl acetate and the combined organic layers were washed with water. After drying over anhydrous magnesium sulfate and the desiccant was removed by filtration; the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (510 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=O)=[CH:19][CH:18]=[CH:17][CH:16]=3>C(O)C>[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=[N:2][OH:3])=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: NO
Reactant: O=Cc1cn2c(cnc3ccccc32)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1cn2c(cnc3ccccc32)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A solution of 1.4 g of hydroxylamine hydrochloride, 1.9 g of sodium acetate and 5 ml of water was added to a suspension of 3.10 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde in 30 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was evaporated to dryness. The white crystalline residue was triturated with water and was filtered. The product was dried in vacuo over phosphorus pentoxide to obtain 2.83 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 243°-245° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CCCCCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN(C)/C=N/c1nnc(C(C)(C)C)s1
Temperature: 100 °C

Procedure:
A mixture of 5-tert-butyl-1,3,4-thiadiazol-2-amine (Aldrich) (10.0 g, 63.6 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (26.3 mL, 197 mmol) in 200 mL of toluene was heated at 100° C. for 12 hours. The mixture was cooled to room temperature and hexane was added. The solid was collected by filtration (hexane wash) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.C[I:29].[C:30]1(C)C=CC=CC=1>C(#N)C>[I-:29].[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([CH3:30])=[CH:12][CH:11]=[CH:10]2
Reactant: CI
Reactant: COC1(c2cc(F)cc(OCc3ccc4ncccc4c3)c2)CCOCC1
Reactant: Cc1ccccc1
Solvent: CC#N
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc[n+]4C)c3)c2)CCOCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]quinoline (0.367 g), methyl iodide (0.13 ml), toluene (1 ml) and acetonitrile (6 ml) was stirred at ambient temperature for 16 hours. The precipitate was filtered off to give 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]-1-methylquinolinium iodide (0.19 g) in 37% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:33])[F:34])[CH:26]=2)=[CH:36][CH:37]=1
Reactant: CCC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Reaction time: 2 h
Yield: 72.4 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-1-(2-oxobutyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.44 g, 0.82 mmol, example 363) was dissolved in methanol (8 mL) and DCM (1 mL), then cooled to 0° C. Sodium borohydride (0.93 g, 2.46 mmol) was added portion wise over 20 min and reaction was stirred in the cold for 2 h. The reaction solvent was removed under reduced pressure then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil. The oil was purified using an 40 g silica gel flash column eluted with 1% methanol/DCM to give 7-(4-chlorobenzyl)-1-(2-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.32 g, 73% yield) as a white solid. LCMS retention time=4.265 min and 97% purity, LCMS MH+ 539. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.38-7.45 (m, 5H), 7.30 (d, 1H, J=12 Hz), 5.43 (s, 2H), 4.56 (d, 1H, J=4 Hz), 3.92-4.00 (m, 1H), 3.65-3.76 (m, 2H), 3.28 (s, 3H), 1.23-1.41 (m, 2H).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]#[N:23])[CH:15]=1.[CH2:25]([NH2:28])[C:26]#[CH:27]>C1C=CC=CC=1>[CH2:25]([NH:28][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]#[N:23])[CH:15]=1)[C:26]#[CH:27]
Reactant: COc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Reactant: C#CCN
Solvent: c1ccccc1
Product: C#CCNc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a mixture of 0.20 g of 4-methoxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one and 10 ml of benzene was added 34.3 mg of propargylamine, and the mixture was heated under refluxing for 3 hours and 45 minutes. After cooling to room temperature, precipitated crystals were filtered to obtain 68.0 mg of 4-propargylamino-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (20b)] as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([Cl:10])=[CH:4][CH:3]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:11])[C:5]([Cl:10])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nc(Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Br)ccc1Cl
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a solution of 6-bromo-3-chloropicolinaldehyde (10.0 g, 45.45 mmol) in 200 mL THF stirring at −78° C. under N2 was slowly added methylmagnesium bromide (3.0 M in diethyl ether, 16.63 mL, 50 mmol). The reaction was stirred at this temperature for 3 hours, and then saturated ammonium chloride was added. The mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc/hexanes over 20 minutes) to provide 1-(6-bromo-3-chloropyridin-2-yl)ethanol (8.4 g, 78%).
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19].OC1C(OC2C=CC=CC=2Cl)=CC=CC=1C(CC)C(O)=O>C(OC(=O)C)(=O)C.I>[CH2:21]([CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:3]=2[O:19][C:18]1=[O:20])[CH3:22]
Reactant: CCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Agent: CCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1O
Agent: I
Solvent: CC(=O)OC(C)=O
Product: CCC1C(=O)Oc2c(Oc3ccccc3Cl)cccc21
Yield: 62.3 %

Procedure:
A solution of 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyric acid (4.1 g) in acetic anhydride (10 ml) and hydriodic acid (55-58%, 20 ml) were treated in a similar manner to that of Example 10-(7). The resultant oily residue, i.e. 2-[2-hydroxy-3-(2-chlorophenoxy)phenyl]butyric acid was treated with acetic anhydride (10 ml) in a similar manner to that of Example 10-(7). The resultant crystalline residue was recrystallized from ethanol to give 3-ethyl-7-(2-chlorophenoxy)-2,3-dihydrobenzofuran-2-one (2.3 g). mp 78°-79° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC(C(F)(F)F)=O.[NH2:24][C@@H:25]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([C@@:28]1([CH3:31])[CH2:30][O:29]1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:24][C@@H:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26]([C@@:28]2([CH3:31])[CH2:30][O:29]2)=[O:27])=[O:12])[CH2:16][CH2:15]1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (1.02 g, 4.44 mmol) was added (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (1.34 g, 4.44 mmol), HATU (2.02 g, 5.33 mmol), and DMF (10 mL). The mixture was cooled to 0° C. and DIEA (3.09 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-70% ethyl acetate/heptane) provided tert-butyl ((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.33 g, 72%) as a colorless solid. MS (EI) for C23H32N2O5, found 417.3 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N:18]([CH2:25][C:26]#[N:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>O1CCCC1>[OH:8][C:9]1[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(O)c(C#N)n2-c1ccccc1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
A mixture of 8.4 g (0.075 mole) of potassium tert.-butoxide in 200 ml of tetrahydrofuran (under a nitrogen atmosphere) was stirred and cooled in an ice bath. A solution of 13.7 g (0.046 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid methyl ester in 150 ml of tetrahydrofuran was added over two hours, the ice bath was removed, and the new mixture was stirred for an additional 42 hours. The total reaction mixture was added to 1.1 kg of ice/water and acidified with 12.0 ml of glacial acetic acid to precipitate the crude product. The solid was filtered, washed with water, and recrystallized from aqueous methanol to yield 10.3 g (84% yield) of the nitrile product. A sample recrystallized again as above was analytically pure, mp 182° C.-dec.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[C:13](C(O)=O)=[CH:12][C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5]1>N1C=CC=CC=1>[Br:1][C:13]1[C:4](=[O:3])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[N:8][CH:7]=2
Reactant: BrBr
Reactant: O=C(O)c1cc2ccncc2[nH]c1=O
Solvent: c1ccncc1
Product: O=c1[nH]c2cnccc2cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
Bromine (0.539 mL, 10.52 mmol) was added dropwise to a 0° C. mixture of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (1.00 g, 5.26 mmol) in pyridine (25.0 mL). The mixture stirred at 0° C. for 20 minutes and then at room temperature for 18 hours. The reaction was then heated at 50° C. for 18 hours. The reaction mixture was then concentrated to afford a brown solid. This material was partitioned between DCM and saturated aqueous sodium thiosulfate solution. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford a brown solid. The resulting material was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-10% MeOH in DCM to afford 3-bromo-1,7-naphthyridin-2(1H)-one (0.562 g, 2.497 mmol, 47.5% yield) as a tan solid. m/z (ESI) 225.0, 227.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:27]1[CH2:28][CH2:29][C:24]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:25][CH2:26]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCC2(CC1)OCCO2)C(=O)OC(C)(C)C

Procedure:
2-Chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester, dichloromethane (60 ml), triethylamine (82 ml), and 1,4-dioxa-8-aza-spiro[4.5]decane(1.59 g) were reacted as above. Purification by flash chromatography (eluent 50% hexane/diethyl ether) yielded the title compound as a green gum (1.57 g). Rf 0.35 (50% hexane/diethyl ether).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)N(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)CCOc1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
18.6 g of p-phenoxyphenol are dissolved in 100 ml of dimethylformamide. 18.2 g of ethyl (2-chloroethyl)-methylcarbamate and 27.6 g of potassium carbonate are added thereto and the reaction mixture is heated at 80° C. while stirring for 15 hours. The reaction mixture is poured into 300 ml of water and extracted with diethyl ether. The ether extract is washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography on silica gel using n-hexane/ethyl acetate (9:1) as the eluent yields ethyl [2-(p-phenoxyphenoxy)ethyl]methylcarbamate; nD20 =1.5503.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BA above and using phenylacetyl chloride (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>ClCCl>[C:18]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]3[CH:12]([CH2:13][N:14]([C:11](=[O:17])[CH2:10][C:25]4[CH:4]=[CH:3][CH:2]=[CH:7][C:24]=4[N:26]4[CH2:29][CH2:30][CH2:28][CH2:27]4)[CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCCC3)CC12
Reaction time: 0.67 h

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-[2-(1-pyrrolydinyl)phenyl]acetic acid (1.42 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 1 hour at 20° C. It is washed with distilled water (2×20 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 2 cm, height 25 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) and collecting 100 cc fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (5 cc). The crystals are drained, washed with ethylene oxide (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-[2-(1-pyrrolidinyl)phenyl]acetyl]-4-perhydroisoindolone (2.2 g) melting at 178° C. is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Reactant: OB(O)c1ccccc1
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Yield: 20.8 %

Procedure:
Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.66 g, 1.4 mmol) and phenyl boronic acid (0.20 g, 1.6 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125–135 was followed. The crude product was recrystallized from methanol and then purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10). The solid was then purified by HPFC to provide 0.14 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as Off-white needles, mp 207–208° C.