Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH:43][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)Cc1cccc(-c2ccccc2N)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (61 mg, 0.32 mmol) and Et3N (44 μL, 0.32 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) and DMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) (50 mg, 0.21 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (72) (46 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H); 3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m, 3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz); 8.31 (br.d, 1H, J=7.8 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([CH3:14])([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9].[CH2:15](O)[CH3:16].[C:18]1(C)C=CC=C[CH:19]=1>>[CH2:18]([O:9][C:8](=[O:10])[C:7]([CH3:14])([CH3:6])[C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH3:19]
Reactant: CCO
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)C(=O)OCC
Reaction time: 3 h

Procedure:
0.023 ml of concentrated sulfuric acid are cautiously added to a solution of 4 g of 2,2-dimethylmalonic acid in 30 ml of a 1:2 absolute ethanol/toluene mixture. The reaction mixture is refluxed, distilling the azeotropic water/toluene mixture and adding every few an ethanol/toluene mixture. After 3 hours, the reaction mixture is added with 50 ml of water and extracted with ethyl acetate (3×15 ml). The combined organic extracts are dried over sodium sulfate and solvent is evaporated off under reduced pressure. The residue is purified by silica gel chromatography (eluent 2:1 hexane/AcOEt). 3.3 g of 2,2-dimethylmalonic acid diethyl ester are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])C(O)=O)=[CH:7][C:6]=1OC)(=[O:3])[CH3:2].[C:22](=O)=[O:23]>[Cu].N1C2C(=CC=CC=2)C=CC=1>[C:15]([NH:14][CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH2:2][O:23][CH3:22])=[CH:19][CH:18]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(C=C(NC(C)=O)C(=O)O)ccc1OC(C)=O
Reactant: O=C=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COCC(=O)Oc1ccc(C=CNC(C)=O)cc1

Procedure:
18.0 g (0.06 mol) of 4-acetoxy-α-acetylamino-3-methoxy-cinnamic acid are heated with 30 ml of quinoline and 1.2 g of copper powder to 160°-170° C for 3 hours, in the course of which carbon dioxide is evolved. Thereafter, the quinoline is distilled off under reduced pressure and the residual mass is taken up in ethyl acetate. After filtering off the copper powder, the ethyl acetate solution is extracted with 25 ml of 1 N hydrochloric acid and is then washed with water and subsequently with sodium bicarbonate solution. The organic phase is dried over sodium sulphate and thereafter the solvent is removed by distillation under reduced pressure. The resulting oil yields 4-(2-acetylaminovinyl)-2-methoxy-acetoxy-benzene, of melting point 169°-170° C, from ethyl acetate.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@@:12]2([CH3:26])[O:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13]2)=O)=CC=1)([O-])=O.[N+](C1C=CC(C(OC[C@H]2OC(=O)N(C3C=CC(OC)=CC=3)[C@H]2C)=O)=CC=1)([O-])=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[CH2:13][C@:12]([CH2:11][OH:10])([CH3:26])[O:16][C:15]2=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2C[C@@](C)(COC(=O)c3ccc([N+](=O)[O-])cc3)OC2=O)cc1
Agent: COc1ccc(N2C(=O)O[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@@](C)(CO)OC2=O)cc1
Yield: 95 %

Procedure:
The same procedure of Reference Example 11 was repeated except that (S)-(+)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-ylmethyl p-nitrobenzoate obtained in Reference Example 10 was used in lieu of (4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-ylmethyl p-nitrobenzoate to give the title compound (yield 95%).
Reaction SMILES: [H-].[Na+].C(ONC(=O)OC(C)(C)C)C1C=CC=CC=1.[C:19]([O:23][C:24](=[O:38])[N:25]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26]C(C)C)([CH3:22])([CH3:21])[CH3:20].IC>CN(C)C=O>[CH2:31]([O:30][N:25]([CH3:26])[C:24](=[O:38])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.48 g of 80% in mineral oil, 16 mmol) was added to a solution of tert-butyl N-benzyloxycarbamate (Compound 54 Part A, 3 g, 13 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture was stirred for 20 minutes then iodomethane (1.1 mL, 18 mmol) was added dropwise with cooling in an ice bath. The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere overnight. The reaction mixture was quenched with water (50 mL) then extracted with diethyl ether (150 mL). The organic layer was washed with water (5×50 mL), dried over magnesium sulfate then concentrated to provide 3.1 g of tert-butyl N-benzyloxy-N-methylcarbamate as a yellow oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(#N)C.C(O)C>[OH2:2].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[O:28]1[C:26]2[C:25]3[CH:24]=[CH:23][O:30][C:10]=3[CH:9]=[CH:14][C:1]=2[O:4][CH2:11][C@@H:12]1[CH2:13][NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH3:7])[CH2:16][CH2:17]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1N1CCC(CN)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccccc1N1CCC(CNC[C@H]2COc3ccc4occc4c3O2)CC1
Product: O
Reaction time: 90 h
Yield: 187 %

Procedure:
A mixture of the product from the previous reaction (2.80 g), potassium carbonate (10.0 g) and 1-[(2-methoxyphenyl)piperid-4-yl]methylamine (1.88 g) in dry acetonitrile (100 ml) was heated under reflux with stirring for 90 hours. The cooled mixture was filtered and the filtrate evaporated under reduced pressure to leave a pale-yellow oil. Purification by flash column chromatography on silica eluting with a 19:1 mixture of dichloromethane and methanol gave a pale-yellow oil which was then dissolved in ethanol (5 ml) and treated with a solution of fumaric acid (0.70 g) in ethanol (5 ml). The solvent was evaporated from the resulting solution under reduced pressure to give (S)-N-(2,3-dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine monofumarate monohydrate (3.06 g) as a pale-yellow solid m.p. 95-6° C., [α]D =−38.5° (C=0.301, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1

Procedure:
In 500 ml of dichloromethane is dissolved 5.05 g of 1,3,5-trimethoxybenzene and the solution was cooled to -5°~-10° C. A solution of 6 ml of chlorosulfonic acid in 400 ml of dichloromethane was added dropwise, and the mixture was allowed to stand at room temperature. The reaction mixture was then treated as in Reference Example 1. The resulting product was crystallized from carbon tetrachloride and filtered. Yield 610 mg (6.3%), m.p. 126°-129° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][CH2:5][C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].O>C(Cl)Cl>[C:17]([O:16][C:15]([NH:14][C@@H:6]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][N:4]([CH2:3][C:2]([F:22])([F:23])[F:1])[C:31](=[O:32])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H](CNCC(F)(F)F)CC1CCCCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)CN(CC(F)(F)F)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of tert-butyl (S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate (1.7 g, 5 mmol) and Et3N (2 mL, 15 mmol) in CH2Cl2 (20 mL) was added dropwise a solution of CbzCl (1.02 g, 6 mmol) in CH2Cl2 (10 mL) at 0° C. After stirring for an additional 2 h, water (30 mL) was added. The mixture was extracted with CH2Cl2 (2×20 mL), the organic layers were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica chromatography to obtain benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclohexyl-propyl-2,2,2-trifluoroethylcarbamate (250 mg, yield 10% for 2 steps) as an oil. 1H NMR (CDCl3, 400 MHZ) δ 0.90 (m, 2 H), 1.25 (m, 4 H), 1.44 (s, 9 H), 1.70 (m, 7 H), 3.33 (m, 2 H), 3.85 (m, 3 H), 4.45 (brs, 1 H), 5.20 (s, 2 H), 7.36 (m, 5 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(I)ccc1OCc1ccccc1
Temperature: 120 °C

Procedure:
67.2 g (0.48 mol) of potassium carbonate are added to a solution of 100 g (0.40 mol) of 2-hydroxy-5-iodobenzaldehyde (Example 1A) in 1.5 l of dimethylformamide and, after a few minutes, 51 ml (0.44 mol) of benzyl chloride are added. The reaction mixture is stirred under reflux at 120° C. for 24 h. After stirring at RT for a further 24 h and the addition of 1.5 l of water, a solid crystallizes out. The precipitate is collected by suction filtration, washed twice with water and dried in vacuo. The solid is recrystallized from 230 ml of ethanol. 122.9 g (90% of theory) of product are obtained.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[ClH:2].[ClH:1].[ClH:2].[CH:24]([NH:27][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][NH:17][CH:16]([CH3:11])[CH3:15])[CH:15]=1)[CH:10]=2)([CH3:26])[CH3:25]
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Reactant: CC(C)N
Agent: Cl
Product: CC(C)NCCOc1ccc2cc3ccc(OCCNC(C)C)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and isopropylamine as described in Example 15, giving 1.1 g. of the desired product as yellow crystals, m.p. 232°-234° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:16]=[C:17]3[C:22]=2[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[CH2:23][N:15]1[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c3c(nn2CC(F)(F)F)CCCC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Cn1nc2c(c1C1CCNCC1)CCCC2

Procedure:
A solution of 500 mg (1.3 mmol) of 1-tert-butoxycarbonyl-4-(2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)piperidine (from Step B) in 4.1 mL of CH2Cl2 at 0° C. was treated with 2.7 mL of trifluoroacetic acid. After 30 min volatiles were removed under reduced pressure. The residue was partitioned between 25 mL of CH2Cl2 and 25 mL of 1 N NaOH. After separating phases, the aqueous layer was extracted with 25 mL of 1 N NaOH. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound, which was used without further purification. 1H-NMR (500 MHz) δ 1.68–1.95 (m, 9H), 2.61–2.71 (m, 7H), 3.17–3.20 (m, 2H), 4.61 (q, J=8.3, 2H).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]2[CH2:21][CH2:22][CH2:23][N:12]([CH2:13][CH2:14][N:15]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][CH2:17]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2]>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:25]([CH2:24][N:15]1[CH2:14][CH2:13][N:12]2[CH2:23][CH2:22][CH2:21][N:18]([CH2:19][CH2:20][N:9]([CH2:8][C:1]([OH:3])=[O:2])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN1CCN2CCCN(CC1)CCN(CC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCN2CCCN(CC1)CCN(CC(=O)O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 166.2 %

Procedure:
Compound 5 (1.25 g, 2.84 mmol) was dissolved in a 1:1 (vol:vol) mixture of CF3CO2H (TFA) and CH2Cl2 (45 mL). The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue which was triturated with Et2O to provide white solid 6 (1.55 g, 98% yield).
Reaction SMILES: [Na].Cl[CH:3](Cl)[CH2:4][NH:5][C:6](=[O:26])[CH:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O>C(O)C.C(Cl)(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH:7]([C:6]1[O:26][CH:3]=[CH:4][N:5]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O=C(NCC(Cl)Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(OC(c2ccc(Cl)cc2)c2ncco2)c1

Procedure:
Sodium (0.595 g., 0.026 mole) is dissolved in absolute ethanol (20 ml.). N-(β ,β-dichloroethyl) (3-trifluoromethylphenoxy) (4-chlorophenyl)acetamide (4.69 g., 0.011 mole) is then added and the solution refluxed for 20 minutes. A precipitate forms and the solution becomes dark orange and then brown. The reaction mixture is cooled in an ice bath and then diluted with 50 ml. of water. The solution is extracted with 50 ml. of ether and then with 2 × 25 ml. of ether. The ether extracts are combined and washed successively with a sodium hydroxide solution (2 × 25 ml., 1 N), hydrochloric acid (2 × 25 ml., 1 N) and then with water until neutral. The ether solution is then washed with a saturated sodium chloride solution (25 ml.), treated with charcoal and then filtered to remove the charcoal. The ether solution is then dried over anhydrous magnesium sulfate, filtered and the ether removed under vacuum to afford 3.24 g. of an orange oil. The orange oil is dissolved in chloroform and chromatographed on a silica gel column employing as the eluant a mixture of chloroform and ethyl acetate (20:1). One ml. portions are collected and analyzed by thin layer chromatography and IR. The first 32 ml. collected contain no product. The next 18 ml. contain a mixture of starting material and final product. The next 53 ml. contain 2.03 g. of product obtained by evaporation of the solvent. Recrystallization from n-hexane affords 2-[α-(3-trifluoromethylphenoxy) 4-chlorobenzyl]oxazole, m.p. 66°-67°C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1.O>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:20][C:21](=[O:23])[CH3:22])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C=Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of quinoline-6-carboxaldehyde (5.29 g) and 1-triphenylphosphoranylidene-2-propanone (1.5 equiv) in dimethyl sulfoxide (100 ml) was stirred at room temperature for 24 hr. The solution was poured into water (600 ml) which was subsequently extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane/ethyl acetate (4:1 v/v) elution to give 1-(quinolin-6-yl)but-1-ene-3-one as a white solid. Pmr spectrum (CDCl3 ; δ in ppm : 2.41 (3H,s); 6.83 (1H,d); 7.3-9.0 (7H,m).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[N:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)C>C(O)(=O)C>[N:5]1[N:2]=[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:8][CH:7]=1
Reactant: CN(C)C=NC(=O)c1cccnc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: c1cncc(-c2nnc[nH]2)c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3.1 g. of hydrazine hydrate in 100 ml. of acetic acid is added 10.0 g. of N-(dimethylaminomethylene)nicotinamide. The reaction mixture is stirred at 90° C. for 1.5 hours, then concentrated in vacuo to about 15 ml. The addition of 50 ml. of ether causes the desired product to precipitate as 7.8 g. of colorless crystals, mp. 169°-172° C.
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:22][O:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1>C(O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:22][O:23][NH2:24])[N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Hydrazine hydrate (9 mL) was added to a suspension of 2-{[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}isoindole-1,3-dione (3.9 g) in ethanol (90 mL). The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was filtered to remove a precipitate and the filter cake was washed with ethanol and dichloromethane. The filtrate was concentrated under reduced pressure, diluted with aqueous 1N hydrochloric acid (100 mL), and then washed sequentially with dichloromethane (2×50 mL) and ethyl acetate (1×50 mL). Analysis of the organic washes by LCMS indicated that they did not contain product. The aqueous acidic layer was made basic (˜pH 9) with solid sodium carbonate and then extracted sequentially with dichloromethane (1×100 mL), ethyl acetate (1×100 mL), and dichloromethane (1×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 2.07 g of O-{[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}hydroxylamine as a tan foam.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][N:10]([C:11]=23)[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=2[NH:7]1.[Cl:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)(Cl)Cl>[ClH:24].[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][N:10]([C:11]=23)[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=2[N:7]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CN(C)CCCC1Nc2ccccc2N2CCc3cccc1c32
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2ccccc2N2CCc3cccc(c32)C1CCCN(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A stirred solution of 6.1 g of N,N-dimethyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-propanamine in 100 ml of chloroform was treated at room temperature with 2.1 ml of ethyl chloroformate. A thick solid precipitated out of solution within 5 minutes. After stirring the mixture for 4.5 hours at room temperature under nitrogen, another 50 ml of chloroform was added and the mixture was refluxed overnight. TLC at this point showed the reaction to be about half complete, with some solid still undissolved. Dilution with 500 ml of chloroform and overnight reflux produced an improvement in the proportion of product. After addition of another 0.38 ml of ethyl chloroformate and 3 more hours of reflux, the mixture was cooled to room temperature, poured into a separatory funnel, and washed with water (2×100 ml) to remove unreacted starting material as the hydrochloride salt. The chloroform phase was washed with 200 ml of saturated sodium chloride solution and thereafter dried over anhydrous sodium sulfate. Filtration of the mixture and concentration of the filtrate in vacuo afforded 4.7 g of a gum which TLC showed to be a product essentially free of unreacted starting material. This material was dissolved in 150 ml of ether, gravity-filtered to remove insoluble material, and the filtrate was concentrated in vacuo to a gum weighing 4.07 g. This material was taken up in 50 ml of ether and filtered, and hydrogen chloride-saturated ether was added to the filtrate. Crude hydrochloride formed as a gum which was solidified by decanting the liquid, rinsing twice with fresh ether and triturating with a third portion of fresh ether. Filtration and drying in vacuo afforded 3.62 g of solid. Recrystallization twice from absolute ethanol/ether afforded 2.25 g of solid, m.p. 201°-204° dec.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.48 g, 1.4 mmol) in acetonitrile (10 mL), was added 4-chloro-benzoyl chloride (0.27 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.6 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (390 mg, 62% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.18 min (98.0%); mp, 276-278° C.; 1HNMR (DMSO-d6)2.18-2.23 (m, 1H, CHH), 2.58-2.93 (m, 6H, CHCH2, CH3), 4.97-5.08 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.96 (m, 7H, Ar), 9.01 (t, 1H, J=6 Hz, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.21, 56.54, 117.66, 124.16, 125.52, 128.45, 129.17, 132.95, 133.95, 136.13, 140.69, 148.52, 154.84, 161.10, 165.23, 169.54, 172.63. LCMS MH=439, 441; Anal Calcd For C22H19N4O4Cl+0.1H2O: C, 59.96; H, 4.39; N, 12.71; Cl, 8.05. Found: C, 59.80; H, 4.13; N, 12.61; Cl, 8.30.