Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:5](/[CH:6]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([F:11])[CH:3]=1
Reactant: Nc1cc(F)c(C=O)c(F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C/c1c(F)cc(N)cc1F
Temperature: 23 °C
Reaction time: 0.42 h

Procedure:
To a solid mixture of 4-amino-2,6-difluoro-benzaldehyde (6.5 g, 41.4 mmol, 1.0 equiv.) and (carbethoxymethylene)triphenylphosphorane (18.75 g, 53.8 mmol, 1.3 equiv.) at 23° C. was added ethanol (97 mL). After stirring for 25 min at 23° C., the reaction mixture was concentrated, pre-absorbed with silica gel and purified by flash column chromatography eluting with a gradient increasing in polarity from 0 to 30% ethyl acetate in hexane. Relevant fractions were combined to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(Cl)Cl.OS(O)(=O)=O.[Br:22]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:22][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (215.0 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402.0 g, 2.26 mol) in equal portions over seven hours. The reaction mixture was stirred for four days at room temperature, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water and subsequently treated with saturated NaHCO3 (1.5 L) for two hours. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%).
Reaction SMILES: [NH3:1].CO.[N:4]1[N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[N:19]=[N:18][C:17]=3[C:23]([O:25]CC)=O)[CH:12]=[CH:11][CH:10]=2)[N:6]=[CH:7][CH:8]=1>>[N:6]1[N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[N:19]=[N:18][C:17]=3[C:23]([NH2:1])=[O:25])[CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:8][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Temperature: 35 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
Ammonia in methanol (3.94 g, 5 mL, 35.0 mmol) was added to ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (100 mg, 289 μmol) and stirred at 35° C. for 16 h. The mixture was concentrated in vacuo to give 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (90 mg, 284 μmol, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 12.30 (s, 1H), 9.13 (s, 1H), 9.54 (s, 1H), 8.94 (s, 1H), 8.29 (s, 1H), 8.27 (s, 2H), 8.05 (t, J=8.1 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H); MS (EI/CI) m/z: 316.9 [M+H].
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.CC([O-])(C)C.[K+].[CH3:40][C:41]([CH3:51])([CH3:50])[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O.C1CCCCC1>C1COCC1>[CH3:40][C:41]([CH3:51])([CH3:50])[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[CH:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=1
Reactant: CC(C)(C)C(=O)c1ccccc1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (341 mg; CAS 473659-21-1) at r.t. in THF (7.5 ml) under an argon atmosphere was added potassium tert-butylate (83 mg). The mixture was then stirred at r.t. for 15 minutes, and 2,2-dimethylpropiophenone (0.1 ml) was added in one portion. The mixture (clear brown orange solution) was heated to 80° C. and stirring at that temperature was continued for 24 hours. The reaction mixture was directly adsorbed on silica gel. The product was isolated by chromatography (gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give 4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (135 mg; not completely pure) as light yellow solid. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.25 ml) was added to a solution of the product of Step 2 (1.46 g, 4.4 mmol), 1H-inden-2(3H)-one (0.46 g, 4.5 mmol) and NaBH(OAc)3 (1.4 g, 6.55 mmol) in anhydrous 1,2-dichloroethane (17 ml). The resulting mixture was stirred overnight at room temperature under N2 and to it more of NaBH(OAc)3 (0.4 g, 1.9 mmol) was added. After 2 h of stirring at room temperature, the mixture was quenched by addition of 1N NaOH aq (5 ml). This was diluted to 60 ml with Et2O and washed with H2O and brine. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a creamy solid (1.4 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0 Hz, 1H), 7.34-7.5(m, 5H), 7.12-7.21(m, 4H), 7.05(dd, J=2.6, 9.0 Hz, 1H), 6.49(d, J=2.6 Hz, 1H), 4.17(m, 1H), 4.08(m, 1H), 3.19-3.27(m 2H), 2.73-2.83(m, 2H), 2.7(s, 3H), 1.22(s, 9H).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].CO>[C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)N1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N1CCC(N)CC1

Procedure:
A solution of N-benzyl-1-tert-butylpiperidin-4-amine (150 mg) and 10% palladium on carbon (200 mg) in 30 mL of MeOH was hydrogenated in a Parr shaker at 50 psi for 16 h. The solution was filtered and concentrated to give 1-tert-butylpiperidin-4-amine which was used without further purification. Mass spectrum (ESI) 157 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: CC12CCC(=O)NC1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4, 4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide ! 0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH3:13][S-:14].[Na+]>CS(C)=O>[CH3:13][S:14][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: FC(F)(F)c1cc(Br)cnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
The product of Example 6 (3.0 g, 0.012 mol) was dissolved with stirring in dimethyl sulphoxide (30 mL) and sodium methanethiolate (1.2 g, 0.017 mol) was added. The mixture was stirred at room temperature overnight, poured into ice-water, and extracted with hexane (2×50 mL). The organic extracts were combined, washed with water and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10% ethyl acetate:hexane) gave 2-methylthio-3-trifluoromethyl-5-bromopyridine (2.2 g) as a clear oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36](O)=[O:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C@H:35]([NH:39][C:40]([C:42]3[S:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)=[O:41])[C:36]([N:1]3[CH2:2][CH:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:4]3)=[O:37])=[CH:32][CH:33]=2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirring solution of tert-butyl azetidine-3-carboxylate (64.55 mg, 0.41 mmol) in DMF (1 mL) were added DIEA (169.6 mg, 1.31 mmol), and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (100.0 mg, 0.21 mmol). The solution was cooled to 0° C. at ice bath and then HATU (74.11 mg, 1.31 mmol) in 1 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×10 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. to afford 117.6 mg (85%) of tert-butyl (S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)azetidine-3-carboxylate INT-38 as a solid powder without further purification for next step. LCMS-ESI (m/z) calculated for C30H35BrN4O4S: 626.2. found 627.2 [M+H]+, tR=3.884 min. (Method 16).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc2oc(S)nc2cc1Cl
Reactant: CN1CCCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(N3CCCN(C)CC3)nc2cc1Cl

Procedure:
5-Chloro-6-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-6-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (183 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[O:21]([CH2:28][CH2:29]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:29][CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.81 g) in dimethylformamide (25 mL) under argon was treated with 55% sodium hydride (0.437 g), stirred for 15 minutes and treated with the mesylate of 2-phenoxyethanol (2.38 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude residue in dichloromethane was passed through a plug of silica gel (5 g) and evaporated and the resulting solids were crystallized from diethyl ether-hexane to give 1.85 g of alpha-oxo-4-[[2-(phenoxy)ethyl]oxy]benzeneacetic acid methyl ester mp 79°-81° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:30]5[C:29]([CH3:35])([CH3:28])[CH2:33][O:32][C:31]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC1(C)COC(=O)N1
Product: CC1(C)COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 43 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95 and 4,4-dimethyloxazolidin-2-one (138 mg), the title compound (198 mg) was obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:27])=[C:24]([C:37]([OH:40])([CH3:39])[CH3:38])[N:23]=[C:22]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])=[O:27])=[C:24]([C:37]([OH:40])([CH3:38])[CH3:39])[N:23]=[C:22]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:16][CH:15]=1)([OH:7])=[O:5]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 96(b) bun using 396 mg of pivaloyloxymethyl 1-{4-[2-(t-butoxycarbonyl)phenyl]phenyl}methyl-2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5 -carboxylate [prepared as described in step (a) above], 312 mg of the hydrochloride of the title compound were obtained as an amorphous powder, melting at 65° C. (with softening).
Reaction SMILES: [C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6])(O)=[O:2].Cl.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(N(C(C)C)C(C)C)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[CH:5]([CH3:7])[CH3:6])=[O:2])=[CH:38][CH:39]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: NCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)NCCc1ccc(O)cc1)C(C)C
Reaction time: 1 h

Procedure:
0.5 g of the compound from Example 16, 0.21 g of tyramine hydrochloride, 0.225 ml of N-ethyldiisopropylamine, 0.164 g of 1-hydroxybenzotriazole and 0.296 g of dicyclohexylcarbodiimide are stirred at room temperature in 4 ml of DMF for 48 h. After evaporating the solvent in vacuo, the residue is stirred in a mixture of 4 ml of CH2Cl2 -MeOH-AcOH 94:3:3 for 1 h. After evaporating, the mixture is separated by means of flash chromatography (100 g, system N6). After lyophilizing from t-BuOH, the product is obtained as an amorphous powder. FAB-MS: m/e=555 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl>O.C(OCC)C>[CH3:16][C:13]([CH3:17])([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:2]1[CH2:11][C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:14][OH:15]
Reactant: CC(C)(CO)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(CO)n1c(Cc2ccccc2)nc2cnc3ccccc3c21
Temperature: 130 °C

Procedure:
A mixture of 26.7 g (0.115 mole) of 2-[(3-amino-4-quinolinyl)amino]-2,2-dimethyl-1-ethanol and 42.8 g (0.180 mole) of triethyl orthophenylacetate was heated at 130° C. for four hours. The mixture was diluted with water, acidified to pH 5 with 6N hydrochloric acid and diluted with diethyl ether. The solid which precipitated was separated by filtration, rinsed with diethyl ether and slurried in saturated sodium bicarbonate solution. The solid was separated by filtration and dried to provide beta,beta-dimethyl-2-phenylmethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: C(Cl)(=O)[C:2]([Cl:4])=O.[CH3:7][O:8][C:9]([CH:11]1[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12]1)=[O:10]>ClCCl.CN(C)C=O>[Cl:4][CH2:2][C:16]([CH:14]1[O:15][CH:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: COC(=O)C1CCC(C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(C(=O)CCl)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.55 ml) was added to a stirred solution of (2RS, 5SR) -5-methoxycarbonyltetrahydrofuran-2-ylcarboxylic acid (2.00 g) in dichloromethane (30 ml). Dimethylformamide (1 drop) was added and the mixture stirred at room temperature for 1 h, and then heated to reflux for 10 min. The mixture was cooled and the solvent removed on a rotary evaporator. Chloroform was then evaporated from the residue twice. The residue was dissolved in dichloromethane (100 ml) and the solution cooled in an ice bath, then excess diazomethane was passed into the solution. The mixture was stirred at 0° C. for 15min and then excess hydrogen chloride was passed into the solution. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.02 g) was isolated by column chromatography of the residue using gradient elution (silica gel, 4:1 going to 1:1 hexane:ethyl acetate); νmax (CHCl3) 1740 cm-1 ; δH (CDCl3) 1.9-2.5 (4 H, m), 3.71 (3 H, s), 4.45-4.8 (2 H, m), 4.54 (1 H, d, J 18 Hz) and 4.89 (1 H, d, J 18 Hz).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23](=[O:32])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (119.0 mL of a 2.0 M solution, 0.238 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (22.04 g, 0.112 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of p-anisoyl chloride (35.00 g, 0.106 mol) dissolved in THF (30 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (80 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(O[C:9](=[O:11])[CH3:10])(=O)C.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:9](=[O:11])[CH3:10])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
To a suspension of AlCl3 (144 g, 1.08 mol) in CH2Cl2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes before a solution of 1-(phenylsulfonyl)indoline (46.9 g, 0.180 mol) in CH2Cl2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and was quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (42.6 g).