Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnnn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnnn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g) in methylene chloride (18 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (12 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 232) (350 mg).
Reaction SMILES: O1CCCC1.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].CS[C:19]1[S:23][CH:22]=[CH:21][S+:20]=1>C(O)C>[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].[S:20]1[CH:21]=[CH:22][S:23][C:19]1=[N+:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: c1csc(=[N+]2CCOCC2)s1
Temperature: 25 °C

Procedure:
To 20 ml of tetrahydrofuran, 1.0 ml of morpholine was dissolved, and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration and recrystallized from ethanol, whereby 2.4 g (yield: 83.3%) of 4-(1,3-dithiol-2-ylidene)morpholinium perchlorate (Compound No. 26) was obtained as crystals having a melting point of from 177° to 178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([C:15]([O:17]CC)=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[N:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 76.6 %

Procedure:
Ethyl 5-(4-nitrophenyl)thiazole-2-carboxylate (Intermediate 2, step A, 3.6 g) was dissolved in THF (90 ml). 1 Molar aqueous NaOH (52 ml) was added and stirred at RT for 15-20 minutes. The reaction mixture was acidified with 1M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get pale yellow colored solid. Solid was crystallized in EtOAc/Pet ether to yield 2.48 g (76%) of the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 14.21 (bs, 1H), 8.7 (s, 1H), 8.31 (d, 2H), 8.1 (d, 2H); MS (ES+): m/z 251 (M+1).
Reaction SMILES: C(OC[C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12](O)[CH2:11]1)C1C=CC=CC=1.[Si](OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)(C(C)(C)C)(C1C=CC=CC=1)[C:45]1[CH:50]=CC=C[CH:46]=1.C(OC[C@@]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H](OC(OC2C=CC=CC=2)=S)C1)C1C=CC=CC=1>>[CH2:50]([C@@H:12]1[C@@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:31])([CH3:32])[CH3:33])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:34][C@@H:10]([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[CH2:11]1)[CH:45]=[CH2:46]
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=S)Oc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Product: C=CC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 58 %

Procedure:
Utilizing the procedures of Examples 16 and 17 wherein compound 18 was obtained from compound 3 via compound 17, compound 2 is used as the starting material in place of compound 3. Compound 2 is converted via the procedure of Example 16 to an intermediate compound similar to compound 17 except this intermediate differs from compound 17 in that it does not have a blocking group on its heterocyclic base. The intermediate is then treated as per the procedure of Example 17 to give the title compound in 58% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), with sodiumborohydride (1.2 mmol)) methanol (10 ml) at a temperature 0-25° C. for 2 hours in 78% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:40])=[CH:35][N:34]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 5 °C
Yield: 41 %

Procedure:
To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 0.420 g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −40° C., followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 579 in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (582, 0.25 g, 41%). MS (ESI) [M+H+]=623.1.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)=[O:12]>O>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([C:11]([CH:10]=[O:4])=[O:12])[CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: O=CC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
To a solution of 9.4 g. of selenium dioxide in a solvent mixture of 50 ml. of dioxane and 1.7 ml. of water, was added 16.5 g. of 3-benzyloxyacetophenone. The mixture was refluxed for 4 hrs. with stirring. The resulting precipitates were removed by filtration and the solvents were distilled off from the filtrate under reduced pressure. The residue was dissolved in benzene and washed with water several times. After drying the benzene layer, benzene was removed by distillation to obtain the glyoxal as yellow liquid in a quantitative yield.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH3:34])=[CH:31][CH:32]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CN[C@H](C)c3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and (1R)-1-[4-(trifluoromethyl)phenyl]ethylamine gave the title compound as a colorless oil (71%). M+(LC/MS(ESI)): 502.4. HPLC (Condition A), Rt: 5.04 min (HPLC purity: 99.6%).
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]1[C:6]([C:40]([O:42]C)=[O:41])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]3[C:32]4[C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[CH2:28][C:27]=4[O:26][C:25]4[CH2:24][C:23]([CH3:37])([CH3:36])[CH2:22][C:21](=[O:38])[C:20]3=4)[C:12]=2[CH3:39])=[CH:9][CH:10]=1>C1COCC1.O>[OH:4][C:5]1[C:6]([C:40]([OH:42])=[O:41])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]3[C:20]4[C:21](=[O:38])[CH2:22][C:23]([CH3:36])([CH3:37])[CH2:24][C:25]=4[O:26][C:27]4[CH2:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](=[O:33])[C:32]3=4)[C:12]=2[CH3:39])=[CH:9][CH:10]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(O)c(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 21 h
Yield: 39.1 %

Procedure:
Lithium hydroxide monohydrate (84.6 mg, 2.02 mmol) was added to a solution of the methyl 3-hydroxy-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 11-3 (250 mg, 0.46 mmol) in THF (5 ml) and water (2.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 21 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. A 1 N aqueous solution of hydrochloric acid (2.02 ml) was added to the water layer, and the solution thus mixed was then extracted with dichloromethane seven times. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=3:97 to 6:94, v/v). The fraction thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (95.6 mg, yield: 39%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.[CH3:22]I.[Cl-].[NH4+]>O1CCCC1>[CH3:22][CH:19]1[C:18](=[O:21])[CH2:17][CH2:16][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CC2(CCC1=O)OCCO2
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of lithium bis(trimethylsilyl)amide (1M, 100 ml, 100 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one (15.6 g, 100 mmol) in tetrahydrofuran (50 ml) at −78° C. over about 30 min, and the mixture was stirred for 30 min. Then, methyl iodide (2.5 ml, 120 mmol) was added dropwise over 5 min, and the mixture was stirred at −78° C. for 30 min, and at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (10.6 g, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([OH:12])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=2)=[O:24])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(NC(=O)c2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Yield: 50.2 %

Procedure:
Using the method of Example 12, 3.4 g of 4-amino-2,6-di-t-butylphenol was reacted with 2.3 g of 4-cyanobenzoic acid to provide 2.7 g of 4-cyano-N-(3',5'-di-t-butyl-4'-hydroxyphenyl)benzamide.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]1[CH2:18]CN2C(=NCCC2)[CH2:10][CH2:9]1.BrC(C(Br)C)C>CN(C=O)C>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:18]1)#[N:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CC#N
Agent: CC(Br)C(C)Br
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCCC1
Temperature: -20 °C
Yield: 58 %

Procedure:
A solution of methyl 2-cyanoacetate (30 mL, 340 mmol) in DMF (26 mL) and DBU (112 mL, 748 mmol) was heated to 50° C. for 15 min and then cooled to −20° C. To this stirred solution was added dibromobutane 18. The internal temperature increased to 70° C. during the addition. The reaction was set aside to cool to rt before quenching with H2O (800 mL). The product was extracted with Et2O (3×300 mL). The ether layer was washed with 1N HCl (400 mL) and H2O (400 mL). The combined extracts were dried over magnesium sulfate, and concentrated to a crude oil that was distilled under high vacuum at 80° C. to yield the desired product in 58% yield.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
0.34 mL of triethylamine and 0.15 mL of benzoyl chloride were added to 4 mL of methylene chloride solution containing 0.40 g tert-butyl 2-amino-4-(4-phenylbutyl)benzoate while ice-cooled sequentially and stirred at room temperature for 19 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1]to obtain 0.50 g of tert-butyl 2-(benzamido)-4-(4-phenylbutyl)benzoate as white solid.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O-:13])=[O:12].[Na+].[CH3:15][C:16]1[O:20][C:19](=[O:21])[O:18][C:17]=1[CH2:22]Br>CC(C)=O>[N:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:15][C:16]2[O:20][C:19](=[O:21])[O:18][C:17]=2[CH3:22])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:22][C:17]1[O:18][C:19](=[O:21])[O:20][C:16]=1[CH3:15])=[O:12]
Reactant: O=C([O-])c1ccc(C(=O)[O-])nc1
Reactant: Cc1oc(=O)oc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COC(=O)c1ccc(C(=O)OCc2oc(=O)oc2C)nc1

Procedure:
Analogously to Example 7, 6.3 g of pyridine-2,5-dicarboxylic acid sodium salt are reacted with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and the mixture is boiled under reflux in acetone for 2.5 hours. After chromatography over silica gel with ethyl acetate as the mobile phase, the product is recrystallized from hot ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)[OH:13]>O>[Cl:11][C:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:13])[NH:3][N:4]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: O
Product: O=C(O)c1cc(Cl)n[nH]c1=O

Procedure:
27 g of 3,6-dichloro-pyridazine-4-carboxylic acid were stirred at 50° C. for 6 h in a. 1:1 mixture of concentrated sulphuric acid and water. The pure product crystallized after cooling off the reaction mixture and was filtered.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)N(CCc2ccccc2)Cc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CCc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 75-76° C. C28H27N3O3F2 (MW=491); mass spectroscopy: 491.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Yield: 98.9 %

Procedure:
The solution of 2-Methyl-5-(2-methyl-4-nitro-phenoxy)-pyridine (6.4 g, 26.2 mmol), 10 wt % Pd/C (0.50 g) in ethanol (100 mL) was stirred under 1 atm hydrogen at rt for 24 h. Then the Pd/C catalyst was removed by filtration through a layer of celite. Removal of the solvent gave the desired product as an off-white solid (5.55 g, 99%). 1H-NMR (DMSO-d6) δ 8.04 (d, J=2.7 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H), 7.02 (dd, J=8.7, 3.1 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 6.42 (dd, J=8.4, 2.8 Hz, 1H), 4.96 (br, 2H), 2.39 (s, 3H), 1.97 (s, 3H). LCMS RT=1.04 min; [M+H]+=215.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCCCO
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c3c1ncn3CCCCO)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Platinum (IV) oxide (3.5 g) was added to a solution of 4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (prepared as described in Example 9 of U.S. Pat. No. 6,664,264, 4.00 g, 15.6 mmol) in trifluoroacetic acid (200 mL), and the mixture was shaken under hydrogen pressure for 2 days on a Parr apparatus. The reaction mixture was concentrated under reduced pressure, carefully diluted with methanol, and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with a solution of 4 M hydrogen chloride in 1,4-dioxane (100 mL) and stirred at ambient temperature for 1 hour, and then 4 M aqueous sodium hydroxide was added to adjust to pH 13. The mixture was transferred to a separatory funnel, and dichloromethane was added. The mixture was shaken and allowed to stand overnight at ambient temperature. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.0 g of 4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol as a white solid.