Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:21]([CH2:22][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][C:18]([OH:20])=[O:19])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.1, starting from commercial 4-chloro-1,2-phenylenediamine and 3-phenylglutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-phenylbutanoic acid•HCl was obtained as light red solid in three steps.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCOCC1>[CH2:14]([O:21][C:22]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 500 mg (4.95 mmol) azetidine-3-carboxylic acid was added 10 mL dioxane and 10 mL H2O and the solution cooled to 0° C. 1.38 g (10 mmol) potassium carbonate was added followed by 0.78 mL (11 mmol) benzylchloroformate, and the reaction stirred at room temperature for 18 hours. The mixture was acidified with 25 mL 1 M HCl, extracted with DCM (2×20 mL), the combined organic layers dried over Na2SO4. After filtration the solvent was evaporated to give the desired product which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:27])[F:29])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCNC2)CC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC[C@@H](n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 104 %

Procedure:
Combine 4-[(R)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1-piperidin-3-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.49 mmol; 741 mg); formaldehyde (5 equiv; 7.46 mmol; 560 μL); sodium triacetoxyborohydride (2 equiv; 2.98 mmol; 632 mg) and THF (25 mL) and stir at 20° C. for 20 min. Dilute with EA, wash the organic phase 2× with saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate to provide the title compound (790.3 mg; 1.55 mmol; 104%). MS (ES+): m/z=511 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=O)[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[C:20](O)(=O)C.[NH2:24][NH2:25]>O>[NH:24]1[CH:20]=[N:13][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=[C:2]3[Br:1])=[N:25]1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: NN
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nc[nH]n3)cc12
Temperature: 80 °C
Yield: 93 %

Procedure:
The title compound was prepared by reacting 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (15.13 g, 46.67 mmol) with N,N-dimethylformamide dimethlyl acetal (134 mL) and heating to 80° C. for 3 hours. The reaction was allowed to cool to room temperature, and condensed to a brown oil that was exposed to atmospheric conditions minimally. To the crude oil was added glacial acetic acid (220 mL) and hydrazine (23 mL), and then the mixture was heated to 115° C. for 1.5 hours. The reaction was allowed to cool to room temperature, and subsequently added to water (500 mL) resulting in the formation of a white precipitate which was filtered and dried in a vacuum oven (15.05 g, 93% yield): ES-MS (m/z) 350 [M+1]+.
Reaction SMILES: C(O[C:4]([NH:6]/[C:7](/[C:14]([F:17])([F:16])[F:15])=[CH:8]\[C:9]([O:11]CC)=O)=[O:5])C.[CH:18]([NH2:21])([CH3:20])[CH3:19].O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH:18]([N:21]1[C:9](=[O:11])[CH:8]=[C:7]([C:14]([F:15])([F:16])[F:17])[NH:6][C:4]1=[O:5])([CH3:20])[CH3:19]
Reactant: CCOC(=O)/C=C(\NC(=O)OCC)C(F)(F)F
Reactant: CC(C)N
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Yield: 61 %

Procedure:
A stirred mixture of ethyl 3-[(ethoxycarbonyl)amino]-4,4,4-trifluorocrotonate, (Z)-(2.04 g, 8 mmol), isopropylamine (0.567 g, 9.6 mmol), and 1,8-diazabi-cyclo[5,4,0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 100° C. for 3 hours, cooled, and diluted with ethyl acetate. Water is added, and the resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a solid. The solid is crystallized from methanol/water to give the title product as a solid (1.08 g, 61% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1

Procedure:
15 g of 2-tert-butyl-4-piperazin-1-yl-6-propyl-pyrimidine (57.2 mmol), 9 g of 1-bromo-3-chloropropane (57.2 mmol), 8.7 g of triethylamine (86.2 mmol) in 200 ml of acetonitrile were heated to reflux for 3 h. The precipitate was filtered off and the remaining filtrate evaporated to dryness. The thus obtained crude product was purified by chromatography on silica gel with dichloromethane/methanol (0-5%). Yield: 6 g (31%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61](Cl)(=[O:63])=[O:62])([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])(=[O:63])=[O:62])([O-:54])=[O:53]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 48 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 2-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 48% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][S:6][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][C:8]([C:7]2[S:6][CH2:5][CH2:4][O:3][C:2]=2[CH3:1])=[O:10])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: N#Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cccc(C#N)c2)SCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
5,6-Dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.0 g, 0.031 mole) and thionyl chloride (4.1 g, 0.034 mole) were heated under reflux in methylene chloride for about 2 hours, then evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride and the chilled solution treated dropwise with a solution of 3-aminobenzonitrile (3.7 g, 0.031 mole) and triethylamine (3.2 g, 0.032 mole) in methylene chloride. The reaction mixture was stirred at room temperature for a further 3 hours and then worked up by washing with dilute hydrochloric acid and dilute sodium hydroxide. Evaporation of the solvent gave a solid residue, which was recrystallized from methanol to give a white solid, m.p. 119°-121° C. (5.5 g, 67% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NC[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])C>CN(C)C1C=CN=CC=1.ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)OCCN(C)C)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a mixture of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-carboxypent-1-yl]oxy-4-methylphenyl]benzamide (250 mg), 2-dimethylaminoethyl (99 mg) and 4-dimethylaminopyridine (36 mg) in dichloromethane (10 ml) was added N-ethyl-N'-(3-dimethylaminoprop-1-yl)carbodiimide hydrochloride (71 mg) at 0° C. and stirred at the same temperature for 7 hours. The mixture was diluted with chloroform (20 ml) and the solution was washed with water (20 ml×2) and brine. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. This residue was purified by silica gel column chromatography (SiO2 30 g, 1-10% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(2-dimethylaminoeth-1-yl)oxycarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (238 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([OH:10])[CH3:9])[CH2:3]1.COC([CH2:16][CH2:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])=O.CC[O-:25].[Na+].O>CO.C1(C)C=CC=CC=1>[CH3:11][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:16](=[O:25])[CH2:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH3:9])[CH2:3]1
Reactant: CC[O-]
Reactant: CC(O)C1CCCC(C)(C)C1
Reactant: COCC(=O)CCC(=O)OC
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COCC(=O)CC(=O)OC(C)C1CCCC(C)(C)C1

Procedure:
78 g (0.5 mol) of 1-(3,3-dimethyl-cyclohexyl)-ethanol, 80.3 g (0.55 mol) of 4-methoxy-3-oxo-butanecarboxylic acid methyl ester and 0.6 g sodium ethylate in 50 g methanol were placed in a 500-ml stirred vessel and boiled under reflux, distilling-off the methanol via a still head. Then 100 ml water and 100 ml toluene were added to the reaction solution at room temperature, the aqueous phase was separated, the organic phase was washed with water until neutral and concentrated by evaporation. The raw product (136 g) was fractionated on a 30-cm Vigreux column in vacuum.
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].CC(C)=O.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([NH:7][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH2:1][OH:8])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(CO)(CO)CO
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)NC(CO)(CO)CO

Procedure:
66.6 g (0.55 mol) of tris(hydroxymethyl)aminomethane are dissolved in 200 ml of distilled water, and 400 ml of acetone are added. 59.6 g (0.5 mol) of phenyl isocyanate are added dropwise, while stirring, whereupon a heavy white precipitate forms. When the addition has ended, the mixture is stirred for a further 2 hours and the precipitate is filtered off with suction. It is then digested successively with in each case 150 ml of water, acetone and diethyl ether. Finally, the compound (11), which is obtained in virtually analytically pure form, is dried at 75.C.
Reaction SMILES: [CH2:1]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:28].[Na+].[OH2:33]>CO>[CH2:1]([S:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=1)(=[O:28])=[O:33])[CH2:2][CH2:3][CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: CCCCSCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: CCCCS(=O)(=O)CCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 3.8 g. of 4-[11-(n-butylthio)undecylamino]benzoic acid and 11 g. of sodium metaperiodate in 50 ml. of water and 200 ml. of methanol is stirred under reflux for 24 hours and filtered while hot. The filtrate was allowed to cool and then extracted with methylene chloride. The extract is dried over magnesium sulfate and evaporated to yield a solid. Recrystallization from acetone-chloroform affords the product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(C)(=O)=O
Yield: 74.1 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.17 mmol) was reacted with methanesulfonyl chloride (172 μL, 2.17 mmol) to provide 720 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as a yellow powder, m.p. 109-110° C. Analysis: Calculated for C22H33N5O3S: %C, 59.04; %H, 7.43; %N, 15.65; Found: %C, 58.78; %H, 7.38; %N, 15.48.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].C[C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1.[C:29](=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH3:27][C:25]1[CH:24]=[C:23]([O:28][CH2:1][C:2]([CH3:19])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH:22]=[CH:21][C:26]=1[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C)cc(O)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C(C)(C)COc1ccc(C)c(C)c1
Temperature: 170 °C
Yield: 52.6 %

Procedure:
A reaction vessel was charged with methyl 2,2-dimethyl-3-tosyloxypropionate (Intermediate A7, 100 g, 0.35 mol), 3,5-dimethylphenol (45 g, 0.37 mol), potassium carbonate (73 g, 0.53 mol), and dimethylacetamide (300 mL). The mixture was heated on a steam bath for 16 hr and in a 170° C. bath for 6 hr. The cooled reaction mixture was diluted with 1 L water and extracted with 2×200 mL portions of ethyl acetate. The combined organic layers were washed with water, 0.5 M sodium hydroxide (twice), water, and saturated aqueous sodium chloride. The solvent was removed at aspirator pressure and high vacuum. The residue was taken up in dichloromethane and washed with several portions of 1 M sodium hydroxide, water, and saturated sodium chloride. The solution was concentrated, and the residue was distilled at 2 torr to yield 43.5 g (52%) of the title compound.
Reaction SMILES: [O:1]([CH2:8][CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][C:22]1[C:23](O)=[N:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].ON1C2C=CC=C[C:35]=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[O:1]([CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:20][CH2:21][C:22]2[C:23]([CH3:35])=[N:24][C:25]([CH3:29])=[CH:26][C:27]=2[CH3:28])=[O:17])=[CH:18][CH:19]=1)[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(COc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)COc3ccccc3)cc2)c(C)n1
Yield: 77.2 %

Procedure:
A mixture solution of 4-(1-phenoxypropan-2-yl)benzoic acid (60 mg, 0.2 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (37 mg, 0.2 mmol), 1-Hydroxybenzotriazole (30 mg, 0.2 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.2 mmol) and triethylamine (0.1 mL) in dichloromethane (50 mL) was stirred at room temperature for 18 hours. The mixture solution was diluting with ethyl acetate (50 mL), washed with water (20 mL). The organic layer was concentrated to dry. The residue was purified by column chromatography (silica-gel, dichloromethane/methanol=30:1) to give 4-(1-phenoxypropan-2-yl)-N-((2,4,6-trimethylpyridin-3-yl)methyl)benzamide as a yellow solid (60 mg, 64%). LRMS (M+H+) m/z: calcd 391.19. found 391.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:49]=[CH:48][C:34]([O:35][CH2:36][C:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>>[C:43]([O:42][C:41]([NH:40][C:37]([CH3:39])([CH3:38])[CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:49][CH:48]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Yield: 91.8 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (58 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (222 mg) according to an analogous synthetic method to Example 212, the title compound (92 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][Cl:20])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][Cl:20])=[N:12][C:7]=3[C:8]([NH2:33])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CC(C)Cn1c(CCl)nc2cnc3cc(Br)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (13.9 g, 39.4 mmol) in chloroform (300 mL) at room temperature was added mCPBA (77% pure, 17.7 g, 78.8 mmol) over ten minutes. The reaction mixture was stirred at room temperature for 3 hours, then concentrated ammonium hydroxide (150 mL) was added, followed by p-toluenesulfonyl chloride (9.00 g, 47.3 mmol, added in portions over 10 minutes). The mixture was stirred at room temperature for 1 hour, then was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered through CELITE filter agent, and concentrated under reduced pressure. The crude product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with ethyl acetate in hexanes) to yield 7.69 g of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow foam.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCCO)c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl palmitate was prepared by the procedure of Example 1 from 16 grams (0.1 mole) of ethylene glycol monobenzoate and 26 gms (0.1 mole) of palmitoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][N:19]=[C:20]2[C:23]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][CH3:34])[CH2:26][CH2:25][CH2:24]2)=[CH:15][C:14]=1[O:35][CH3:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C.Br>CC(O)C.CO>[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][CH:20]2[C:23]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][CH3:34])[CH2:24][CH2:25][CH2:26]2)=[CH:15][C:14]=1[O:35][CH3:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)=NCC2
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)NCC2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Sodium cyanoborohydride (0.8 g) was added to a mixture of 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-3,4-dihydroisoquinoline (2.8 g, prepared as described in Example CA32), acetic acid (20 ml) and methanol (10 ml) at 0° C. and stirred for 60 hours at ambient temperature. The mixture was poured onto water (300 ml) and extracted with dichloromethane. The organic layer was washed with aqueous ammonia solution (100 ml), then brine (100 ml), and dried over magnesium sulphate. The solvent was removed by evaporation to yield a gum. The gum was dissolved in propan-2-ol and treated with excess 48% aqueous hydrobromic acid. Evaporation of the solvent yielded a solid which was triturated with petroleum ether (b.p. 60°-80° C.), then isolated by filtration to give 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.