Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][C:16]([NH-:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[Li+].CC(N)(C)CC(C)(C)C.C([Li])CCC>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:23][C:16]([CH3:22])([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CC(C)(C)CC(C)(C)[NH-]
Agent: CC(C)(C)CC(C)(C)N
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
In an argon atmosphere, a solution obtained by dissolving 5.14 g (22.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl in 10 mL of hexane was added to a lithium(1,1,3,3-tetramethylbutylamide) solution prepared by adding 10 mL of hexane and 2.94 g (22.8 mmol) of 1,1,3,3-tetramethylbutylamine to 13.8 mL (22.8 mmol) of a hexane solution (concentration: 1.65 mol/L) of butyllithium and stirring the mixture at room temperature for 14 hours, and the resulting mixture was stirred at room temperature for 24 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was sublimated (heating temperature: 180° C./64 Pa) to obtain 1,3-di-tert-butyl-2-(1,1,3,3-tetramethylbutyl)amino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHtOct) as a white solid (yielded amount: 5.85 g, yield: 81%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:34]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (9.38 g, 19.5 mmol) in ethanol (150 mL) was added to a Parr vessel containing 10% palladium on carbon (0.83 g). The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) over two rights. Starting material remained as evidenced by a TLC analysis, and additional 10% palladium on carbon (1.02 g) was added. The reaction was continued for an additional eight hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol and methanol. The filtrate was concentrated under reduced pressure, and the residue was several times dissolved in toluene and concentrated under reduced pressure to yield a yellow powder, which was dried under high vacuum to provide 7.37 g of N-[2-(2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[CH:13][N+:14]([O-:16])=[O:15])=[CH:5][N:6]=1.[CH:17](=[O:22])[CH2:18][CH2:19][CH:20]=O.Cl>C(#N)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:9]3=[C:13]([N+:14]([O-:16])=[O:15])[CH:20]4[O:22][CH:17]([N:10]3[CH2:11][CH2:12]2)[CH2:18][CH2:19]4)=[CH:5][N:6]=1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1cnc(Cl)s1
Reactant: O=CCCC=O
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3cnc(Cl)s3)CCN2C2CCC1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a 50 ml round bottom flask was added 1.30 g (0.005 mol) 1-((2-chlorothiazol-5-yl)methyl)-2-(nitromethylene)imidazolidine, 30 ml dry acetonitrile, 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 63% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C=O.[C:23](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:23])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1OC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1OC
Yield: 82.3 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-[(oxan-4-yl)amino]benzoate (500 mg, 1.67 mmol) in 1,2-dichloroethane (16 ml) at room temperature under nitrogen was added paraformaldehyde (300 mg, 10 mmol) followed by acetic acid (0.57 ml, 10 mmol). This mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.12 g, 10 mmol). After stirring for 64 hours deionized water (30 ml) was added and the mixture was neutralized with solid NaHCO3 and the phases were separated. The aqueous layer was extracted with EtOAc (3×15 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 431 mg (82%) of the title compound as a colorless oil. LC-MS 98%, m/z=314.0/316.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.30 (d, J=2.5 Hz, 1H), 7.04 (d J=2.5 Hz, 1H), 4.00 (dd, J=11.3, 4.3 Hz, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.70 (ddt, J=11.7, 7.7, 3.8 Hz, 1H), 3.39 (t, J=11.1 Hz, 2H), 2.71 (s, 3H), 1.84 (qd, J=12.3, 4.6 Hz, 2H), 1.66-1.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][OH:12])=[N:6][CH:7]=1.[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:15][C:16]1[C:17]([O:12][CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1
Reactant: Cc1ncc(Br)c(Cl)n1
Reactant: Cc1ccc([C@H]2C[C@@H]2CO)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol (1.58 g, 9.7 mmol) in THF (25 mL) was added sodium hydride (466 mg, 11.6 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. Next, a solution of 5-bromo-4-chloro-2-methylpyrimidine (2.0 g, 9.7 mmol) in THF (10 mL) was added and the reaction mixture was stirred at ambient temperature for two hours. Aqueous sodium bicarbonate (20 mL) was carefully added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated to the resulting residue, which was purified by column chromatography on silica gel (10% to 50% EtOAc in hexanes) to afford the title compound as a yellow solid. LC/MS m/z=334.1 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)(O)=[O:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:2]
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 578.2 g of 4-carboxy-1-ethoxycarbonylpiperidine in 1200 ml of toluene is treated firstly with 1.0 g of N,N-dimethylformnamide and then, at from 68 to 70° C. and within the space of 2 hours, with 369.0 g of thionyl chloride. The mixture is subsequently stirred at 70° C. for a further 30 min, after which the toluene is distilled off in vacuo and the residue is then degassed at RT for approximately 30 min under HV. This results in the title compound in the form of a weakly yellow oil [IR (Film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1 ]. The product distils without decomposition at a m.p. of 96-98° C. (0.08-0.09 Torr).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][OH:14])=[O:4].CC(C)([O-])C.[K+]>CC(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:14][CH2:13][C:7]=2[CH:8]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1COCc2cc(Cl)ccc2N1
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
To a suspension of 2-bromo-N-(4-chloro-2-(hydroxymethyl)phenyl)acetamide (3.60 g, 12.9 mmol) in 2-propanol (129 ml) was added in small portions potassium tert-butoxide (3.77 g, 33.6 mmol) at 0-5° C. The reaction mixture was stirred for 90 minutes and then poured on ice/water (500 ml). The precipitate was collected by filtration and washed with water. Residual water was removed by evaporation of two 50 ml-portions of toluene to give the title compound (2.34 g, 92%) as light yellow solid. MS m/e: 196 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.CO>C(Cl)Cl>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1
Reactant: OCCC1CNC1
Reactant: Fc1ccccn1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC1CN(c2ccccn2)C1
Temperature: 150 °C

Procedure:
2-(Azetidin-3-yl)ethanol (4.92 mmol, 0.498 g), 2-fluoropyridine (9.85 mmol, 0.846 ml, 0.956 g), triethylamine (14.77 mmol, 2.053 ml, 1.495 g) and methanol (2.5 ml) were combined and heated to 150° C. in a microwave for 40 minutes. TLC analysis showed some starting material remained and therefore the solution was heated for a further 40 minutes. The resulting solution was dissolved in DCM (c. 20 ml) and washed with water. Solvent was removed under reduced pressure to yield a crude product. This was then purified by flash chromatography (10 g silica column, DCM to 3% MeOH in DCM gradient). Appropriate fractions were combined and solvent removed under reduced pressure to give final product. 1H NMR (CDCl3) δ: 8.17 (d, 1H), 7.42 (t, 1H), 6.57 (t, 1H), 6.26 (d, 1H), 4.16 (t, 2H), 3.70 (m, 4H), 2.88 (m, 1H), 1.95 (q, 2H).
Reaction SMILES: [CH2:1]1[O:23][P:21]([OH:24])(=[O:22])[O:20][C@H:3]2[C@@H:4]([OH:19])[C@H:5]([N:7]3[C:17](Br)=[N:16][C:9]4[C:10]([N:12]=[C:13]([NH2:15])[NH:14][C:8]3=4)=[O:11])[O:6][C@H:2]12.C1C=C(N2C(=S)S/C(=C\C3C=CC(C(O)=O)=CC=3)/C2=O)C=C(C(F)(F)F)C=1>>[CH:17]1[N:7]([C@@H:5]2[O:6][C@@H:2]3[CH2:1][O:23][P:21]([OH:24])([O:20][C@H:3]3[C@H:4]2[OH:19])=[O:22])[C:8]2[NH:14][C:13]([NH2:15])=[N:12][C:10](=[O:11])[C:9]=2[N:16]=1
Reactant: Nc1nc(=O)c2nc(Br)n([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Agent: O=C(O)c1ccc(/C=C2\SC(=S)N(c3cccc(C(F)(F)F)c3)C2=O)cc1
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1

Procedure:
The result shown in FIG. 21 demonstrate that 8-Br-cGMP increases JV across hfRPE monolayers from 6.0 to 19.5 μl·cm−2·hr−1. This can be blocked by the addition of CFTR inhibitor CFTRinh-172, and a reduction in Jv from 19.5 to 11.5 μl·cm−2·hr−1 is observed. In four experiments, an increase in Jv from 7.4±1.1 to 15.8±1.6 μl·cm−2·hr−1 was observed, and addition of CFTR inhibitor reduced the increase in Jv to 8.9±1.3 μl·cm−2·hr−1.
Reaction SMILES: [OH:1][CH:2]([C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3](N)=[O:4].[CH2:20]([OH:22])[CH3:21]>O>[OH:1][CH:2]([C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([O:22][CH2:20][CH3:21])=[O:4]
Reactant: CCO
Reactant: CC(c1ccccc1)(c1ccccc1)C(O)C(N)=O
Solvent: O
Product: CCOC(=O)C(O)C(C)(c1ccccc1)c1ccccc1

Procedure:
2.15 g (8.4 mmol) of 2-hydroxy-3,3-diphenylbutyramide were dissolved in 15 ml of ethanol, 15 ml of conc. HCI were added and the mixture was refluxed for 40 hours. The solvent was stripped off under reduced pressure, and the residue was taken up in water. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed twice with 10% strength sodium hydroxide solution. Drying with MgSO4 and stripping off the solvent under reduced pressure resulted in 1.75 g (73%) of ethyl 2-hydroxy-3,3-diphenylbutyrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH2:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[C:27]=1[CH:28]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])/[C:10](/[S:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:28]\[C:27]2[C:30]([O:36][CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[O:25][CH3:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)c2ccc(OC)cc2)cc1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Product: COc1ccc(CS(=O)(=O)/C(=C/c2c(OC)cc(OC)cc2OC)C(=O)c2ccc(OC)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-methoxyphenyl)-2-(4-methoxybenzylsulfonyl)ethanone (10 mmol) and 2,4,6-trimethoxybenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography. m.p. 60-62° C.
Reaction SMILES: OO.[C:3]1([C:9]2[S:10][C:11]([C:15](=[S:17])[NH2:16])=[C:12]([NH2:14])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[NH2:16][C:15]1[S:17][N:14]=[C:12]2[N:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[S:10][C:11]=12
Reactant: NC(=S)c1sc(-c2ccccc2)nc1N
Agent: OO
Solvent: CO
Product: Nc1snc2nc(-c3ccccc3)sc12
Temperature: 22 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
7 parts of 30 percent strength by weight hydrogen peroxide are added to 12.8 parts of 2-phenyl-4-amino-5-thiocarbamoylthiazole in 150 parts of methanol. The mixture is stirred for 12 hours at 22° C. and the product is then filtered off. 7.9 parts of 3-amino-5-phenyl-thiazolo-(4,5-c)-isothiazole (62% of theory) of melting point 176°-179° C. are obtained.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Reactant: CCC(O)[C@H](N)CC
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)[C@@H](CC)Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4R)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 11 mg (41%). (57% de 4R,3S: 43% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.85-1.06 (m, 6H, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.57 (d, 6H, J=6.79 Hz, & —CH(CH3)2), 1.42-1.65 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.31 Hz, OH), 3.57-3.70 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.91-4.03 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3) OH), 4.57-4.76 (m, 1H, —CH(CH3)2), 4.86-4.98 (m, 2H, —HNCH2-Pyr), 5.18-5.29 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 6.73-6.89 (m, 1H, —HNCH2-Pyr), 7.15-7.25 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.90 Hz, Pyr-H), 7.56 (s, 1H, —N═CH—N—), 7.63-7.70 (m, 1H, Pyr-H), 8.60 (d, 1H, J=4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (35), 307 (37), 297 (25), 289 (20). Accurate Mass (M+H): Actual: 384.2512 Measured: 384.2523.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: Cc1ccccc1-c1ccc(C=O)cc1
Product: Cc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Methyl[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][C:15]([CH2:18][OH:19])([OH:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[OH:19][CH2:18][C:15]1([OH:17])[CH2:14][CH:13]2[NH:8][CH:9]([CH2:10][O:11][CH2:12]2)[CH2:16]1
Reactant: OCC1(O)CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCC1(O)CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 9-benzyl-7-hydroxymethyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound V) (0.080 g, 0.30 mmol) and Pd/C (20 mg) in MeOH (2 mL) was stirred under H2 at room temperature overnight. The mixture was filtered and the filtrate was concentrated to give Compound S (0.040 g, 77.0%). LC/MS: calc'd 174 (MH+), exp 174 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1.ClC1C=CC=CC=1C(=O)CN1C=NN=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:15])[CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1
Reactant: O=C(Cn1ncnn1)c1ccccc1Cl
Agent: O=C(Cn1cnnn1)c1ccccc1Cl
Product: O[C@@H](Cn1ncnn1)c1ccccc1Cl

Procedure:
The same procedure as in Preparation Example 3 was repeated, with the exception that 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one, prepared in Preparation Example 2, was used instead of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one, to afford (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter referred to as “2N alcohol”). The conversion rate and optical purity of the product are given in Table 1, below.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:9][C:8]=2[N:7]=1.C(N(CC)CC)C>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:30][O:31][CH2:32][CH3:33])[N:18]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:21])[CH3:22])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:1](=[O:3])[CH3:2])=[CH:9][C:8]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.6 %

Procedure:
Acetyl chloride (180 μL, 2.53 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 1.18 g, 2.30 mmol) and triethylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0° C. After approximately 20 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The solution was transferred to a separatory funnel and washed with water (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) to yield 0.34 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide as a tan solid, mp 90-110° C.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10](O)([CH3:13])([CH3:12])[CH3:11].ClCCl.[OH:18][C:19]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]1>[Cu]Cl.C(O)(=O)C>[OH:18][C:19]1([C:22]([O:24][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(O)C1(O)CC1
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1(O)CC1
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (48 ml) was added dropwise to a dichloromethane suspension (120 ml) of 1-hydroxycyclopropanecarboxylic acid (17.12 g) using an ice bath over 15 minutes. The temperature was brought back to room temperature, followed by stirring for 40 hours, and then acetic acid (11.5 ml) was added and stirred for 1 hour. The reaction suspension was filtered, and ice water and sodium hydrogen carbonate were added to the filtrate for neutralization. After the precipitate was filtered off, the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After pentane was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to afford tert-butyl 1-hydroxycyclopropanecarboxylate (11.65 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:25]=1[CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:25]=1[CH2:26][N:3]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH2:1][CH3:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCNc1ccc(C(=O)OC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of methyl 6-ethylaminonicotinoate (152 g, 84.4 mmol) in DMF (50 ml) was cooled to 0° C. and treated with sodium hydride (60%. 75 mmol). The reaction was stirred for 1 hour and a solution of 2-benzyloxy-5-bromobenzylbromide (25 g, 70.2 mmol) in DMF (50 ml) added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched with water and extracted with ethyl acetate (three times). The organic layers were combined, washed with water and brine twice, dried (MgSO4) and evaporated to give a white solid. Recrystallisation from ethyl/acetate/hexane gave methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (22.7 g, 71%).