Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:13]1[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:19][CH:20]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCC#Cc1cccc(C=O)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC#Cc1cccc(/C=C/C(=O)OCC)c1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of 3-(1-dodecynyl)benzaldehyde (23.0 g) in toluene (150 ml) was added carbethoxymethylenetriphenylphosphorane (35.5 g) in one portion. The mixture was warmed at 80° C. for 5 hr, allowed to cool to room temperature, and concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with ethyl acetate/hexane/1:15). The appropriate fractions were collected and evaporated to afford 21.1 g (73%) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[C:34](OC(=O)C)(=[O:36])[CH3:35].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:30]1[CH:29]=[CH:28][C:27](=[O:33])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:18]3[N:14]([CH2:13][C:11]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH:12]=4)[O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH:15]=[N:16][CH:17]=3)=[CH:25][N:24]=2)[CH:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 50 mg, 0.11 mmol) was dissolved in CH2Cl2 (550 tl) and treated with acetic anhydride (208 μl, 0.22 mmol). DIEA was then added until pH=7-8. The reaction mixture was stirred at room temp. for 2 hours. Saturated NaHCO3 was added (10 mL) and the solution was extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to yield the final product.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2>CO>[ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.25 M HCl in MeOH (3.0 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (32 mg, 0.060 mmol), and the resulting solution was stirred under N2 at ambient temperature for 18 h. The solution was concentrated under reduced pressure, the resulting residue was diluted with MeOH (1 mL) and Et2O (10 mL), and the solids were collected by filtration to provide the title compound (31 mg, quant.) as a yellow powder: mp 310-314° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 2H), 9.15 (dd, J=1.0, 1.0 Hz, 1H), 8.41-8.35 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (dd, J=7.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.42-3.40 (m, 2H), 3.36-3.32 (m, 2H), 3.30-3.28 (m, 2H, overlaps with H2O), 3.17 (t, J=6.5 Hz, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 98.83% (AUC), tR=13.9 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:26]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:27][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: BrCCc1cccc2ccccc12
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][S:10]([CH3:9])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CCCC1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1CCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-methylcyclopentanamine hydrochloride (0.100 g, 0.7 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.100 g, 84%). The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#N.Br[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1.Cl.CC[O:22]CC>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([C:16]1[CH:17]=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=1)=[O:22]
Reactant: CCOCC
Reactant: COc1ccccc1C#N
Reactant: Cc1cccc(Br)c1
Agent: Cl
Product: COc1ccccc1C(=O)c1cccc(C)c1

Procedure:
A mixture of 2-methoxybenzonitrile (4.3 ml) and the Grignard reagent of m-bromotoluene (6.6 g) in ether was refluxed for 1 h and hydrolysed with dilute hydrochloric acid with heating. The aqueous layer was then extracted with ether, and the resultant organic layer was dried and evaporated to give the title compound (5.5 g) as an oil.
Reaction SMILES: S1[CH:5]=[C:4]([CH2:6][C:7](O)=O)N=C1.S1[CH:14]=[C:13]([C:15](O)=O)N=C1.CO.[C:20](OCC)(=O)[CH3:21]>>[CH3:7][CH2:6][CH2:4][CH2:5][CH2:15][CH2:13][CH2:14][CH2:20][CH3:21]
Reactant: O=C(O)Cc1cscn1
Reactant: O=C(O)c1cscn1
Reactant: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCC

Procedure:
Following the procedure of Example 1, 2- 4-fluorobenzoyl!amino!-4-thiazoleacetic acid (1.10 g, 3.93 mmol) was allowed to react with N-(4-aminobutyl)-3-azabicyclo 3.2.2.!-nonane (0.77 g, 3.13 mmol) for 24 hours to give after flash column chromatography on silica gel eluting with 15% methanol in ethyl acetate, the title compound (0.79 g, 57%). The hydrochloride salt was prepared with ethereal HCl to give a tan powder after recrystallization from ethyl acetate and hexane: m.p. 220°-222° C.
Reaction SMILES: [CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]2[OH:18])[C:8]2[C:3](=[C:4]([NH2:19])[N:5]=[CH:6][N:7]=2)[C:2]=1[C:20]#[N:21].[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[NH2:19][C:4]1[C:3]2[C:2]([C:20]#[N:21])=[CH:1][N:9]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]([O:17][S:41]([CH3:40])(=[O:43])=[O:42])[C@H:11]3[O:18][S:41]([CH3:40])(=[O:43])=[O:42])[C:8]=2[N:7]=[CH:6][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cc(C#N)c3c(N)ncnc32)[C@H](OS(C)(=O)=O)[C@@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a stirred solution of toyocamicin 43 (5.83 g, 20.0 mmol) in anhydrous pyridine (100 mL) at 0° C. was added tert-butylchlorodiphenylsilane (6.2 mL, 24.0 mmol). The resulting mixture was stirred at room temperature for 18 h and then cooled to 0° C., and methanesulfonyl chloride (3.4 mL, 44.0 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, cooled with ice, quenched by adding water (2 mL), and stirred at room temperature for 30 min. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with brine three times, dried (Na2SO4) and concentrated. Chromatography on silica (ethyl acetatehexanes 3:2) gave 8.41 g of the titled compound as a colorless solid.
Reaction SMILES: C1(C)C=CC=CC=1.Br/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C([Sn](CCCC)(CCCC)/[CH:31]=[CH:32]/[CH:33]([O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC.C(OCC)C>CCCCCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:25]=[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1/[CH:10]=[CH:9]/[CH:31]=[CH:32]/[CH:33]([O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCCCCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)OC1CCCCO1
Reactant: COC(=O)CCCC(=O)c1ccccc1/C=C/Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCC(/C=C/C=C/c1ccccc1C(=O)CCCC(=O)OC)OC1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
To 1ml of toluene was added 0.1g (0.35 mol) of the product of Example 4, 0.11g (0.38 mmol) of the product of Example 9, and 5.0mg of tetrakis(triphenylphosphine)palladium(O). The solution was degassed with argon and then heated at reflux under argon for approximately 5 hours. The reaction mixture was then cooled to room temperature and flash chromatographed. Gradient elution with hexane, 1% diethyl ether in hexane, 5% diethyl ether in hexane, and 10% diethyl ether in hexane produced 0.90mg (0.19 mmol) of the titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].[C:42](O)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:42]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2cccnc2)c1
Temperature: 75 °C
Yield: 74.5 %

Procedure:
A stirred solution containing 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.508 g, 0.863 mmol), nicotinic acid (0.108 g, 0.863 mmol), 2-chloro-1-methylpyridinium iodide (0.272 g, 1.04 mmol) and triethylamine (0.288 mL, 2.07 mmol) in CH2Cl2 (8.63 mL) was heated at 75° C. in a sealed tube for 3 days. The reaction was cooled to ambient temperature and concentrated. The crude product was purified on Biotage KP-Sil eluting with a 10 & 15% acetone/hexane step gradient to give 0.446 g (74%) of the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.58 (s, 3 H), 2.18 (s, 6 H), 2.35 (s, 3 H), 7.18 (s, 2 H), 7.36-7.46 (m, 3 H), 7.68-7.72 (m, 1 H), 7.98 (d, 1 H), 8.15 (dd, 1 H), 8.22-8.26 (m, 2 H), 8.50-8.53 (m, 2 H), 8.95 (dd, 1 H), 9.30 (d, 1 H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23](NC)[N:24]=[CH:25]2)=CC=1>>[CH3:25][NH:24][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: CNc1cc2ccc(Br)cc2cn1
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Product: CNc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromo-N-methylisoquinolin-3-amine. +ESI (M+H) 203.1; 1H NMR (400 MHz, CD3OD, δ): 8.87 (s, 1H), 8.51 (s, 1H), 7.98 (dd, J=8.88, 1.66 Hz, 1H), 7.58 (d, J=8.78 Hz, 1H), 6.60 (s, 1H), 2.93 (s, 3H).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH:5]4[CH2:7][CH2:6]4)=[O:11])=[CH:14][N:15]=3)=[C:25]([CH3:26])[O:24][N:23]=2)=[CH:32][CH:31]=1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of cyclopropanemethylamine (0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (56 mg, 70%) which was obtained as a white solid. MS: m/e=398.4 [M+H]+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>CO.O1CCCC1.C(O)=O>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:24]
Reactant: NCc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C=NCCCl
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(NCCCl)N(Cc1ccccc1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of 3.0 g of L-arabinose, 4.3 g of benzylamine and 10 ml of methanol is heated at 60° C. for one hour under stirring. After the reaction, the mixture is condensed to dryness under reduced pressure and the residue is washed with ether, whereby 4.7 g of 1-benzylamino-1-deoxy-L-arabinose are obtained as a crude product. 4.7 g of said crude product are dissolved in 30 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise thereto at 0° to 5° C. The solution is stirred at room temperature for one hour. Then, the reaction solution is condensed under reduced pressure, and the residue thus obtained is dissolved in 15 ml of formic acid. The formic acid solution is allowed to stand at room temperature for 15 minutes, and 150 ml of ether-n-hexane (3:1) are added thereto. The resultant oil is collected by decantation, washed with ether and then purified by silica gel chromatography (Solvent: chloroform-ethyl acetate-methanol (2:5:1)). 6.2 g of 1-(2-chloroethyl)-3-benzyl-3-(L-arabinopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[O:33][C:34]1[NH:38][C:37]([C:39](Cl)=[O:40])=[CH:36][CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[O:33][C:34]1[NH:38][C:37]([C:39]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])=[CH:36][CH:35]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)[nH]1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)[nH]3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-1H-pyrrole-2-carbonyl chloride: ESMS m/e: 634.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4]C.ClCCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CC)=NC=2N.N1CCCCC1.CO>ClCCl>[CH3:28][O:27][C:12]1[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:29])[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH3:4])[N:15]=2
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Agent: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 9-(5-chloropentyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine but with purification on silica using a 0-25% methanol in dichloromethane gradient.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[N:10][O:11][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(C=NOCc2ccc(CC(=O)O)cc2)cc1

Procedure:
The title compound was prepared as a white solid (0.193 g, 41%) from 4-tert-butyl-benzaldehyde oxime and 4-bromomethyl-phenyl-acetic acid using a procedure similar to example 2. mp=93.3-96.2° C.; mass spectrum (−APCI, M−H) m/z 324. 1H NMR (400 MHz, DMSO-d6); δ 12.30 (bs, 1H), 8.23 (s, 1H), 7.52 (d, 2H), 7.42 (d, 2H), 7.33 (d, 2H), 7.24 (d, 2H), 5.10 (s, 2H), 3.55 (s, 2H), 1.25 (s, 9h). Elemental analysis: Calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30, Found: C, 73.15; H, 7.14; N, 4.01.
Reaction SMILES: [CH3:1]N(C)CCNC.[Li]CCCC.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI>C1COCC1.CCCCCC>[CH3:1][C:23]1[CH:24]=[CH:25][CH:26]=[C:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:20]=1[CH:21]=[O:22]
Reactant: O=Cc1ccccc1N1CCCCC1
Reactant: CNCCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cccc(N2CCCCC2)c1C=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Reactant: C1CCNC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid (E89) (0.201 mg, 0.55 mmol)), 1,3-diisopropylcarbodiimide (44 μl, 0.6 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.6 mmol) were dissolved in a mixture of dichloromethane (2 ml) and dimethyl formamide (1 ml). After stirring at room temperature for 0.5 hours, pyrrolidine (41 μl, 0.5 mmol) was added and the resulting mixture was allowed to stir for 16 hours. The crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E90); MS (ES+) m/e 419 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:20][Cl:21].C([O-])([O-])=O.[K+].[K+]>>[ClH:21].[ClH:21].[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26])[CH2:20][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1N1CCN(Cc2cc(OC)c(OC)c(OC)c2)CC1
Product: Cl
Yield: 112.3 %

Procedure:
3.85 g of N-(2-methoxyphenyl)-piperazine, 4.33 g of 3,4,5-trimethoxybenzyl chloride and 3.5 g of K2CO3 are reacted and processed according to example 2. 5.0 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-methoxyphenyl)-piperazine dihydrochloride is obtained.