Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(S(O)(=O)=O)=CC=CC=1.C1C=CC=CC=1>[CH2:9]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: Oc1ccc(SCc2ccccc2)cc1

Procedure:
4-(Benzylthio)phenol was prepared as follows. Seventy grams of 4-mercaptophenol, 30 drops of toluene sulfonic acid and 100 milliliters of benzene were placed in a flask. Eighty-three grams of benzyl alcohol were added and the flask contents stirred at reflux for five hours to collect the water formed. A white substance precipitated from solution and was filtered. It was washed with hexane. The substance had a melting point of 96° C. to 98° C., a percent sulfur of 14.4 and a hydroxyl number of 259.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][CH2:21][CH2:22][C:23]#[CH:24]>>[CH3:19][O:20][CH2:21][CH2:22][C:23]#[C:24][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Reactant: C#CCCOC
Product: COCCC#Cc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of bromide 57 with 4-methoxybut-1-yne gave tert-butyl 3-(3-(4-methoxybut-1-ynyl)phenyl)propylcarbamate as yellow oil. Yield (0.83 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (m, 2H), 7.16-7.21 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.51 (bs, 1H), 3.60 (t, J=7.8 Hz, 2H), 3.41 (s, 3H), 3.10-3.16 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.76-1.84 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+]>C(O)C>[CH2:11]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(=O)O)cn1
Yield: 59.8 %

Procedure:
Separately, 5 g of 6-hydroxypyridine-3-carboxylic acid and 10 g of n-octyl bromide were dissolved in 50 ml of ethanol, 50 ml of a 3N aqueous solution of potassium hydroxide was added to the solution, and the mixture was refluxed for 24 hours. Ethanol was removed from the reacted liquid by distillation, and the residue was neutralized with dilute hydrochloric acid and extracted with ethanol. The excess of n-octyl bromide was separated from the extract by the silica gel column chromatography using n-hexane as the developing solvent. Recrystallization from a mixed solvent of hexane and chloroform gave 5.4 g of 6-octyloxypyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC#CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCC#CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of dec-3-yn-1-ol (1.54 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.2 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (150 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-dec-3-yne (1.57 g, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, d, J=7.2 Hz), 2.70 (2H, m), 2.14 (2H, m), 1.20–1.55 (8H, m), 0.88 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 82.89, 77.05, 31.62, 30.68, 29.06, 28.78, 23.65, 22.86, 18.99, 13.38.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]3[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]3[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of methyl 1-[(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylate (Example 18) (130 mg, 0.31 mmol) in 1,4-dioxane (33 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (25 mg, 0.60 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. Further lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added and the mixture stirred for 3 hours. The mixture was then treated with hydrochloric acid (2M), diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCb to afford the title compound as a foam (110 mg).
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[C:13]1([C@@H:19]2[CH2:21][C@H:20]2[C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:22]([C@@H:20]3[CH2:21][C@H:19]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:23])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CC(N2CCNCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirring slurry of 4A (130 mg, 0.610 mmol) in anhydrous DCM (3.5 mL) under an argon (g) atmosphere was added TEA (0.162 mL, 1. 16 mmol). After 1 min. trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.096 mL, 0.55 mmol) was added in one portion to the now clear solution. The reaction was left to stir for ca. 1.5 h at ambient temperature before being washed with H2O (2×2 mL), dilute aq. K2CO3 (1×2 mL), H2O (1×2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was subjected to flash chromatography (basic alumina—8 g; gradient elution: 5% EtOAc/Hexane for 1 min. then 5-55% EtOAc/Hexane over 7 min. at 18 mL/min) to afford 90 mg 4B as a white solid (57% yield). m/z (ES+) M+1=285.2; HPLC tR=1.54 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.80-3.46 (m, 4H), 2.72 (quintet, J=7.9 Hz, 1H), 2.47 (ddd, J=9.0, 6.3, 4.0 Hz, 1H), 2.39-2.25 (m, 4H), 2.08-1.98 (m, 2H), 1.95 (td, J=4.4, 3.7 Hz, 1H), 1.92-1.81 (m, 2H), 1.78-1.59 (m, 3H), 1.27-1.24 (m, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])([CH3:25])[CH2:22][CH2:23][CH3:24])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])([CH3:25])[CH2:22][CH2:23][CH3:24])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCCC(C)(Oc1ccccc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(C)(Oc1ccccc1C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 65.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 0.35 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethysilyloxy-8-[(2RS)-2-(2-methylphenoxy)-2-methylvaleryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 76, above] and 11.1 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.16 g of the title compound as white crystals, melting at between 161° and 163° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:40])[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[NH2:39])=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:39][C:33]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][N:28]=1)=[O:40])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in Example 4-E from 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (2.80 g, 89%).
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([NH:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:5]=2[N:4]=1.N1([C:46](N2C=CN=C2)=[O:47])C=CN=C1.C(N(CC)CC)C.O>O1CCCC1>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([NH:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]4[CH2:30][C:31]([CH3:34])([CH3:32])[O:33][C:46]4=[O:47])[CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:5]=2[N:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOC[C@@H]4C)nc(NC[C@H]4CC[C@H](NCC(C)(C)O)CC4)n3)c2c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOC[C@@H]4C)nc(NC[C@H]4CC[C@H](N5CC(C)(C)OC5=O)CC4)n3)c2c1
Reaction time: 3 h

Procedure:
1-({trans-4-[({4-[2-(Difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}amino)-2-methylpropan-2-ol (100 mg) was dissolved in tetrahydrofuran (2 mL), and di-1H-imidazol-1-ylmethanone (131 mg) and triethylamine (50 μL) were added thereto, followed by stirring for 3 hours while heating and refluxing. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 3-{trans-4-[({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}-5,5-dimethyl-1,3-oxazolidin-2-one (100 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[B:14](OC)([O:17]C)[O:15]C.Cl>C1(C)C=CC=CC=1.CCCCCC.O1CCCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: Fc1ccccc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1cccc(F)c1F
Temperature: -60 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
First, 100 g of 1,2-difluorobenzene and 350 ml of dehydrated tetrahydrofuran were put in an argon-replaced 2 flask, and cooled to −60° C. Then, 700 ml of a hexane solution containing n-butyllithium at a concentration of 1.6 mol/l was dropped into the resultant mixture while being stirred for two hours, and further stirred keeping the same temperature for another two hours. Subsequently, 175 g of trimethyl borate was dropped and stirred keeping the same temperature for one hour. The resultant mixture was left to gradually resume room temperature, stirred for eight hours, and again cooled to 0° C. The resultant reaction solution was poured into dilute hydrochloric acid to acidify the reaction solution. Toluene was then added, and the resultant toluene layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The crystallized residue was immersed in a heated hexane solution and washed, to obtain 80.8 g of 2,3-difluorophenylboronic acid. The purity of the resultant compound was 99.5% as measured by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]CC3C=CC=CC=3)=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13]1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13]1
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Yield: 41.1 %

Procedure:
The benzyl group of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-5-(phenylmethoxy)-1H-indole (15.82 g) was cleaved in a Parr hydrogenation apparatus in absolute ethanol (200 ml) over 10% Pd-C (1.58 g) at 50 psig and 50° C. for 7.5 hours. The catalyst was removed by filtration through a pad of celite and the solids washed with absolute ethanol. The combined filtrate was concentrated and the product purified via preparative HPLC (silica gel, 3:1 dichloromethane/EtOAc) affording 5.0 g of the desired product as an oil. Addition of EtOAc solidified the product which was recrystallized from EtOAc to give a solid, m.p. 157°-160° C.
Reaction SMILES: [CH2:1]([N:5]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:6]1(=[O:8])=[O:7])[C:2]([CH3:4])=[O:3].C[O-].[Na+].Cl>C(O)C>[C:2]([CH:1]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5]1)(=[O:3])[CH3:4]
Reactant: CC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C1NS(=O)(=O)c2ccccc2C1=O
Temperature: 40 °C
Yield: 68 %

Procedure:
The N-acetonylsaccharin of Section B of this Example was treated with sodium methoxide in accordance with Zinnes et al, J. Org. Chem., 30:2241 (1965), U.S. Pat. No. 3,284,450, and Rasmussen, J. Org. Chem., 39:1554 (1974). Laboratory reagent sodium methoxide (0.9 mole) was blended with 50 ml of absolute ethanol and heated to 40° C.; 0.04 mole of the N-acetonylsaccharin was then added and the resulting mixture heated with stirring to 60° C. The mixture was then cooled and acidified with 5% HCl, resulting in the formation of a precipitate. The precipitate was washed, dried, filtered and evaporated to give an oily solid in 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](Cl)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][CH2:21][NH2:22].[BH4-].[Na+].Cl>CCOCC.ClCCl.CO.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]3[C:23]4[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:25]([O:26][CH3:27])[CH:24]=4)[CH2:20][CH2:21][NH:22]3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reaction time: 1.5 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (22.9 g) in ether (200 ml) was added to a stirred mixture of 3,4-dimethoxyphenethylamine (18.1 g), triethylamine (13.9 ml) and ether (300 ml). The mixture was stirred for 1.5 hours and then water was added. The ether layer yielded a residue which was dissolved in dichloromethane (100 ml) and added to polyphosphate ester (195 g) under nitrogen. The mixture was kept at 75°-82° C. for 16 hours and then added to water (1,200 ml). The organic phase was washed with water and basified with excess aqueous ammonia solution. The basic aqueous solution was extracted with ether. The ether extract yielded an oil which was dissolved in methanol (200 ml). Twelve portions of sodium borohydride (12 g in total) were added over twenty minutes. The mixture was stirred for 16 hours and acidified by the careful addition of 5N hydrochloric acid. The mixture was allowed to stand for 16 hours and the resulting solid was separated by filtration. Water was added to the filtrate which was then basified and extracted with ethyl acetate. The extract gave a residue which was dried by azeotropic distillation with propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, a sample (8.8 g) of which was heated at 90°-95° C. with formic acid (5 ml) and 37-40% aqueous formaldehyde solution (6.2 ml) for 16 hours. Water was added and the mixture basified with aqueous sodium hydroxide solution and extracted with ether. The extract yielded a gum which was heated under reflux with 48% aqueous hydrobromic acid (100 ml) for 31/2 hours. Charcoal and industrial methylated spirits (100 ml) were added and the mixture filtered. Removal of the solvent from the filtrate gave a residue which was dried by azeotropic distillation with propan-2-ol. The residue was taken up in a 1:1 mixture of propan-2-ol and ethanol and the solvent removed by evaporation. The residue was heated under reflux with ethanol for 30 minutes and then cooled. The solid was collected by filtration and washed with a small amount of cold ethanol to give 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 220° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1C=O.[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:3]=1[NH:28][CH2:29][CH2:30][NH:31][C:32]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Temperature: 25 °C

Procedure:
The product from Example 1, Step A (1 eq) and tert-butyl N-(2-aminoethyl)carbamate (3 eq) are dissolved in methanol, to which sodium cyanoborohydride (1.5 eq) is added in portions at 0° C. The reaction is stirred at room temperature until complete, and then quenched by the addition of saturated aqueous ammonium chloride and stirred until hydrogen evolution ceases. The resulting suspension is concentrated in vacuo and then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel with ethyl acetate and hexane to provide the title product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ccccn2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a stirred solution of ethyl 2-(piperidin-4-yl)acetate, hydrochloride (2.0 g, 9.63 mmol) in DMF (40 mL) was added K2CO3 (3.99 g, 28.9 mmol) followed by 2-bromopyridine (1.521 g, 9.63 mmol) and stirred at 130° C. for 16 h. Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (2×100 mL), brine (100 mL) and dried over Na2SO4 filtered and concentrated under reduced pressure. The residues was purified by column chromatography using 100-200 silica gel by eluting with 20% ethyl acetate in petroleum ether to afford ethyl 2-(1-(pyridin-2-yl)piperidin-4-yl)acetate (600 mg, 19.86% yield) as color less liquid. LCMS (ES) m/e 249.20 (M+H)+.
Reaction SMILES: O1C2=NC=CC=C2C(N)C1.CO[N:13]=[C:14]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>>[O:16]1[C:17]2=[CH:18][N:19]=[CH:20][CH:21]=[C:22]2[CH:14]([NH2:13])[CH2:15]1
Reactant: CON=C1COc2cnccc21
Agent: NC1COc2ncccc21
Product: NC1COc2cnccc21

Procedure:
This compound was prepared using a method analogous to that of 2,3-dihydrofuro[2,3-b]pyridin-3-amine (A.2.1.2), furo[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-b]pyridin-3(2H)-one O-methyl oxime;
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccccc1NC

Procedure:
Add 23.6 g (0.22 mol) N-methylaniline into 92 g (0.2 mol) 14% hexane solution of N-butyllithium and stir it for 10-20 minutes. Add 33.3 g (0.1 mol) octadecylbromide into the above solution, while stirring it. Add 200 ml water into the solution, after heating and refluxing the solution for about 17 hours and cooling it down to room temperature. Add 6N hydrochloric acid to the solution after concentrating the solution extracted by 300 ml diethyl ether and deposit it. 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline is obtained by refinement through crystaiization with ethyl alcohol and water. Dissolve the obtained 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline into 250 ml concentrated sulfuric acid. Add 30 ml concentrated nitric acid into the solution while stirring it in an ice water bath. Leave it about one hour after adding the nitric acid. Add the solution into ice water, filter off the deposit from it, and refine it by crystallization with ethyl alcohol and water. With the above step, 14.5 g (0.036 mol) N, N-octadecylmethyl-o -nitroaniline is obtained. Add 100 ml 2N hydrochloric acid into this 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline which is dissolved into 200 ml ethyl alcohol. 11.7 g (0.031 mol) N, N-octadecylmethyl-o-phenylene-diamine is obtained after adding 11.75 (0.18 mol) zinc dust into the above solution to be heated and refluxed for one hour.