Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CN(C)C(Cl)=O.[N:13]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[N+:21]([O-])[CH:22]=1)=[N+:14]=[N-:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:13]([CH2:16][C:17]1[C:22]([C:5]#[N:6])=[N:21][C:20]([CH3:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(CN=[N+]=[N-])c(C#N)n1
Reaction time: 23 h
Yield: 77.4 %

Procedure:
Trimethylsilyl cyanide (6.4 ml, 48 mmol) and dimethylcarbamyl chloride (4.2 ml, 46 mmol) were added in that order to a solution of the 5-(azidomethyl)-2-methyl-1-pyridiniumolate (7.08 g, 43.2 mmol) in methylene chloride (80 ml) at room temperature and the mixture was stirred at the same temperature for 23 hours. After confirming completion of the reaction by thin layer chromatography, saturated aqueous sodium hydrogencarbonate (80 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate, the aqueous layer was separated and extraction was performed with ethyl acetate. The collected organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.79 g, 56%, two steps) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11]CC1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11]
Reactant: BrCCCCCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCOCCCCCCBr
Yield: 98 %

Procedure:
A solution of [(2-[(6-bromohexyl)oxy]ethoxy)methyl]benzene (1.5 g) in EtOAc (20 ml) and EtOH (20 ml) was hydrogenated over 10% palladium on carbon (200 mg). After 2 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.05 g). TSP+ve 242 (MNH4)+, 244 (MNH4)+
Reaction SMILES: [C:1]1(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:18]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: OCCO
Reactant: O=C1CCCCCCCC(=O)CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCCCCCC2(CCCCCCC1)OCCO2

Procedure:
To a solution of 44.0 g (175 mmol) of 1,9-cyclohexadecanedione in 125 ml of toluene is added 13.1 g (210 mmol) of ethylene glycol and 500 mg (2.5 mmol) of p-toluenesulphonic acid. The mixture is then heated with a water separator until visible amounts of water are no longer eliminated. Washing with sat. NaHCO3 solution is then carried out, the phases are separated, the organic phase is dried over Na2SO4, filtration is carried out, and the solvent is removed on a rotary evaporator. This gives 57.7 g of a solid comprising 3 components having the following GC content: 1,9-cyclohexadecanedione (33.7%); 1,4-dioxaspiro-[4.15]-eicosan-13-one (52.5%); 1,4,14,17-tetraoxadispiro-[4.7.4.7]-tetracosane (13.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: CC1CCCCC1n1ccc(Cl)c(C=NO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1CCCCC1n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 102.7 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(2-methylcyclohexyl)pyridin-2(1H)-one obtained in Step D (1.19 g) in acetonitrile (9.0 mL) was added phosphorus oxychloride (0.412 mL) at room temperature. The reaction mixture was heated at 90° C. for 30 min, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: CCCCCC.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[S:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:11]1[CH:22]([C:21]1[CH:24]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[O:25][CH3:26])[OH:23]
Reactant: c1ccc2sccc2c1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Br)cc1C(O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1.6 M n-butylithium hexane solution (30.5 mL) was added to a mixture of benzo[b]thiophene (6.6 g, 0.049 mol) and tetrahydrofuran (66 mL) at −78° C. After stirred for 0.5 hours, the reaction mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-methoxybenzaldehyde (10.0 g, 0.047 mol), further stirred for five minutes and warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain pale yellow crystal (1-benzothien-2-yl)(5-bromo-2-methoxyphenyl)methanol (11.3 g, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9](C)[C:10]([C:12]3[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([O:27][CH2:28][C:29]1[C:30]([C:36]2[N:40]([CH3:41])[C:39]3[CH:42]=[CH:43][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:45][C:38]=3[N:37]=2)=[N:31][CH:32]=[CH:33][C:34]=1[Cl:35])(=O)C.[OH-].[Na+]>C(O)C.O>[C:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[CH:14][N:13]=3)[N:11]([CH3:24])[C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4].[C:46]([C:44]1[CH:43]=[CH:42][C:39]2[N:40]([CH3:41])[C:36]([C:30]3[C:29]([CH2:28][OH:27])=[C:34]([Cl:35])[CH:33]=[CH:32][N:31]=3)=[N:37][C:38]=2[CH:45]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(Cl)ccnc1-c1nc2cc(C(C)(C)C)ccc2n1C
Agent: Cn1c(-c2nccc(Cl)c2CO)nc2cc(C(C)(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2nccc(Cl)c2CO)nc2ccc(C(C)(C)C)cc21
Temperature: 19 °C
Reaction time: 2 h

Procedure:
A mixture of 160l and 160j (480 mg, 1.3 mmol), and sodium hydroxide (104 mg, 2.6 mmol) in ethanol (20 mL) and water (20 mL) was stirred at 19° C. for 2 h. See FIG. 5. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×2). The organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford (2-(6-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methanol 160k and (2-(5-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methanol 160l as a mixture of regioisomers (400 mg, 94%). MS-ESI: [M+H]+ 330.2.
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([S:9]([C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:26])[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=S([O-])c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The crude 6-chloro-pyridine-3-sulfinic acid sodium salt (4.7 mmol) was suspended in DMF (20 mL). Pyridine (0.8 mL) and ethyl α-bromoisobutyrate (1 mL) were added. The reaction was stirred at 50° C. under nitrogen for 18 h. The reaction mixture was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography (silica, eluent heptanes, 0-25% ethyl acetate) afforded 0.83 g of 2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18]Cl)=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:21].[K+]>C(O)C>[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:21])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Reactant: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C

Procedure:
N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide (0.741 mole) and potassium iodide (1.62 mole) were refluxed in ethanol (3400 ml) for 5 hours with stirring. The reaction mixture was then cooled, the inorganic salts were filtered off and the solvent was evaporated under vacuum. The obtained residue was purified by washing first with water and then with cold ethanol. M.p. 135°-137° C. Yield 87%.
Reaction SMILES: [OH:1][C:2]1([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:14][O:1][C:2]1([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCC1(O)CC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
tert-Butyl (1-hydroxycyclopropyl)methylcarbamate (150 mg) was dissolved in dry DMF (2 mL) and Cs2CO3 (313 mg, 0.961 mmol) was added, followed by MeI (0.053 mL, 0.841 mmol). The light yellow suspension was stirred in a sealed vessel at room temperature overnight. More MeI (0.050 mL, 0.801 mmol) was added and stirring was continued for 2 d. The reaction mixture was partitioned between aqueous saturated NaHCO3 (25 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 (2×25 mL). The organic layer was washed with brine (2×25 mL) and dried on Na2SO4 before concentration in vacuo to give a yellow oil. The product was filtered over a plug of silica (eluent heptane/iPr2O 1:1) to give the title compound (90 mg, 16% from 1-(aminomethyl)cyclopropanol) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH:13]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[CH2:19][NH:20][O:21][CH3:22])([CH3:15])[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[O:16][CH:13]([CH3:15])[CH3:14])[O:21][CH3:22])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccccc1OC(C)C
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccccc1OC(C)C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 93 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-isopropoxy-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (93% yield): mp 103° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (6H, d, J=6.0 Hz, CH3), 1.75 (6H, s, CH3), 3.68 (3H, s, OCH3), 4.60 (1H, m, CH), 4.95 (2H, broad s, NCH2), 6.44 (1H, s, CH), 6.89 (2H, m, aromatics), 7.2-7.3 (2H, m, aromatics). Anal. calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.22; H, 6.33; N, 3.87.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C:11](Cl)=[O:12])[CH:2]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:26][N:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:11]([O:10][C:3]4[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=4)=[O:12])[CH2:34][CH2:33]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
4-Nitrophenyl chloridocarbonate (268 mg, 1.33 mmol) was added to a mixture of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine (460 mg, 1.33 mmol), diisopropylethylamine (0.695 mL, 4 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred at ambient temperature for 30 min, then concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 give 456 mg (67%) of 4-nitrophenyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, 1H, J=2.7 Hz), 8.25 (d, 2H, J=9.2 Hz), 8.14 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.37-7.27 (m, 3H), 4.45-4.30 (m, 2H), 3.98 (d, 2H, J=5.1 Hz), 3.16-3.03 (m, 4H), 3.00-2.88 (m, 1H), 2.21-2.06 (m, 1H), 2.04-1.92 (m, 2H), 1.55-1.35 (m, 2H); LRMS (ESI), m/z 512 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 83 %

Procedure:
A solution of phenyl acetic acid (27.2 g.), benzyl alcohol (21.6 g.) and p-toluenesulfonic acid (380 mg.) in 100 ml. of toluene was heated under reflux under a Dean-Stark trap until the theoretical (3.6 ml.) quantity of water had been collected. On cooling, the solution was washed with dilute NaHCO3 and saturated NaCl and solvent was removed in vacuo.. The resulting oil was distilled at 125°-129° (0.4 torr)1 to give pure benzyl phenylacetate, 37.7 g. (83% yield). ##STR230##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].CCC[CH2-].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])=[CH:17][CH:16]=1.O>C1COCC1>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][S:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:16][CH:17]=1)(=[O:36])=[O:35]
Reactant: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1
Reactant: C1COCCN1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(C(=O)N3CCOCC3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of morpholine (0.69 ml) in THF (10 ml) was added, at −78° C., N-butyllithium (1.6 M, 3.3 ml), and the solution was stirred for 10 min. A solution of 4-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid methyl ester (1 g) was added and the solution was warmed up to room temperature and stirred for a further 30 minutes. After the addition of water (100 ml), the mixture was extracted with ethyl acetate (2×50 ml). The organic phases were dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (450 mg) with a molecular weight of 434.5 g/mol (C21H26N2O6S).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[I-].[CH3:12][CH2:13][CH3:14].O>CN(C=O)C>[CH3:12][CH:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH3:14]
Reactant: Cc1ccc(O)cn1
Reactant: CCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-hydroxy-2-methylpyridine (11.0 g, 100 mmol) was dissolved in N,N′-dimethylformamide (100 mL), added sodium hydride (7.2 g, 150 mmol) and 1-methylethane iodide (12 mL, 121 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. Then, 1-methylethane iodide (4 mL) was added, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was added water, and extracted with diethylether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine (12.7 g (yield 84%)) was obtained as a yellow oil.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCI
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2ccccc2)cc1
Yield: 166 %

Procedure:
Iodoethane (68.7 g, 35,57 mL, 440.6 mmol) was added to a suspension of 50 g (170.2 mmol) of 4-hydroxy-1,1′-biphenyl and 40.6 g (293.75 mmol) K2CO3 in 600 mL acetone. The resulting reaction mixture was stirred under reflux for 16 hours. After cooling to room temperature the acetone was removed under reduced pressure, the residue was dissolved in ethyl acetate and extracted with water. The aqueous layers where extracted 3 times with ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated to yield 56 g of the desired compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCC1(c2ccc(Br)cc2)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-methanol (11.42 g, 50.29 mmol) was dissolved in CH2Cl2 (171 mL) and the solution was cooled to −78° C. Triethylamine (8.41 mL, 60.35 mmol) was added followed by methanesulfonyl chloride (4.30 mL, 55.31 mmol) and the reaction stirred at −78° C. for 1 hour. The reaction was allowed to slowly warm to 0° C. while stirring for an addition 1.5 hours. The reaction was submitted to standard aqueous workup and was then diluted with DMF (90 mL) and evaporated to remove any residual CH2Cl2. Sodium cyanide (7.39 g, 150.8 mmol) and DMF (20 mL) were added and the reaction was heated to 70° C. for 3 hours. The reaction was cooled and submitted to standard aqueous workup to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:33][CH2:34][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2cc(CCn3ccc(OCc4ccccc4)cc3=O)ccc2C1

Procedure:
6-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 24.1 from 604 mg (3.00 mmol) 4-benzyloxy-1H-pyridin-2-one and 1.30 g (3.01 mmol) 6-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10c).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2([CH:12]([CH3:15])[CH:13]=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.C(=O)([O-])[O-].[K+].[K+]>C(O)COCCO>[C:1]1([S:7][CH2:8][C:9]2([CH:12]([CH3:15])[CH3:13])[CH2:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C=O)C1(CSc2ccccc2)CC1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)C1(CSc2ccccc2)CC1
Temperature: 150 °C
Yield: 101.8 %

Procedure:
A mixture of 14 (2.12 g, 8.62 mmol), hydrazine hydrate (55% in water, 7.4 mL, 131 mmol) and potassium carbonate (3.2 g, 23.2 mmol) in diethylene glycol (21 mL) was heated at 150° C. (bath temperature) for 3 hr. After cooled to ambient temperature, the mixture was poured into ice water and extracted with n-hexane. The combined organic layers were washed with cold diluted hydrochloric acid, water, sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 1.81 g of an oily material, which was purified by column chromatography (silica gel 20 g, 1-2% ethyl acetate in n-hexane) to give 1.69 g (85.1%) of 15, as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, benzenesulfonyl chloride (0.201 g, 1.16 mmol) was reacted with 2-azidoethanamine (0.100 g, 1.16 mmol) and triethylamine (0.235 g, 2.32 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)benzenesulfonamide (0.289 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, 2H), δ 7.55 (m, 3H), δ 5.47 (s, 1H), δ 3.39 (t, 2H), δ 3.12 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.8, 133.2, 129.5, 127.2, 50.9, 42.6 ppm; HRMS (ESI) calcd for C6H8N4O2S (M+) 226.0524, found 226.0523.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Al](Cl)(C)C.[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][C@@H:23]([CH3:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:19]([C:32](OCC)=[O:33])=[CH:18][C:16]=2[CH:17]=1>ClCCCl>[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][CH:23]([CH3:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][C:19]([C:32]([NH:1][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)=[O:33])=[CH:18][C:16]=2[CH:17]=1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(O[C@@H](C)Cc2ccccc2)c2sc(C)cc2c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1cc2cc(C(=O)Nc3ccn(C)n3)cc(OC(C)Cc3ccccc3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
3-Amino-1-methyl pyrazole (649 mg, 6.69 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (6.69 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-7-[(1S)-1-methyl-2-phenylethoxy]-1-benzothiophene-5-carboxylate (237 mg, 0.669 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (155 mg, 57%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.59 (s, 3 H) 2.95 (dd, J=13.75, 6.22 Hz, 1 H) 3.16 (dd, J=13.75, 6.03 Hz, 1 H) 3.74 (s, 3 H) 4.78-5.01 (m, 1 H) 6.89 (d, J=2.26H) 7.00 (d, J−1.13 Hz, 1 H) 7.12-7.23 (m, 1 H) 7.26-7.42 (m, 6 H) 7.81 (d, J=1.13 Hz, 1 H) 9.60 (s, 1 H). LCMS m/z 406.0 (M+H)+.