Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH2:28][C@@H:29]([CH2:32][CH3:33])[CH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:28][CH:29]([CH2:30][OH:31])[CH2:32][CH3:33])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](N)CO
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2nc(Cl)ncc2Cl)CC1
Solvent: CCO
Product: CCC(CO)Nc1ncc(Cl)c(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)n1

Procedure:
1-(2,5-Dichloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide (20 mg, 0.05 mmol) was dissolved in absolute ethanol (1 mL) then (S)-2-amino-butanol (0.1 mL) was added. The mixture was heated in a sealed Teflon reaction vial at 80° C. overnight. The resulting mixture was purified by preparative TLC (1 mm silica; eluent ethyl acetate) to afford the title compound as a colorless oil (4 mg). LC/MS Rt=4.42 minutes; 483.0 (M+1); 1H NMR δ 7.88 (s, 1H) 7.26 (m, 4H) 5.21 (NH) 4.97 (m, 1H) 3.91 (dd, J=11.2, 3.8, 1H) 3.86 (dd, J=11.2, 5.8, 1H) 3.7 (m, 1H) 3.66 (m, 5H) 3.62 (m, 1H) 3.54 (m, 4H) 1.65 (m, 1H) 1.54 (m, 1H) 1.26 (OH) 0.99 (t, J=7.5, 3H).
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[C:5]([CH3:11])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>O1CCOCC1>[I:10][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]2[NH:13][N:14]=[CH:8][C:7]=12
Reactant: NN
Reactant: Cc1cnc(F)c(C=O)c1I
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc2[nH]ncc2c1I

Procedure:
2-fluoro-4-iodo-5-methyl-pyridine-3-carbaldehyde (510 mg, 1.924 mmol) was dissolved in dry Dioxane (10 mL) and Hydrazine monohydrate (288.9 mg, 280.8 μL, 5.772 mmol) was added in one portion
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([CH3:25])[C:12]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:28][O:29][CH2:30][C:31]([O:17][C:16]1[C:15]([F:18])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:25])=[C:12]([C:26]#[N:27])[C:11]=1[NH2:10])=[O:32]
Reactant: COCC(=O)Cl
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCC(=O)Oc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Diisopropylethylamine (0.64 ml, 3.7 mmol) was added to an ethyl acetate (8 ml) solution of 4-amino-3-cyano-6-fluoro-5-hydroxy-2-methylbiphenyl (I-41) (180 mg, 0.74 mmol), then with cooling with ice, methoxyacetyl chloride (0.17 ml, 1.85 mmol) was added, followed by stirring for 16 hours with gradually heating up to room temperature. Aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate water and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (1:1) was concentrated under reduced pressure to obtain the entitled compound (229 mg, 99%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27](=O)[CH3:28]>>[CH2:27]([N:15]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=2[CH:4]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 57.9 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.055 g, 0.16 mmol) was reacted with acetaldehyde (90 μL, 1.6 mmol) to give 0.035 g (58%) of the title compound as a yellow oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1.[NH4+].[OH-]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]=[C:1]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[NH:18][C:13]=2[CH:12]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccc(Cl)cc1N
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc2nc(-c3ccncc3)[nH]c2c1
Yield: 49.1 %

Procedure:
To a mixture of isonicotinic acid (4.9 g., 0.04 mol) and 4-chloro-o-phenylenediamine (5.8 g., 0.041 mol) was added polyphosphoric acid (20 ml.). The mixture was heated to 200° and maintained at this temperature for 45 min. After cooling, the reaction mixture was poured onto ice and the solution made basic with conc. NH4OH. The resulting yellow solid was removed by filtration, dissolved in isopropanol, filtered and the filtrate concentrated to a solid. After recrystallization from EtOH-H2O, 4.5 g. of 5-chloro-2-(4-pyridyl)benzimidazole (49.1%) was obtained; m.p. 306-307.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:37][N:38]([C:40]([C:42]([CH3:47])([OH:46])[C:43]([NH2:45])=[O:44])=[O:41])[CH3:39]>O1CCCC1>[C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([NH:37][N:38]([C:40]([C:42]([CH3:47])([OH:46])[C:43]([NH2:45])=[O:44])=[O:41])[CH3:39])=[O:18])=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2]
Reactant: CN(N)C(=O)C(C)(O)C(N)=O
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NN(C)C(=O)C(C)(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetylalanylalanylproline (2 mmole) and N-methylmorpholine (2 mmole) are dissolved in dry tetrahydrofuran (200 ml) and cooled to -20° to -25°. Isobutyl chloroformate (2 mmole) is added, and the mixture is stirred at -20° for 10 minutes. A solution of 2-azaalanyl-dl-lactamide (2 mmole) in tetrahydrofuran (10 ml) is added dropwise, and the mixture is allowed to warm to room temperature over a period of 2 hours and stirred for a further 3 hours. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography of the residue on silica gel (70 gm) and elution with 18% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanyl-dl-lactamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([F:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CNC[C@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-fluoropyrrolidine-1-carboxylate (380 mg, 1.2 mmol) in DCM (20 mL) was added TFA (0.34 mL, 3.4 mmol, 3 mol eq). The resulting reaction was stirred at ambient temperature for 2 hr. More TFA (0.34 mL, 3.4 mmol, 3 mol eq) was added and stirring at ambient temperature continued for another 2 hr. The volatiles were removed to give a colorless residue. DCM (30 mL) and aqueous K2CO3 (1 M, 5 mL) were added. The organic layer was separated, extracted with more DCM (30 mL), dried over Na2SO4 and evaporated to give the title compound as a colorless gum (246 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.43 (m, 5 H) 4.80-5.21 (m, 4 H) 4.07-4.28 (m, 1 H) 3.46 (br. s., 1 H) 2.96-3.30 (m, 2 H) 2.74 (br. s., 1 H). 19F NMR (376 MHz, chloroform-d) δ ppm −72.38 (s, 1F). m/z (APCI+) for C12H15FN2O2 239.2 (M+H)+. Chiral purity was determined as below (using the racemic sample to compare):
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.F[C:17]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(=O)C.Cl>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cnc(F)c(C(=O)O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a slurry of sodium hydride (60% dispersion) (21.74 g, 543 mmol) in DMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol (60.7 g, 351 mmol) over the course of 5 minutes. Stirred at 0° C. for two minutes then removed from the ice bath and stirred for an additional 5 minutes at room temperature. Added 2-fluoro-5-methoxynicotinic acid (30 g, 175 mmol) portionwise over 10 minutes and heated the resulting slurry at 140° C. After cooling to RT the mixture was then poured onto 1 kg of ice and was quenched with acetic acid (50.2 mL, 877 mmol) and then 75 mL of 6 N HCl. Stirred vigorously for 1 hour, leading to the formation of a red slurry containing a very fine white precipitate. The slurry was filtered to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH3:16]
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccc(C2=CCCCCC2)cc1

Procedure:
Analogously to the process described in Example 1, using 13.2 g of p-(1-cycloheptenyl)-phenol and 21.1 g of 4-bromobutyric acid ethyl ester as starting material gives crude 4-[p-(1-cycloheptenyl)-phenoxy]-butyric acid ethyl ester of boiling point 160° C at 0.03 mm Hg, after chromatography on silica gel with methylene chloride as the eluant and subsequent fractional distillation in a high vacuum.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[I:9][C:10]1[N:11]=[C:12]([CH:23]=O)[N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1.O.[OH-].[Na+]>CS(O)(=O)=O.C(Cl)(Cl)Cl>[I:9][C:10]1[N:11]=[C:12]2[N:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]2[O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[CH:14]=1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (223 mg, 2.02 mmoles) in methanesulfonic acid (3.4 mL) is added a solution of 4-Iodo-1-phenethyl-imidazole-2-carbaldehyde (example 2B) (220 mg, 0.675 mmoles) in chloroform (1 mL). The reaction mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the pH is adjusted to 9-10 by adding 12N NaOH dropwise. The aqueous phase is extracted three times with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5) to give 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 126° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][OH:17])[CH2:3]1.[H-].[Na+].S(OCC)(O[CH2:24][CH3:25])(=O)=O.O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][O:17][CH2:24][CH3:25])[CH2:3]1
Reactant: CCOS(=O)(=O)OCC
Reactant: CN1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of (3) (2.4 g, 8.6 mmol) in tetrahydrofuran (40 ml) was added 60% NaH (0.69 g, 17 mmol) and stirred at room temperature for one hour. Diethyl sulfate (1.4 ml, 11 mmol) was added and the reaction mixture stirred over night. Water was added and the reaction mixture was extracted with diethyl ether (3×40 ml). The combined organic phases was dried with magnesium sulfate and evaporated to dryness. Column chromatography, using a mixture of dichloromethane, methanol and ammonia (aq) (9:1:1%) yielded 1.5 g (56%) of product (9) (oil).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][C:11]=2[CH3:20])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:17][C:13]1[CH:12]=[C:11]([CH3:20])[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:15]([CH3:16])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC(=O)CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Zinc dust (10 g) was added in portions over 10 minutes to 2-cyclopentyl-N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (1.45 g) in tetrahydrofuran (40 mL) and acetic acid (10 mL) cooled to 0° C. The reaction mixture was stirred 2 hours at 25° C., neutralized with solid sodium carbonate and filtered through silica (50 g), which was washed with ethyl acetate (200 mL). The organic phase was concentrated in vacuo to furnish 1.15 g (89% yield) of the title compound as a light orange solid. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.96 (s, 6H), 2.22 (m, 1H), 2.23 (d, 2H), 4.81 (b, 2H), 6.23 (s, 2H), 8.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C.C(N(CC)CC)C>[CH2:23]([NH:27][C:28]([O:21][CH:20]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2ncccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC(=O)OC1c2cccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 3 hours. n-Butyl isocyanate (2.9 cc.) and triethylamine (2 drops) are then added and heating at the reflux temperature is continued for a further 30 minutes. After concentrating the mixture to dryness under reduced pressure (40 mm.Hg), the residue is triturated with diisopropyl ether (10 cc.). The precipitate is filtered off and recrystallised from acetonitrile (41 cc.) to give 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.8 g.) melting at 215° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1.BrB(CC)CC.O>ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13][CH2:12]1
Reactant: COCOc1ccccc1C1(c2ccc(C)cc2OC)CC1
Agent: CCB(Br)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)ccc1C1(c2ccccc2O)CC1
Reaction time: 8 h

Procedure:
A solution prepared from 490 mg (1.64 mmol) of 1-(2-methoxymethoxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane and 6.1 ml of a 1 M solution (8.2 mmol) of bromodiethylborane in dichloromethane was stirred overnight under an argon atmosphere. Ten ml of water were added, the phases were separated, and the aqueous phase was extracted twice with 20 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 1-(2-hydroxyphenyl)-1-(2-methoxy-4-methylphenyl)cyclopropane. The proton NMR spectrum was consistent with the assigned structure. This was dissolved in 0.8 ml (8.2 mmol) of a 5 M solution of bromodimethylborane and allowed to stir overnight. Nothing happened. The mixture was cooled to 0° C. and 3.3 ml (3.3 mmol) of a 1 M solution of boron tribromide was added with stirring under an argon atmosphere. After a short reaction period 2 ml of water was added and the mixture was extracted with 2 ml of 5 percent aqueous sodium bicarbonate then with 2 ml of water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 350 mg (84 percent of theory) of the title compound as a foamy brown oil. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][C:23]=2[O:30][CH3:31])[CH2:7]1
Reactant: COc1cc(C(=O)c2ccccc2)ccc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(C(=O)c2ccccc2)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-benzoyl-2-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C[Li].CCOCC.[O:20]1[C:25]2[C:26]([C:33](OCC)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3>C1COCC1>[O:20]1[C:25]2[C:26]([C:33]([O:12][CH2:11][CH:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]3)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3
Reactant: CCCCN1CCC(CO)CC1
Reactant: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCN1CCC(COC(=O)c2c3c(n4ccccc24)CCCO3)CC1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
A stirred solution of (1-butyl-4-piperidinyl)methanol (125 mg, 0.72 mmole) in dry THF (5 ml) at 5° C. under argon was treated with 1.5M methyllithium in ether (0.35 ml, 0.50 mmole). After 10 minutes, a solution of ethyl 3,4-dihydro-2H-pyrano[2,3-b]indolizine-10-carboxylate (55 mg, 0.22 mmole) in dry THF (5 ml) was added and the mixture heated under reflux for 3 h. The mixture was then allowed to cool and concentrated in vacuo. The residue was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×40 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform to afford the title compound as a pale pink oil (65 mg, 78%).
Reaction SMILES: C(=O)(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)OC.[C:12](=O)([O:20]C1C=CC=CC=1)[O:13][C:14]1C=CC=CC=1>>[C:12]([O:13][CH3:14])(=[O:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Product: COC(=O)c1ccccc1
Yield: 39 %

Procedure:
In Example 20, the same procedures as in Example 20 were used, except that the reaction temperature was 180° C., and the contents were reacted for three hours. As a result, the yield of methyl phenyl carbonate was 18%, and the yield of diphenyl carbonate was 21%. Furthermore, methyl benzoate was produced as a by-product with a yield of 39% (the yield is given in terms of phenyl benzoate).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OC1CCCCC1
Yield: 88 %

Procedure:
A solution of 1.83 g of cyclohexanol and 1.45 g of pyridine in 30 ml of methylene chloride is cooled to -78° C. and, with stirring, 2.0 ml of 1-chloroethyl chloroformate is added dropwise to the solution over a period of 10 minutes. After completion of addition, the cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 3.31 g (yield 88%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2].C(OC(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[CH:46][C:39]=1[N+:36]([O-:38])=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(CN2CCOCC2)cn1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (25 g, 130 mmol) and diethylcarbonate (33.79 g, 286 mmol) in tetrahydrofuran (62.5 ml) under nitrogen at −10° C. was added lithium diisopropylamide in tetrahydrofuran (158.9 ml, 1.8M, 286 mmol) dropwise over 1 hr 10 min. After stirring for an additional 30 mins at −10° C. a solution of 4-nitrobenzonitrile (29.78 g, 195 mmol) in tetrahydrofuran (175 ml) is added dropwise and stirring continued for 3 hrs. The reaction mixture was poured into a cold aqueous hydrochloric solution (375 ml, 2M) at 0° C.; after warming to room temperature the acidic aqueous layer was separated and washed with tert-butyl methyl ether (200 ml). The acidic aqueous layer was cooled in an ice bath and tert-butyl methyl ether (500 ml) was added. The mixture was then made basic (pH 9) by addition of sodium carbonate solution (55 ml, 25 w/w %). The mixture was then warmed to room temperature and the organic phase separated; the basic aqueous phase was extracted with tert-butyl methyl ether (250 ml). The combined organic layer was treated with Celite® (12.5 g), then filtered and the filtrate concentrated in vacuo to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester crude (28.58 g, 51% w/w %). The crude material was dissolved in ethanol (300 ml) then heated to 40° C. and a solution of hydrochloric acid in isopropanol (8 ml, 4.95M, 20.7 mmol) was added followed by addition of seeds (90 mg) and the solution cooled to −10° C. over 10 hrs. The crystals were filtered and washed with tert-butyl methyl ether. After drying at 40° C. under vacuum gave 14.51 g, 25% yield of (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt as red wine crystals. Characterisation data were in accordance with example 7.