Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].[Br:23]Br>C(Cl)Cl>[Br:23][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([NH:11][C:19](=[O:21])[CH3:20])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)Cl
Reactant: Nc1cccc2c1CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6,7,8-tetrahydronaphthalen-1-amine (1 g, 6.8 mmol), triethylamine (1.9 mL, 13.6 mmol) in DCM (50 mL), is added acetyl chloride (587 mg, 7.5 mmol) dropwise. The mixture is stirred at room temperature for 2 hr. Then the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer is separated, washed with brine and dried over sodium sulfate. After concentration, the obtained N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (200 mg) is dissolved in acetic acid (30 mL). To this solution is added bromine (170 mg, 1.06 mmol) dropwise. The mixture is heated at 50° C. overnight. The reaction is quenched by adding sodium sulfite aqueous solution. The mixture is extracted with ethyl acetate (3×20 mL). The organic extracts are combined and washed with sodium bicarbonate aqueous solution, brine, and dried over sodium sulfate. After concentration, the crude N-(4-bromo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is obtained as brown solid. The solid obtained is dissolved in methanol (5 mL) and concentrated HCl (15 mL). The mixture is refluxed at 95° C. overnight. After cooling to room temperature, the mixture is poured into ice water, and basified to pH=12 with conc. NaOH aqueous solution. Then the mixture is extracted with ethyl acetate (3×20 mL). The combined organic layer is dried over Na2SO4 and concentrated. The crude product is purified with silica gel chromatography (15% ethyl acetate in hexanes) to give 4-bromo-5,6,7,8-tetrahydronaphthalen-1-amine as beige solid. ESMS m/z 226 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:15][CH2:16][CH2:17][CH2:18][NH2:19])(C)(C)C>>[CH2:1]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=Cc1ccccc1
Product: NCCCNCc1ccccc1

Procedure:
Example 20 was prepared in a similar fashion to Example 18 (CZ-25) from benzaldehyde and tert-butyl(3-aminopropyl)carbamate. 1H NMR (500 MHz, D2O) δ 7.49 (quint, J=3 Hz, 5H), 4.26 (s, 2H), 3.17 (t, J=8 Hz, 2H), 3.07 (t, J=8 Hz, 2H), 2.09 (quint, J=7.5 Hz, 2H). 13C NMR (125 MHz, D2O) δ 130.6, 129.9, 129.8, 129.4, 51.4, 44.1, 36.7, 23.9. LRMS [M+H]+291.3.
Reaction SMILES: IC.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[C:14]([C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH3:19])[NH:16][C:17]=2[CH3:18])=[O:12])=[CH:6][C:5]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25].[C:34](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[C:14]([C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH3:19])[N:16]([CH3:34])[C:17]=2[CH3:18])=[O:12])=[CH:6][C:5]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25]
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)Cc2ccc(F)c(C(=O)N3CCC(OC)CC3)c2)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Iodomethane (0.029 mL, 0.46 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (57) (0.100 g, 0.23 mmol) and potassium carbonate (0.048 g, 0.35 mmol) in DMF (5 mL). The resulting suspension was stirred at room temperature for 16 hours. The reaction was incomplete and further iodomethane (0.029 mL, 0.46 mmol) was added and the suspension was stirred at room temperature for a further 4 hours. The reaction was incomplete so the temperature was increased to 50° C. and the reaction mixture was stirred for a further 3 hours. The reaction mixture was poured into water (75 mL), extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.082 g, 79% yield); m/z (LC-MS, ESI+), RT=2.06 min (M+H=445.30).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1

Procedure:
To a solution of 2-bromo-5-hydroxy-benzaldehyde compound 1 (15.0 g, 74.62 mmol) in toluene (100 mL) was added ethylene glycol (12.5 mL, 223.86 mmol) and p-TSA (1.42 g, 7.46 mmol). The solvent was removed under reduced pressure to give crude product 2 (20.0 g crude), which was used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.38 (d, J=8.6 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.62 (d, J=8.2, 2.3 Hz, 1H), 6.01 (s, 1H), 4.20-4.01 (m, 4H).
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]2[C:21](OCC(OC)=O)=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH:2]=C.I([O-])(=O)(=O)=[O:29].[Na+].CCCCCC.[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[OH:29][CH2:2][CH2:1][C:4]1[O:5][C:6]2[C:21]([CH2:41][C:40]([O:43][CH3:44])=[O:42])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: C=CCc1oc2c(OCC(=O)OC)cccc2c1CCOC1CCCCO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc2c(CCOC3CCCCO3)c(CCO)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Methyl (2-(2-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (0.97 g) and osmium tetroxide (0.07 M solution in t-butyl alcohol, 0.37 ml) were dissolved in dioxane/water (3:1) and the solution was cooled to 0° C. To this solution, sodium periodate (1.38 g) was added for 10 minutes. After stirring the reaction solution at 0° C. for 30 minutes, the solution was stirred at room temperature for additional 30 minutes. The reaction solution was filtered through Celite and the precipitate was washed with THF (12 ml). The filtrate was cooled to 0° C. and sodium borohydride (98 mg) was added, followed by stirring the resultant for 40 minutes. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1)using silica gel to obtain the desired compound (412 mg, yield: 42%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:19])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:4].[Cl-].[NH4+]>CCO.O.C(Cl)Cl.[Fe]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:19])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4]
Reactant: COC(=O)c1nc(C)sc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Iron powder (53.7 mmol) is added to a suspension of 2-methyl-5-(3-nitro-phenyl)-thiazole-4-carboxylic acid methyl ester (44.1 mmol) and ammonium chloride (221 mmol) in a mixture of EtOH (100 mL) and water (50 mL). The mixture is stirred at 80° C. for 4 h, iron powder (53.7 mmol) is added and heating is continued for additional 3 h. After addition of a third portion of iron powder (26.8 mmol) the mixture is heated at 80° C. for additional 3 h, cooled to RT, diluted with DCM and filtered through Celite. The residue is washed with DCM and water and the filtrate is concentrated in vacuo. A sat. aq. NaHCO3 solution and DCM are added and the layers are separated. The organic layer is washed with water, dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.67 min; [M+H]+=249.4.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][CH:7]=1.[CH3:33][OH:34].[Li+].[OH-:36].Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]([OH:36])=[O:34])[N:3]=2)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1)[CH3:12]
Reactant: [OH-]
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(C(=O)O)nc12
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A mixture of 2-bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (2.00 g, 3.86 mmol, Preparation #5) and PdCl2(PPh3)2 (0.406 g, 0.579 mmol) in DMF (25 mL) was degassed under reduced pressure and the solution was placed under an atmosphere of CO. MeOH (4.70 mL, 116 mmol) and TEA (2.15 mL, 15.4 mmol) were added and then the mixture was degassed under reduced pressure and the solution placed under an atmosphere of CO. The mixture was then heated to 95° C. under an atmosphere of CO maintained via a balloon for 6.5 h. The solvents were evaporated under reduced pressure then the material was dissolved in 1,4-dioxane (50 mL). Water (10 mL) and LiOH (0.65 g, 27 mmol) were added then the mixture was heated to 75° C. for 90 min. The mixture was cooled to rt and then most of the 1,4-dioxane was removed under reduced pressure. The mixture was treated with water (50 mL) and Et2O (50 mL). The layers were separated then the organic layer was extracted with water (4×50 mL). The combined aqueous extracts were acidified with aqueous HCl (5.0 N, 6.2 mL, 31 mmol) and then extracted with DCM (50 mL, 2×30 mL). The organics were combined and dried over anhydrous MgSO4 then filtered and concentrated under reduced pressure to give 7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (0.92 g, 49%): LC/MS (Table 2, Method a) Rt=2.63 min; MS m/z 484 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][N:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:37])=[O:8])[CH:25]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Yield: 90 %

Procedure:
According to the procedure descnbed in Example 1(a), 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 1.2 g (90%) of 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow powder, mp 138-40° C. 1H NMR (CD3OD): δ 7.98 (bs, 1H), 7.82 (bd, 1H, J=8.4 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=1.6 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.55 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.5 Hz), 4.19 (d, 1H, J=9.0 Hz), 2.98 (dd, 1H, J=6.9, 16.5 Hz), 2.64 (d, 3H, J=4.7 Hz), 0.98 (s, 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm−1. HRFABMS: Calculated for C22H26N4O4 Cs (M+Cs+): 543.1008. Found 543.1021. Anal. Calculated for C22H26N4O4•0.4 EtOAc: C, 63.60; H, 6.60; N, 12.57. Found: C, 63.80; H, 6.77; N, 12.57.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(OCC)C>CO>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: OCc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of 3-benzyl-4-fluorobenzaldehyde (5 g) in methanol (75 cm3) was cooled to 0° C. Sodium borohydride (1.34 g) was added in portions, and the mixture stirred for 1 hour. The reaction mixture was then poured cautiously into a mixture of water and diethyl ether, and the organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave a pale yellow oil which was purified by distillation in a kugelrohr apparatus to give 3-benzyl-4-fluorobenzyl alcohol (4.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C(C(OO)=O)=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Agent: O=C(OO)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccn1-c1ccc(CBr)cc1
Yield: 94 %

Procedure:
A solution of 1-(4-methylphenyl)pyrrole-2-carbonitrile (4.9 g), N-bromosuccinimide (5.5 g) and perbenzoic acid (65 mg) in carbon tetrachloride was heated under reflux in light radiation for 2 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford a colorless syrup (6.6 g, 93%).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.O>CC(C)=O>[NH:14]([C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)[C:11]([NH2:12])=[S:10]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CN(C)Cc1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
Benzoyl chloride (0.18 ml) was added to a solution of ammonium thiocyanate (0.12 g) in acetone (7 ml) and heated under reflux for 5 min. Subsequently, a solution of the compound (0.21 g) obtained in Example 38 in acetone (6 ml) was added. The reaction mixture was stirred at room temperature for 20 min and then water was added to give a yellow precipitate, which was separated off by filtration. To the recovered product, 10% aqueous sodium hydroxide solution (20 ml) was added and heated under reflux for 5 min. The reaction mixture was made acidic with 35% HCl, then weakly alkaline with 28% aqueous ammonia solution, and concentrated to 20 ml under reduced pressure. The resulting precipitate was filtered off and the filtrate was extracted with chloroform; the organic layer was dried with anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=5:1) to give 0.1 g of the titled compound (yield, 35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=[O:13])[CH:6]=1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C.C(OC(=O)C)(C)C.C(O)(C)C>[Br:15][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:6]=[C:7]([CH:12]=[O:13])[C:8]=1[OH:11]
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)OC(C)C
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a 2 L round bottom flask with magnetic stirrer, thermocouple, and ice water bath was added (3-formyl-4-hydroxyphenyl)acetic acid methyl ester (308 g, 1.59 mol) and N,N-dimethylformamide (1 L). The reaction mixture was stirred and cooled to −5 to 5° C. A solution of N-bromosuccinimide (311 g, 1.75 mol) in DMF (1.5 to 2 L) was added dropwise, at such a rate to keep the internal temperature between 5 and 10° C. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and monitored for completion by HPLC analysis. The reaction time was about 4 h. The reaction mixture was diluted with isopropylacetate (3 L), and the resulting solution was extracted with water to remove the DMF. Concentration of the organic phase afforded a reddish solid that was dissolved in hot isopropanol (400 mL) and allowed to cool while stirring. The resulting off-white crystalline product was filtered and washed with cold IPA (−20° C.; 400 mL) to yield methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (368 g, 84.7%) as off-white crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CO.C(Cl)Cl>[Br:25][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:9][CH2:10][CH2:11]2
Reactant: c1ccc2c(c1)CCCN2CCN1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCCN2CCN1CCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 57.7 %

Procedure:
A solution of 1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline (490 mg, 2.13 mmol) in 10 mL of carbontetrachloride was cooled to 0° C. then treated with NBS (378 mg, 2.13 mmol) portionwise. The resulting suspension was stirred at 0° C. for 3.5 hours. The mixture was filtered through celite and the filter pad was rinsed with 3×20 mL hexanes. The filtrate was concentrated to give a light brown residue which was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a light brown oil (380 mg, 57.7%). 1H-NMR (CDCl3) δ: 7.09 (dd, J=2.4, 8.7 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H), 3.42 (t, J=7.8 Hz, 2H), 3.29 (t, J=5.7 Hz, 2H), 2.76-2.55 (m, 8H), 1.95-1.89 (m, 2H), 1.82-1.77 (m, 4H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>O>[CH:20]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(C2NCCc3ccccc32)c1C#N
Temperature: 170 °C
Yield: 30 %

Procedure:
A mixture of 3-nitrophthalonitrile (2.04 g, 11.8 mmol), freshly dried potassium carbonate (6.0 g, 42 mmol) and 1,2,3,4-tetrahydroisoquinoline (16.5 mL) was heated at 170° C. for 4 h. The reaction mixture was poured into water (250 mL) and extracted with dichloromethane (2×200 mL); the combined organic layers were washed with hydrochloric acid (1 M, 2×200 mL), dried (Na2SO4) and the solvent removed. The product was purified by recrystallisation from methanol to give 9 as a beige powder (906 mg, 30%)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[ClH:21]>ClCCl.CCOCC>[ClH:21].[ClH:21].[O:1]1[CH2:2][CH2:3][N:4]([C@H:7]2[CH2:8][CH2:9][C@H:10]([NH2:13])[CH2:11][CH2:12]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 324I (19.2 g) in dichloromethane (100 mL) was added HCl (100 ml, 4M in dioxane) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ether and solid salt was filtered off and dried to give the title compound.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30][C:31]([CH3:33])=[O:32]>>[C:31]([OH:2])(=[O:32])[CH3:33].[CH3:30][C:31]1([CH3:33])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:18]1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Reactant: CC(C)=O
Reactant: CO
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
110 ml of methanol, 80ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 6.8 g (16.9 mmol) of N1-benzyl-N5-decyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of ethanol. To the solution were added 80 ml of water and 7 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol/ether to obtain 2.9 g of colorless crystals having a melting point of 106 to 108° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:39]=[C:22]3[CH:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=4)[CH2:24][CH2:25][CH2:26][N:21]3[N:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.C(OCC)(=O)C>CO.[Cl-].[Na+].O>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:39]=[C:22]3[CH:23]([C:27]4[CH:28]=[CH:29][C:30]([CH:33]([OH:38])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:31][CH:32]=4)[CH2:24][CH2:25][CH2:26][N:21]3[N:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: CCCCC(=O)c1ccc(C2CCCn3nc(/C=C/c4ccc(-n5cnc(C)c5)c(OC)c4)nc32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCCCC(O)c1ccc(C2CCCn3nc(/C=C/c4ccc(-n5cnc(C)c5)c(OC)c4)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Sodium tetrahydroborate (0.166 mg) was added to a solution of (−)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one obtained in Example 3 (2 mg) in methanol (0.5 mL), and the reaction solution was stirred in a nitrogen atmosphere at room temperature for one hour. Brine and ethyl acetate were added to the reaction solution and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 1.19 mg of the title compound.