Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.[OH-].[Na+].[F:7][C:8]([F:18])([F:17])[C:9](=O)[CH2:10][C:11]([O:13]CC)=O.[CH:19]([OH:22])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:2]1[N:3]=[C:11]([OH:13])[CH:10]=[C:9]([C:8]([F:7])([F:17])[F:18])[N:1]=1)([CH3:21])[CH3:20]
Reactant: N#CN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
11.25 g (263 mmol; 1.05 eq) of cyanamide was placed is isopropanol (800 ml per tool of ethyl trifluoroacetoacetate; EtTFAA) at 50° C. and HCl gas (18.3 g; 500 mmol; 2.0 eq) was passed through the mixture for one hour. When the introduction of HCl had ended, the mixture was stirred for 2 hours at 70° C. It was then allowed to cool to room temperature and 3/4 of the solvent was evaporated off on a rotary evaporator. 80 ml of water (320 ml per mol of ethyl trifluoroacetoacetate) was added at room temperature to the O-isopropylisourea hydrochloride formed. Aqueous NaOH solution (78.87 g; 1.09 eq; 14 percent according to titration) was then added over 5 minutes at room temperature until the pH had shifted from 0.5 to 11.5, and stirring was continued for 15 minutes. The temperature was kept at ≤30° C. during the addition of the NaOH. Ethyl trifluoroacetoacetate (46.5 g; 500 mmol; 1.0 eq) was then added dropwise to this solution at room temperature. The temperature rose to 30° C. during this process and two phases formed. This mixture was refluxed for 2 hours. The organic solvents were then distilled off until the top temperature reached ca. 96° C. Stirring was continued for 2 hours at 85° to 90° C. The light yellow emulsion was allowed to cool to room temperature, the pH of 7.3 was adjusted to 5.0 with a small amount of 2 N aqueous HCl solution and the granular solid was filtered off after 20 minutes at room temperature. The moist solid obtained after filtration was taken up again with distilled water (~1 g moist product/ml water) and refluxed for 1 hour. After cooling to room temperature, filtration and drying, a light yellowish solid of relatively high content was obtained: the total yield was 67.8 percent (content: 98.0 percent according to HPLC). The solid was washed with a small amount of cold water and then dried overnight in a vacuum drying cabinet at 40° C. 41.3 g of a yellowish solid was obtained as the product, corresponding to a yield of 69.8 percent (content: 94.5 percent according to HPLC).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C=C>[O:1]=[C:2]([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH:8]=[CH2:23])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Solvent: C=CCO
Solvent: O
Product: C=CCOC(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2.89 g (10.0 mmol) of ethyl 3-oxo-5-phthalimidopentanoate in 14 ml of allyl alcohol was heated at 80° C. in the presence of catalytic amounts of p-toluenesulphonic acid hydrate for 3 days. The solvent was then evaporated in vacuo and the residue was purified by chromatography on 170 g of silica gel (toluene:ethyl acetate 4:1). The title compound was obtained as colorless crystals, melting point: 53°-55° C., Rf: 0.40 (toluene:ethyl acetate 4:1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][NH:17][CH3:18].C(N(CC)CC)C.[Na+].[Cl-]>CN(C)C=O>[N:4]1[C:3]([CH2:2][N:17]([CH3:18])[CH2:16][C:15]([O:14][CH3:13])=[O:19])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: CNCC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)Cc1cn2ccccc2n1
Yield: 25.9 %

Procedure:
0.303 g (1.773 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were dissolved in 15 ml of dimethylformamide with magnetic stirring and then 0.253 g (1.773 mmol) of sarcosine methylester hydrochloride and 0.741 ml (5.32 mmol) of triethylamine were added. The mixture was stirred at r.t. for 16 h, and then treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was concentrated in vacuo. The residue was triturated in 75 ml of isopropanol, the salts were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol, 95/5, v/v). 0.107 g (yield=26%) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were obtained as a pale yellow oil. LC-MS: m/z=234 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.49 (d, J=6.8 Hz, 1H), 7.79 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (ddd, J=9.0, 6.7, 1.2 Hz, 1H), 6.84 (td, J=6.7, 1.1 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1.C([O-])(O)=O.[Na+].[CH3:32][N:33]([CH:35]=O)C>CN(C1C=CN=CC=1)C>[CH:32]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:10](=[O:12])[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:25])([F:26])[F:14])[CH:17]=4)=[O:24])=[CH:7][CH:6]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:35][N:33]=1
Reactant: CN(C)C=O
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Steps one, three and four were performed as in Example 208. Step two is performed as follows: To methyl 3-(4-aminophenyl)propanoate in DMF is added DMAP and 3-trifluoromethylphenyl isocyanate and the solution was stirred at room temperature for 4 hours. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. The compound E210b was purified by flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[N:14]1([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:17]1[CH2:18][CH2:19][N:14]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:15][CH2:16]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
1.8 Grams of 3,4-dimethoxybenzoic acid and 2.75 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were added to a mixed solvent of 20 ml of dioxane with 20 ml of methylene chloride. Under the condition that the outside of reaction vessel was ince-cooled with stirring, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide being dissolved in 5 ml of methylene chloride by keeping its temperature to 10°-20° C. was added dropwise thereto and stirred at the same temperature for 3.5 hours. The crystals formed in the reaction mixture was removed by filtration, and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was dissolved in 100 ml of methylene chloride and the organic layer was washed with 5%-hydrochloric acid aqueous solution, 5%-sodium hydrogencarbonate aqueous solution and water in this order, then the organic layer was dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue thus obtained was recrystallized from chloroform-ethanol to obtain 0.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbony]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-nitropyridine (1 g, 3.7 mmol), ammonium chloride (600 mg, 11.1 mmol), and iron powder (1.05 g, 19 mmol) suspended in THF (6.2 mL), water (2.3 mL) and ethanol (6.2 mL) was heated to 100° C. using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50° C.) MeOH (50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (539 mg, 60%). LCMS (M+H)+=244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)C>[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=2)[CH2:15][CH2:14]1)(=[O:18])[CH3:17]
Reactant: Clc1cc(N2CCNCC2)cc(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)N1CCN(c2cc(Cl)c(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 1-(3,4,5-trichlorophenyl) piperazine (0.5 g) and acetic anhydride (0.4 ml) in ethanol (10 ml) was left to stand overnight at ambient temperature. The solvent was removed in vacuo and the residue was crystallised from ethyl acetate-light petroleum (b.p. 40°-60°) to give 1-acetyl-4-(3,4,5-trichlorophenyl) piperazine (0.43g, 76%), m.p. 133°-136°.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH:17]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH:17]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(S)-2-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (70 mg, 0.14 mmol) in DCM (2 mL) is added TFA (2 mL). After stirring at room temperature for 1 h, the reaction mixture is concentrated down to give crude (S)-2-Amino-1-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-2-cyclohexyl-ethanone, which is used in next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:8]([C:11]#[N:12])=[N:9][CH:10]=1)=[O:5])C.[OH-:21].[K+].Cl>CCO.O>[C:11]([C:8]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([C:4]([OH:3])=[O:5])=[CH:10][N:9]=1)(=[O:21])[NH2:12]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc(C#N)n1COCC[Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C(=O)O)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-cyano-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid ethyl ester (prepared in the previous step)(0.28 g, 0.95 mmol) in 10 mL of 50% EtOH/H2O was added a 2 N KOH soln (0.95 mL, 1.9 mmol) and the mixture stirred for 8 h at RT. The pH was adjusted to 4 with 3 N HCl and the ppt was collected and dried to give 0.24 g (88%) of a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 13.39 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.29 (s, 2H), 3.57 (t, J=7.8 Hz, 2H), 0.87 (t, J=7.8 Hz, 2H), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C11H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][S:21]([CH3:20])(=[O:23])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CO)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of benzyl glycolate (2.0 mL, 14.1 mmol) and triethylamine (2.35 mL, 16.9 mmol) in dichloromethane (30 mL) at 0° C. was added dropwise methanesulfonyl chloride (1.20 mL, 15.1 mL). The reaction was stirred overnight, diluted with dichloromethane, washed with saturated aqueous NH4Cl, and then with saturated NaHCO3, dried with Na2SO4, and concentrated in vacuo to give 2.50 g (73%) of methanesulfonyloxy-acetic acid benzyl ester which was used in the next step without further purification.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:4]=12.[NH:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(CC)CC>O=S(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]3)=[O:14])[S:11][C:4]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 59.7 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.27 g, 10.33 mmole), SOCl2 (10 ml), tert-butyl pyrrolidin-3-ylmethylcarbamate 44a (2.07 g, 10.33 mmole) and Et3N (1.44 ml, 10.33 mmole) in a manner as previously described for example 9d to give a yellow solid (2.44 g, 60%). 1H NMR (300 MHz, CDCl3) δ7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.73 (1H, s), 3.96 (1H, m), 3.85 (1H, m), 3.70 (1H, m), 3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.54 (1H, m), 2.12 (1H, m), 1.43, 1.41 (9H, s); ESIMS (M+): 396.05.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N)CCCCC1>O1CCCC1.CCCCCC>[C:13]([O:12][C:10]([C@@H:9]([C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([OH:8])=[O:7])[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCC=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)[C@@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 5.19 g of 4-tert-butyl hydrogen 2(R)-isobutylsuccinate in 50 ml of dry tetrahydrofuran was cooled to −78° C. while stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 15 minutes. A solution of 5.55 g of cinnamyl bromide in 25 ml of dry tetrahydrofuran was then added dropwise and the mixture was left to come to room temperature gradually. After stirring overnight the tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give an orange oil. This was dissolved in 100 ml of hexane to which 2.35 g of cyclohexylamine were added. The mixture was left to stand for 2 hours and the solid formed was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulphuric acid to give a clear solution. The ethyl acetate solution was washed twice with water and then with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate. After evaporation of the solvent there were obtained 6.41 g of (E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in the form of a pale cream coloured solid.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH:9]([CH3:14])[NH:8][CH2:7][CH2:6]2.C(=O)(O)[O-].[Na+].[C:20](=O)([OH:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>O.O1CCOCC1>[C:22]([O:21][C:20]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([OH:13])=[C:3]([OH:2])[CH:4]=2)[CH:9]1[CH3:14])=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)O
Reactant: CC1NCCc2cc(O)c(O)cc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1c2cc(O)c(O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
6,7-Dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline monohydrobromide (510 mg, 2.9 mol) was dissolved in water (5 ml) and dioxane (5 ml), and the solution was mixed with sodium bicarbonate (410 mg, 4.9 mmol) and t-butyl bicarbonate (470 mg, 2.2 mmol) and stirred at room temperature for 2.5 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with dilute hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was dried under a reduced pressure to obtain crude 2-t-butoxycarbonyl-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (610 mg). Crude 2-t-butoxycarbonyl-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (610 mg) was dissolved in anhydrous N,N-dimethylformamide (6 ml), and the solution was mixed with sodium hydride (60%, 170 mg, 4.1 mmol) and stirred at room temperature for 45 minutes. The reaction solution was mixed with methyl iodide (580 mg, 4.1 mmol) and again stirred for 1 hour. The reaction solution was mixed with ethyl acetate, washed with water and saturated brined and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 190 mg (0. 62 mmol, 32% in yield) of the title compound.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43](Br)[CH:44]=C.[CH2:47]1COCC1>>[CH2:42]([C@@:12]1([CH3:47])[C:13]2=[N:18][CH:17]=[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15](=[O:41])[N:14]2[C@H:10]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:9])[CH2:11]1)[CH:43]=[CH2:44]
Reactant: C1CCOC1
Reactant: C=CCBr
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Product: C=CC[C@]1(C)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 12c (2.155 g, 3.74 mmol) in 16 mL THF at −78° C., was added 1.0 M LIHMDS in THF (7.66 mL, 7.66 mmol). The mixture was stirred at −78° C. for 10 min, then allyl bromide (0.81 mL, 9.34 mmol) was added. The mixture was allowed to slowly warm to −40° C. and was maintained at this temperature for 30 min. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc. The organic phase was washed with 0.5 M HCl and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (40% EtOAc/hexanes) to afford 1.101 g (48%) of 117a as a colorless gum. MS (ESI) 617.2 (M+H+).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:10](O)[CH2:11]CC.CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]1([O:4][CH2:1][CH2:2][CH2:10][CH3:11])[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: CCCCO
Reactant: CC(=O)OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(C)=O
Product: CCCCOC1C=CCC1

Procedure:
2-Cyclopentenyl acetate (0.30 g) and n-butanol (0.40 g) were mixed and stirred vigorously at 40° C. for 4 hours with a solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water. At the end of the reaction period acetone was added to give a single phase, and the solution was analyzed by gas chromatography using an Apiezon column programmed at 60°-220° C. Peaks for the cyclic compounds had the following relative areas.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1COCC1.CO.O.O[Li].O>O>[CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of methyl 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (65 mg, 0.12 mmol) in mixed solvents (THF/MeOH/H2O; 2:2:1; 5 mL) was added LiOH H2O (15 mg, 0.36 mmol) at 0° C. The reaction mixture was allowed to room temperature over 30 min. and stirring was continued for 1 h. The reaction mixture was concentrated to give crude product, which was diluted with water and extracted with MTBE. The aqueous layer was neutralized with 0.5N HCl and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (55 mg, 87%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.28 (dd, J=8.0, 1.6 Hz, 1H), 8.14 (s, 1H), 7.77 (dd, J=13.6, 8.4 Hz, 1H), 7.63 (s, 0.5H), 7.51 (s, 0.5H), 7.23-7.13 (m, 3.5H), 6.95 (d, J=9.2 Hz, 0.5H), 4.79 (s, 1H), 4.48 (s, 1H), 3.77 (s, 1.5H), 3.68 (s, 1.5H), 3.58-3.01 (m, 6H), 2.88-2.80 (m, 2H), 1.60-1.40 (m, 2H), 1.39-1.20 (m, 4H), 1.19-1.00 (m, 2H), 0.99-0.90 (m, 3H), 0.85-0.75 (m, 3H); MS(ESI+) m/z 517.4 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[ClH:34]>>[Cl-:34].[CH3:7][CH:6]([CH3:8])[CH:2]([NH3+:1])[C:3](=[O:4])[NH:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1.[ClH:34]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CC(C)C(N)C(=O)O
Agent: Cl
Product: CC(C)C([NH3+])C(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: [Cl-]

Procedure:
Following the procedure of Example 2, making variations only as required to use 2-amino-3-methylbutyric acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone and then treated with HCl, the title compound was obtained as a white powder of HCl salt (48% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.53, 8.50, 8.12, 7.84, 7.76, 7.68, 7.62, 7.54, 3.90, 3.36, 3.25, 2.20, 0.98. MS (ES+) m/z 451.2 (M+1).