Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[F:21].[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:16]([F:20])[C:15]=1[F:21]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cccc(Br)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Br)c(F)c1F
Temperature: -75 °C
Yield: 21.8 %

Procedure:
Diisopropylamine (7.86 grams (g), 78 mmol) was dissolved in tetrahydrofuran (THF; 104 mL) and cooled to −75° C. utilizing a dry ice/acetone bath. A solution of n-BuLi (2.5 M in hexanes; 22.80 mL, 57.0 mmol) was added dropwise, and the solution was again cooled to −75° C. 1-Bromo-2,3-difluorobenzene (10 g, 51.8 mmol) was dissolved in THF (25.9 mL), and the solution was added dropwise keeping the temperature below −60° C. The reaction mixture was then allowed to warm to −15° C. before cooling again to −75° C. TMSCl (7.29 mL, 57.0 mmol) was then added dropwise, and the reaction mixture was allowed to warm to 25° C. and then concentrated under vacuum. The residue was partitioned between ethyl acetate (EtOAc) and H2O. The organic phase was washed twice more with H2O and concentrated. Kugelrohr distillation at 88° C. provided the product in greater purity but an impurity was distilling at that temperature. Kugelrohr distillation of that purified distillate at 75° C. led to purer product but some product was left in the pot. This process yielded the title compound as a clear oil (3.0 g, 21.83%, 90% purity): 1H NMR (300 MHz, CDCl3) δ 7.28 (ddd, J=7.8, 5.2, 1.3 Hz, 1H), 6.98 (ddd, J=8.0, 4.8, 1.9 Hz, 1H), 0.32 (s, 9H); EIMS m/z 264, 266.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C[O-].[Na+].[Cl-].[NH4+:24].[C:25]([OH:28])(=[O:27])[CH3:26]>CO>[C:25]([OH:28])(=[O:27])[CH3:26].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[NH:24])[NH2:15])[N:6]=1
Reactant: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nc(Cc2ccccc2F)n2ncccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
584 mg (2.315 mmol) of the compound prepared in Example 6A were added to 125 mg (2.315 mmol) of sodium methoxide in methanol (10 ml), and the mixture was stirred at 20° C. for 16 hours. 148 mg (2.778 mmol) of ammonium chloride and acetic acid (0.517 ml) were then added, and the mixture was heated at reflux for 8 h. The mixture was then concentrated to dryness, the residue was taken up in water and ethyl acetate and 1 N aqueous sodium hydroxide solution was added. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated and then dried under high vacuum. This gave 543 mg of the target compound (71% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1C
Yield: 82.3 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 2.5 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-57). This material was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C(O[CH:13](N(C)C)[N:14]([CH3:16])[CH3:15])(C)(C)C>CN(C)C=O>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccncc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccncc1
Yield: 80.2 %

Procedure:
A solution of 47 g 4-picoline and 105.5 g bis(dimethylamino)methyl tertiary-butyl ether in 125 ml dimethylformamide (DMF) was heated at 140° C. under nitrogen for 18 hours. The solvent was removed in vacuo and the crystalline residue dissolved in boiling cyclohexane (about 3 L). The solution was filtered through filter paper containing charcoal and concentrated in vacuo to give 60 g (80%) 4-(2-dimethylamino-1-ethenyl)pyridine as light orange crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(-n2cncn2)cc1

Procedure:
The title compound is obtained as described in Example 18a/b using 1-fluoro-4-nitro-benzene (Fluka, Buchs, Switzerland) and 1,2,4-triazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 161.2 (M+H)+; analytical HPLC: tret=3.29 minutes (Grad 2).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[NH:19][C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([O:27]C(C)C)=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[NH:19][C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (25 mg, 0.06 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 17 mg (76%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:32]=[C:31]([Br:33])[CH:30]=[C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:21])[C:18]=1[OH:34]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:30]=[C:31]([Br:33])[CH:32]=[C:17]([Br:16])[C:18]=2[O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc(Br)cc(Br)c1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(Br)cc(Br)cc3C(=O)Nc3ccc(Br)cc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 3,5,4′-tribromosalicylanilide (900 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (17 mg, yield 6%).
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.CCOCC>[C:1]1([CH3:34])[CH:2]=[CH:3][C:4]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:32])([CH3:33])[CH2:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)cc2)=CCC4(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CCC(C)(C)c3cc4cccc(-c5ccc(C(=O)O)cc5)c4cc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a degassed solution of ethyl 4-[1(tol-4-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 1, 35 mg, 0.08 mmol), in THF (1.5. mL) and MeOH (1.5 mL) was added LiOH (1M solution in water, 0.3. mL, 0.3 mmol). The mixture was stirred at ambient temperature for 16 hours, diluted with ether (60 mL). The mixture was acidified with 10% HCl to pH 4, the product was isolated as an ether insoluble white solid.
Reaction SMILES: Br.Br[CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[C:18](=[S:21])([S-:20])[NH2:19].[NH4+].O.[OH-].[Na+]>CO>[C:12]1([CH:3]2[S:21][C:18](=[S:20])[N:19]=[C:4]2[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)[S-]
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Agent: Br
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: S=C1N=C(c2cccnc2)C(c2ccccc2)S1

Procedure:
42.0 g of the 2-bromo-2-phenyl-1-(3-pyridyl)-ethanone hydrobromide so obtained are dissolved, while stirring, in 500 ml of methanol (95% strength), the solution is cooled to 10° and, in the course of 5 minutes, 14.93 g of ammonium dithiocarbamate are added in portions. The mixture is cooled for a further 5 minutes, the ice-bath is removed, after 45 minutes again 14.93 g of ammonium dithiocarbamate are added and the mixture is then heated at the boil for 90 minutes and concentrated to dryness by evaporation. The residue obtained by concentration by evaporation is digested with 200 ml of water and 65 ml of 2 N sodium hydroxide solution, filtered with suction and washed with a little water. The product is dissolved in 100 ml of 2 N sodium hydroxide solution, filtered and acidified to pH 5 with 2 N hydrochloric acid. The precipitated crystals are filtered with suction, washed twice with a little ice-water, sucked dry, and then thoroughly washed twice with 30 ml of acetone each time and then twice with 50 ml of diethyl ether each time. 5-Phenyl-4-(3-pyridyl)-thiazoline-2-thione having a melting point of 229°-232° is obtained.
Reaction SMILES: C([N:8]1[C@H:12]2[CH2:13][S:14][C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@H:11]2[N:10](CC2C=CC=CC=2)[C:9]1=[O:30])C1C=CC=CC=1.Br.[OH-].[Na+]>>[OH:22][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C@@H:11]2[C@@H:12]([NH:8][C:9]([NH:10]2)=[O:30])[CH2:13][S:14]1)=[O:21]
Reactant: O=C(O)CCCC[C@@H]1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 3.0 g of (3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-pentanoic acid and 24 ml of 48% hydrobromic acid was refluxed at 110° C. to 120° C. for 48 hours. Hot extraction with 10 ml of toluene was carried out four times to remove benzyl bromide. The aqueous layer was concentrated, 15 ml of water and 11.5 ml of 6M aqueous sodium hydroxide solution were added to the residue, subsequently 3.36 g of ethoxycarbonyl chloride was added dropwise, and the reaction was carried out while maintaining pH to 8 to 10, at room temperature for 3 hours. Thereafter, a temperature of the reaction mixture was raised to 70° C. to 80° C., and the reaction was carried out for 20 hours (during the reaction, pH was maintained to 12 by adding 6M aqueous sodium hydroxide solution). pH was adjusted to 7.4 to 7.8 with 7 ml of 16% hydrochloric acid, and filtration was carried out at 90° C. to 95° C. by using 1.0 g of activated charcoal. The filtrate was heated to 80° C. to 85° C., pH thereof was adjusted to 1.8 to 2.2 by using 6 ml of 16% hydrochloric acid, and neutralization crystallization was carried out. After cooling, crystal was collected by filtration and washed with water, and dried by blowing air at 50° C. to give 1.38 g of (+)-biotin as colorless crystal.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:15]([NH:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2.[C:25](Cl)(=[O:30])[CH2:26][C:27](Cl)=[O:28]>CO>[C:20]([C:19]1[CH:18]=[C:17]([N:16]2[C:27](=[O:28])[CH2:26][C:25](=[O:30])[NH:6][C:7]3[C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=[CH:14][C:15]2=3)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3c(c2N)CCC3)c1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCC2)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a dry tetrahydrofuran (75 mL) solution of 3-(4-aminoindan-5-ylamino)benzonitrile (0.75 g, 3.00 mmol) was added malonyl chloride (0.35 mL, 3.60 mmol) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the mixture was added methanol (5 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the reaction mixture was added methanol (25 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1-4/1) to slightly yellow crystal (0.40 g). The crystal was recrystallized from ethyl acetate to give the titled compound as white crystal (0.28 g, yield 29%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][CH:12]1[CH2:15][C:14](=[O:16])[C:13]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][CH:12]1[CH2:13][C:14](=[O:16])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC1CC(=O)C1(Cl)Cl)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of benzyl 3-(2,2-dichloro-3-oxocyclobutyl)propanoate (8) (11.29 g, 37.49 mmol) in AcOH (100 ml) was treated in small portions with zinc powder (12.26 g, 187.44 mmol, 5 eq.) at RT. After addition, the reaction mixture was stirred at 80° C. for 2 h. LCMS analysis after 2 h shows complete consumption of starting material. The reaction was cooled to RT, diluted with TBME (˜100 ml), filtered and concentrated in vacuo. Heptane (250 ml) was added to remove most of the acetic acid azeotropically. Water (100 ml) was added to the resultant viscous liquid and the mixture was extracted with EtOAc (100 ml×2). The combined organic phase was washed with saturated NaHCO3 (100 ml×1), brine, dried over Na2SO4, filtered and concentrated to yield 8.12 g (93% yield at >95% purity by NMR) of 9 as a clear yellow oil. LCMS analysis on MS 19 shows 92% purity. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.30-7.43 (5 H, m), 5.14 (2 H, s), 3.08-3.21 (2 H, m), 2.64-2.76 (2 H, m), 2.34-2.48 (3 H, m), 1.96 (2 H, q, J=7.62 Hz):
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1)[CH3:9])(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[F:18][C:15]([F:16])([F:17])[C:12]1[NH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:14][CH:13]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1ncc(C(F)(F)F)[nH]1

Procedure:
A solution of [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (50 mg, 179 μmol) in 4M HCl in dioxane (2 mL) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo then triturated with ether to give (S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethylamine hydrochloride (35 mg, quantitative) as a yellow oil. LCMS, [M+H]=180.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:22]2[CH:23]=[C:24]([Cl:35])[N:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:21]2=[N:20][C:19]=1[CH3:36])=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][CH3:8])[C:16]([C:18]2[N:22]3[CH:23]=[C:24]([Cl:35])[N:25]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[CH3:34])[C:21]3=[N:20][C:19]=2[CH3:36])=[O:15])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530 mmol) in toluene (1.5 mL) at 0° C. was added 2.0M solution of trimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solution was warmed to room temperature and stirred for 1 h. A solution of 6-chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (32.2 mg, 0.098 mmol) in toluene (1.0 mL) was added at 0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. A solution of Rochelle's salt (2.0 mL) was added carefully at 0° C. and the mixture was vigorously stirred for 30 min. The crude product was extracted with ethylacetate. The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was purified by a reverse-phase preparative HPLC. Yield—21.3 mg (42%). 1H NMR (CD3CN, 500 MHz) δ 7.69 (s, 1H), 7.16 (s, 2H), 3.59 (t, J=7.3 Hz, 2H), 3.39 (d, J=6.9 Hz, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.05 (s, 6H), 1.68 (sextet, J=7.3 Hz, 2H), 1.11 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 0.60 (m, 2H), 0.23 (m, 2H); LC/MS: tR=1.71 min., MS: [M+H]=413.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>ClCCl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1ccc(F)cc1F
Reaction time: 4 h

Procedure:
5.16 g (40 mmol) of 2,4-difluoroaniline and 6.3 g (40 mmol) of bromoacetyl chloride are treated in 200 ml of dichloromethane with 5.17 g (40 mmol) of Hunig base. After 4 h, the mixture is washed twice with 1N hydrochloric acid and once with water, dried (MgSO4) and concentrated.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[CH3:12][NH2:13].[OH-].[Na+].CCOC(C)=O>S(Cl)(Cl)=O.CN(C=O)C.O>[CH3:12][NH:13][C:8](=[O:10])[CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CN
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CNC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (tetrahydropyran-4-yl)acetic acid (500 mg, 3.47 mmol) in thionyl chloride (10 mL) was added DMF (1 drop). The reaction was heated to reflux for 1 h, cooled to rt and the solvent removed in vacuo. The residue was redissolved in THF (5 mL) and added dropwise to a solution of methylamine hydrochloride (2.34 g, 34.7 mmol) and NaOH (1.11 g, 27.7 mmol) in water. The solution was stirred for 30 min and EtOAc (100 mL) added. The mixture was extracted with EtOAc (5×100 mL) and the combined organic phase dried (MgSO4). Solvent was removed in vacuo to give the title compound: δH (CDCl3) 1.14-1.33 (2H, m), 1.48-1.63 (3H, m), 1.97-2.07 (2H, m), 2.74 (3H, s), 3.26-3.41 (2H, m), 3.87 (2H, dd), 5.34 (1H, bs).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][CH2:6][N:7]1[N:11]=[CH:10][CH:9]=[N:8]1.[OH-].[Na+]>CO>[C:16]([O:15][C:13]([NH:12][CH:4]([CH2:5][CH2:6][N:7]1[N:8]=[CH:9][CH:10]=[N:11]1)[C:3]([OH:20])=[O:2])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C(CCn1nccn1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCn1nccn1)C(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 0.50 g (1.6 mmol) of 2-tert-butoxycarbonylamino-4-1,2,3-triazol-2-yl-butyric acid methyl ester in 1.0 mL of MeOH and 3.0 mL (9.0 mmol) of 3M aq. NaOH is stirred at 80° C. for 60 min The mixture was cooled to rt and washed with EtOAc (1×10 mL). After adjusting the pH to 4 with 3M HCl, the mixture is extracted with EtOAc (3×) and the extracts are washed with brine, then dried with Na2SO4, filtered, and concentrated to provide 0.42 g (87%) of 2-tert-butoxycarbonylamino-4-1,2,3-triazol-2-yl-butyric acid as a white solid.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]Cl)[CH:2]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C1(C)C=CC=CC=1.O>[C:1]1([CH2:9][S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=1.[Na+:15].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: ClCc1cccc(CCl)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(CS(=O)(=O)[O-])c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
In a 300-ml egg-plant type flask provided with cooling pipe for reflux, 17.5 g (0.1 mol) of m-xylylene dichloride was dissolved in 40 ml of toluene, and a solution of 28.0 g (0.22 mol) of sodium sulfite in 40 ml of distilled water was put into the flask. The mixture in the flask was heated in an oil bath kept at 130° C. under refluxing for 24 h, while the mixture was vigorously stirred with a magnetic stirrer using teflon-coated stirring pieces. After that the reaction mixture was cooled to room temperature, and a white precipitate was collected by filtration. The precipitate was dried under reduced pressure and purified by well washing with diethyl ether and then recrystallizing in a 2:1 mixture of water and methanol. The purified product was 16.5 g of sodium m-xylylenedisulfonate (53% yield). The sodium salt was dissolved in distilled water and passed through a column of an ion-exchange resin (Duolite C-20 of Wako Junyaku Co.) to obtain the aimed disulfonic acid.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:27]([CH2:28][NH:29][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:14])=[O:13])[CH:26]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: Cl
Product: CC(C)(C)OC(=O)NCc1cccc(CNS(=O)(=O)c2cccc3cnccc23)c1
Yield: 78.1 %

Procedure:
According to Reference Example 5, Step B, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (9 g) and Intermediate 62 (8 g) to obtain the title compound (11.3 g).