Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][NH2:16])[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])[CH3:19]>CCCCCC.C(OC(=O)C)C>[CH3:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30]([NH:16][CH2:15][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[CH2:9][O:8]1)=[O:31])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC1(C)COC(CN)(C2CCCCC2)OC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a stirred solution of (2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylamine (2.27 g 0.100 mole) in 40 ml of n-hexane/ethylacetate (5:1) is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Precipitated solid is filtered, washed with n-pentane/ether (1:1) and dried, yielding 3.85 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-cyclohexyl-5,5-dimethyl-1,3-dioxan-2-yl)methylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][S:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1)[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CSc1nc[nH]n1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)oxirane methanesulphonte salt (5 g, 0.0137 m), 3-mercapto-1,2,4-triazole (5 g, 0.05 m), and anhydrous potassium carbonate (14 g, 0.1 m) were stirred in dry N,N-dimethylformamide (100 ml) at 80° C. for 1 hour. The solvent was then evaporated and the residue was dissolved in water and extracted with methylene chloride. The combined extracts were washed once with dilute sodium bicarbonate solution, dried (MgSO4), and evaporated to give a solid residue which was recrystallized from isopropanol/water to give the title compound, 3.7 g (74%); m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:3]=1.Cl[Sn](Cl)(Cl)Cl.[I:17]I>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:10]([CH2:11][I:17])[CH2:9][C:4]=2[CH:3]=1
Reactant: II
Reactant: C=CCc1cc(F)ccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2c(c1)CC(CI)O2
Reaction time: 18 h
Yield: 54.7 %

Procedure:
To a solution of 4-fluoro-2-(prop-2-en-1-yl)phenol (5 g, 32.9 mmol) in dichloromethane (125 mL) was added SnCl4 (4.28 g, 16.5 mmol) and iodine (8.36 g, 32.9 mmol) at room temperature. After an additional 18 hours, the reaction was quenched with water (150 ml) and the pH value was adjusted to ˜8 with aqueous sodium hydroxide solution (2N). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layer was washed with Na2S2O4 (3×100 mL, 5%) to remove iodine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography using 0.5-1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-fluoro-2-(iodomethyl)-2,3-dihydro-1-benzofuran as a yellow oil (5 g, 54%); 1H NMR (300 MHz, DMSO): δ 7.03-7.08 (dd, J=5.7 Hz, 8.4 Hz, 1H), 6.93-6.86 (dt, J=2.7 Hz, 8.7 Hz, 1H), 6.76-6.70 (m, 1H), 4.88-4.79 (m, 1H), 3.49-3.60 (m, 2H), 3.41-3.32 (dd, J=7.2 Hz, 16.5 Hz, 1H), 2.96-2.88 (dd, J=7.2 Hz, 16.5 Hz, 1H).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[CH3:38])[CH2:27][CH2:26]2)=[O:24])[CH2:12]1)=O)(C)(C)C>O1CCOCC1>[ClH:37].[ClH:1].[NH2:9][CH2:10][C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[CH3:38])[CH2:27][CH2:26]2)=[O:24])[CH2:12]1
Reactant: Cc1c(Cl)cccc1N1CCN(C(=O)[C@@H]2C[C@@H](CNC(=O)OC(C)(C)C)CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cl)cccc1N1CCN(C(=O)[C@@H]2C[C@@H](CN)CN2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (3 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-prolyl]-4-(3-chloro-2-methylphenyl)piperazine (B, 98 mg) in 1,4-dioxane (3 mL) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was concentrated in vacuo. The residue was washed with ether to give the titled compound (61 mg) as a white powder: 1H NMR (400 MHz, ) δ 2.37 (s, 3H), 2.40-2.47 (br s, 2H), 2.83 (br s, 1H), 3.07 (br s, 4H), 3.32 (br s, 3H), 3.77 (m, 5H), 5.02 (br s, 1H), 7.09 (m, 1H), and 7.25 (m, 2H).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].C([CH:10]([CH2:15][CH2:16][CH2:17]C)[CH2:11][C:12]([OH:14])=[O:13])C.[N+]([O-])([O-])=O.[Co+2:23].[N+]([O-])([O-])=O>C1CCCCC1>[CH3:17][CH2:16][CH2:15][CH2:10][CH:11]([C:12]([O-:14])=[O:13])[CH2:1][CH3:2].[CH3:17][CH2:16][CH2:15][CH2:10][CH:11]([C:12]([O-:14])=[O:13])[CH2:1][CH3:2].[Co+2:23]
Reactant: CCN(CC)CC
Reactant: CCCCC(CC)CC(=O)O
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCCCC1
Product: CCCCC(CC)C(=O)[O-]
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Using a 1 liter flask, 0.40 mol triethylamine is added with stirring at room temperature to 0.40 mol 2-ethyl hexane carboxylic acid. After the exothermic reaction has abated, the reaction mixture is diluted with 65 ml cyclohexane and 0.20 mol cobalt nitrate is added. After stirring for 30 minutes, the reaction solution is filtered, leaving a 55.5% blue cobalt octoate solution in cyclohexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:18]([O-])([O:20]C(C)C)=[O:19].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2ccccc2)cc1O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2)c([N+](=O)[O-])c1O

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzophenone (10.0 g, 43.8 mmol) in dichloromethane (100 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.74 g, 5 mol %) followed by isopropyl nitrate (11.5 g, 87.6 mmol). Sulphuric acid (96%, 10 mL) was then added dropwise causing a gently exothermic reaction, and, after stirring for forty minutes, the reaction mixture was poured onto water (300 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was recrystallised from a small volume of ethanol (96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137–139° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent chromatography on silica gel using a petroleum ether:ethyl acetate solvent mixture (2:1) allowed the isolation of a small amount of a minor product, corresponding (TLC) to a standard of the para-nitrated product, 3-hydroxy4-methoxy-6-nitrobenzophenone (1.43 g, 12%), m.p. 154–156° C. (79% combined yield, Ortho:Para selectivity, 5.6:1)
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:13]>C(O)C>[NH2:13][CH2:10][C@H:9]([OH:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC[C@H](O)COc1ccccc1

Procedure:
A stirred solution of (2S)-1-phenoxy-2,3-epoxypropane (1.0 g) and concentrated ammonium hydroxide (10 ml) in ethanol (10 ml) was sealed up at room temperature for 12 hours. The mixture was evaporated in vacuo and dried to give (2S)-1-amino-3-phenoxy-2-propanol (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:17][CH:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23].C[Al](C)C>ClCCCl>[Br:17][CH:18]([CH2:22][CH2:21][OH:20])[C:19]([NH:16][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[CH:13]([CH3:14])[CH3:15])=[O:23]
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: O=C1OCCC1Br
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CC(C)c1c(NC(=O)C(Br)CCO)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (1.0 g, 4.54 mmol), 3-bromotetrahydrofuran-2-one (0.462 mL, 5.0 mmol) and AlMe3 (3.4 mL, 6.8 mmol, 2 M in toluene) in DCE (50 mL) was stirred for 2 hrs at rt followed by 45 min at 50° C. The mixture was then cooled to room temperature, quenched with 1N HCl (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/CH2Cl2 gradient elution) to give 2-bromo-N-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-4-hydroxy-butanamide (1.38 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([CH2:16][CH2:17]Cl)(=[O:15])=[O:14])=[O:11])[N:3]=1.[OH-].[Na+]>C(O)C.O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)CCCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CS(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 40 °C

Procedure:
14.6 g (0.05 mole) of N-(4,6-dimethyl-pyrimidin-2-yl)-N'-(2-chloro-eth-1-yl-sulfonyl)-urea (cf. Example 12) were dissolved in 150 ml of ethanol, and 4 g (0.1 mole) of sodium hydroxide, dissolved in 10 ml of water, were added at room temperature. The reaction mixture was then warmed to 40° C. for 4 hours, concentrated in vacuo and taken up in 150 ml of water. After acidification with 2 N HCl (pH 5), the mixture was extracted with ethyl acetate, and the extracts were then dried and concentrated. After the addition of n-hexane, 8.9 g (69.5% of theory) of N-(4,6-dimethyl-pyrimidin-2-yl)-N'-(vinylsulfonyl)-urea of melting point 131°-3° C. were obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:40])[CH3:39])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]([CH3:39])[CH3:40])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-6-(isopropyl carbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: C1COCCO1
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 3-amino-6-bromopyrazine-2-carboxylate (15 g, 64.6 mmol) was suspended in 150 mL of dioxane at room temperature. Hydrazine hydrate (6.5 g, 130 mmol) was added and the reaction mixture was stirred at 60° C. for 2 hours. Initially the mixture became clear, but after a while a precipitate formed. The mixture was cooled to ambient temperature and crude product filtered off. The solid was washed with TBME and subsequently stirred in water. The material was filtered and washed with acetone to afford 3-Amino-6-bromopyrazine-2-carbohydrazide 4 as slightly yellow solid. The material was dried in vacuo. (10.5 g, 70%).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[C:4]=1[C:2]#[N:3]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCCC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 191a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 191b) and butyryl chloride to in 90% yield as a white solid. MS 288 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CO.C[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OCC(CO)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1000 ml round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were added 132.2 g (1.0 mol) of 2,2-dimethyl-1,3-dioxolane-4-methanol, 202.5 g (1.05 mol) of a 28% methanol solution of sodium methoxide, and 500 ml of toluene. With introduction of nitrogen thereinto, toluene was refluxed under reduced pressure for 1 hour to remove the methanol by evaporation. With maintaining the solution at 80° C., 126.6 g (1.0 mol) of benzyl chloride was added dropwise over a period of 2 hours using a dropping funnel, followed by another 2 hours of reaction. After completion of the reaction, the temperature was lowered to 60° C. and 10 g of KYOWAAD 600 was added, followed by 1 hour of stirring. After filtration of the reaction liquid, the solvent was removed and the residue was purified by distillation (b.p. 93-95° C./266 Pa) to obtain 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[Pd]>[C:19]1(/[CH:18]=[CH:17]\[C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Fc1ccc(-c2n[nH]c3ccc(/C=C\c4ccccc4)cc23)cc1
Reaction time: 5 h
Yield: 45.7 %

Procedure:
A mixture of 3-(4-fluorophenyl)-5-(2-phenylethynyl)-1H-indazole (0.050 g, 0.16 mmol), quinoline (0.030 g), and palladium (5 wt. % on barium carbonate, 0.015 g) in ethyl acetate (10 mL) was stirred under hydrogen for 5 hours. It was filtered with celite and washed with ethyl acetate. The filtrate was washed with 5% hydrochloric acid solution and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) and by HPLC to provide the title compound (0.023 g, 46% yield): 1H NMR (CDCl3) δ 10.15 (br s, 1H), 7.83 (s, 1H), 7.70 (m, 2H), 7.29 (m, 7H), 7.11 (t, 2H), 6.72 (d, 1H), 6.68 (d, 1H); ES-MS (m/z) 315 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Temperature: 125 °C

Procedure:
A mixture of cis-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.39 g, 1.6 mmol) and hydrazine hydrate (0.40 ml, 8.2 mmol) in n-butanol (0.5 ml) was heated at 125° C. over night. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.35 g, 91%) as colorless oil, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and cyclohexanamine (CAN 108-91-8) as starting materials, MS (EI) m/e: 315.1 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Si:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN(C)P(=O)(N(C)C)N(C)C.ICCCC>C(O)(C)C.O1CCCC1.CCCCCC>[Si:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])([S:19]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:1][CH2:2][CH2:3][CH3:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCCCI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC(CCCCO[Si](C)(C)C(C)(C)C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.287 ml, 0.450 mmol) was added to a tetrahydrofuran (4 ml) solution of the 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (200 mg, 0.409 mmol) obtained in Example 15. The temperature of the resulting mixture was raised to room temperature. After cooling to −78° C., hexamethylphosphoric triamide (0.214 ml, 1.23 mmol) and iodobutane (51.1 μl, 0.450 mmol) were added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 20 hours. Isopropanol (0.5 ml) was added to the reaction mixture, followed by concentration. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (5% ethyl acetate-hexane), whereby the title compound (163 mg, 73%) was obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.CC(NC(C)C)C>CO>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]5=[N:6][C:5]=4[CH3:17])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CO
Solvent: CC(C)NC(C)C
Product: COC1CCc2nc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(=O)n2C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4.8 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 6.1 parts of N-(1-methylethyl)--2-propanamine and 16 parts of methanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.5 parts (100%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one as an oily residue. (intermediate 5)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:3]1>C(O)C.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:3]1
Reactant: COC(=O)C1CN(C)C=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.0 g of manganese dioxide was added to a stirred solution of 4.7 g of 38D in ethanol-free, chloroform and the mixture was stirred overnight at room temperature. The mixture was heated at reflux for 1 hour, cooled, 9.5 g of manganese dioxide was added; the mixture was stirred at room temperature for 2 hours and at reflux for 30 minutes. The mixture was cooled and filtered and the filtrate was stripped of solvent to give methyl 1-methylimidazole-4-carboxylate (38E), as a yellow solid, m.p.: 72.5°-81° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C=CCOC(C1C2C(=CC=CC=2)N=CC=1)C1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)CC(C=C)C(CC2)C1.[Br-].C(Cl)Cl.[Br:67][C:68]1[CH:69]=[C:70]([CH:73]=[CH:74][C:75]=1[F:76])[CH2:71]Br>CCOCC.O>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:71][C:70]1[CH:73]=[CH:74][C:75]([F:76])=[C:68]([Br:67])[CH:69]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C=CCOC(c1ccnc2ccccc12)C1CC2CC[N+]1(Cc1c3ccccc3cc3ccccc13)CC2C=C
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)c(Br)c1)N=C(c1ccccc1)c1ccccc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a flame-dried flask was added (benzhydrylidene-amino)-acetic acid tert-butyl ester (250 mg, 0.846 mmol), O-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide (51 mg, 0.085 mmol), and DCM (5 mL). The flask was cooled to −55° C. and CsOH.H2O (1.4 g, 8.46 mmol) was added. The mixture was stirred for 30 min, treated with 3-bromo-4-fluorobenzyl bromide (1.1 g, 4.23 mmol), and stirred at −55° C. overnight. The mixture was diluted with Et2O (5 mL) and water (10 mL), warmed to rt, and washed with water and brine. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography to provide the title compound (300 mg, 74%, er=97:3). MS (ESI+): mass calcd. for C26H25BrFNO2, 482.4; m/z found, 483.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.59-7.54 (m, 2H), 7.41-7.20 (m, 7H), 7.02-6.91 (m, 2H), 6.72 (d, J=6.5 Hz, 2H), 4.11-4.07 (m, 1H), 3.19-3.08 (m, 2H), 1.45 (s, 9H).