Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH2:45][NH2:46])[CH2:9]1)=O)(C)(C)C.[C:47](Cl)(=[O:49])[CH3:48]>>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=4[CH:30]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[CH2:45][NH:46][C:47](=[O:49])[CH3:48])=[CH:32][CH:33]=1)[CH3:44]
Reactant: CC(=O)Cl
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CNC(C)=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
Analogously to example 2a, (3R,4R,5R)-3-aminomethyl-4-[4-((R)-2-ethoxypropoxy-methyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 6a) and acetyl chloride are used to afford the title compound as a yellow oil oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (EtOAc); Rt=4.87 (gradient I).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]1=[O:12].[Cl-].[CH3:15][S+](C)C>CS(C)=O>[CH3:13][C:4]1([CH3:3])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]21[O:12][CH2:15]2
Reactant: CC1CCC(C)C(C)(C)C1=O
Reactant: C[S+](C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1CCC(C)C2(CO2)C1(C)C
Reaction time: 6 h

Procedure:
According to a preferred embodiment of the invention, NaOH is added to a mixture consisting of 2,2,3,6-tetramethyl-1-cyclohexanone and trimethylsulfonium chloride in dimethylsulfoxide. The reaction is slightly exothermic, hence the necessity to maintain an external cooling of the reaction mixture so as to keep the temperature at about 25°-30° C. Good stirring is also applied for about 6 hr. 4,4,5,8-Tetramethyl-1-oxaspiro[2.5]octane is then obtained by extraction of the resulting mixture with petrol ether, concentration of the organic extracts and fractional distillation.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)oc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)O)oc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
A solution of methyl 2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-5-methyl-1,3-oxazole-4-carboxylate (Preparation 173) (2.92 g, 7.43 mmol) in anhydrous dichloromethane (15 ml) was treated with trifluoroacetic acid (7.5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was azeotroped with dichloromethane (×3). The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (0:100 to 40:60) to afford the title compound as a colourless oil (2.50 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[OH-].[Na+]>O.C(O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1

Procedure:
1.00 g of 4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazoline is dissolved in 16 ml of water, 35 ml of ethanol and 1.3 ml of glacial acetic acid and heated to boiling. Then 540 mg of iron powder are added with stirring. The reaction mixture is refluxed for about another 35 minutes. For working up the cooled reaction mixture is diluted with 15 ml of ethanol, made alkaline with 15 N sodium hydroxide solution, combined with 20 g of Extrelute and stirred for about 20 minutes. The precipitate formed is suction filtered and washed with 200 ml of warm ethanol. The filtrate is concentrated by evaporation, mixed with about 30 ml of water and extracted 3× with 70 ml of methylene chloride/methanol (9:1) each time. The combined extracts are dried over sodium sulfate and concentrated by evaporation, leaving a beige solid. Yield: 716 mg (76% of theory); melting point: 191° C.-198° C.; mass spectrum (ESI+): m/z=470, 472 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12].O>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:1](=[O:3])[CH3:2])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Yield: 99.7 %

Procedure:
To a solution of acetyl chloride (0.23 mL, 3.3 mmole) and aluminum chloride (0.88 g, 6.6 mmol) in methylene chloride (30 mL) was added 1H-indole-6-carboxylic acid methyl ester (0.53 g, 3.0 mmol). After stirring 1 hr at room temperature water (300 mL) was added and then this was extracted with ethyl acetate (300 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.65 g (99% yield) of 3-acetyl-1H-indole-6-carboxylic acid methyl ester a light yellow solid. 1H NMR (300 MHz, DMSO) δ 12.27 (s, 1H), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2 Hz), 8.08 (d, 1H, J=1.0 Hz), 7.78 (dd, 1H, J=8.2, 1.0 Hz), 3.86 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14][C:15]#[N:16].[C:17](OCC)(=[O:19])[CH3:18]>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([C:17](=[O:19])[CH3:18])[C:15]#[N:16]
Reactant: COCCOc1cccc(CC#N)c1OC
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1cccc(C(C#N)C(C)=O)c1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 171.1 %

Procedure:
To a suspension of (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.17 g, 0.76 mmol) sodium hydride (40% oil dispersion, 93 mg, 2.3 mmol) in tetrahydrofuran (5 mL), was added ethyl acetate (0.37 mL, 0.38 mmol), and the resulting mixture was stirred at 60° C. for 1.5 hours. Then it was cooled to room temperature, and poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 2. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.17 g, 0.65 mmol, 85% yield). MS (EI) for C14H17NO4: 264 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][Mg]Br>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)O

Procedure:
The general method described in Step 7 of Example 1 was used to react 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (8.5 g, 28.8 mmol) with methylmagnesium bromide (20.6 mL of a 1.4 M solution in toluene/THF, 28.8 mmol) to provide 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (3.54 g) as an off-white solid after chromatography on silica gel (elution with 5% methanol in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Product: CCOC(=O)CCCN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O

Procedure:
1-(2,4-Dimethoxybenzyl)-2,3-dioxopiperazine was reacted with ethyl 4-bromobutyrate by the same method as in Reference Example 12 to obtain ethyl 4-[4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]butyrate as an oil.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[CH2:11]([O:18][C@@H:19]1[C@@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:22][C:20]1([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][C:58]2[C:67]3[C:61]([CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:60]([CH3:68])[CH:59]=2)[CH:52]=1)O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([O:18][C@@H:19]1[C@@H:25]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([CH2:42][O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:22][C@H:20]1[C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][C:58]2[C:67]3[C:61]([CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:60]([CH3:68])[CH:59]=2)[CH:52]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(Cc2cccc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)c2cccccc1-2
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cc2cccc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)c2cccccc1-2
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Boron trifluoride-diethyl ether complex (0.39 ml) and triisopropylsilane (1.23 ml) were added dropwise to a solution of 2,3,4,6-tetra-O-benzyl-1-C-[3-[(3-methylazulen-1-yl) methyl]phenyl]-D-glucopyranose (2.3 g) in acetonitrile (40 ml) at −40° C. and the mixture was stirred for two hours. Saturated aqueous solution of potassium carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-[(3-methyl azulen-1-yl)methyl]phenyl]-D-glucitol (1.47 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.Cl.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17]N.B(F)(F)F.CCOCC>C(O)(=O)C>[F:9][C:10]([F:19])([F:20])[C:11]1[C:12]2[NH:17][C:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]=3[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C1CCNCC1
Agent: Cl
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: FC(F)(F)c1cccc2c3c([nH]c12)CCNC3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 4-piperidone.HCl (1.36 g, 10.0 mmol) and 2-trifluoromethylphenylhydrazine.HCl (2.13 g, 10.0 mmol) in acetic acid (50 mL) was added the 1.0 M borontrifluoride etherate (2.46 mL, 20.0 mmol) and the reaction stirred at 90° C. for 8 hours and then allowed to cool. The mixture was concentrated in vacuo and ethanol (ca 20 mL) added and then cooled to 0° C., the solid was filtered off and the mother liquor was concentrated in vacuo and water (adjusted to pH 14 with 2M NaOH) added to the residue. The solid was filtered off and washed with water and dried under high vacuum.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]=[O:23])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1.[NH4+].[Cl-]>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:23])[CH2:26][CH:25]=[CH2:24])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Yield: 96.5 %

Procedure:
A mixture of compound 16 (448 mg, 1.14 mmol), In powder (150 mg, 1.31 mmol) and allyl bromide (160 μL, 1.87 mmol) were stirred in a mixture of 10 mL THF and 10 mL aq. NH4Cl for 3 hours. THF was removed in vacuo, and residue was extracted with EtOAc and then dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue was purified by SiO2 column chromatography (hexanes/EtOAc=2/1) to yield 17 as a colorless oil (478 mg, 1.10 mmol, 96% yield). 1H NMR (500 MHz, CDCl3) δ 8.13 (d, 1H, J=8.0 Hz), 7.96−7.93 (m, 2H), 7.76 (d, 1H, J=9.0 Hz), 7.68 (t, 1H, J=8.5 Hz), 7.54−7.50 (m, 3H), 7.42 (d, 1H, J=8.5 Hz), 5.89−5.80 (m, 1H), 5.11−5.03 (m, 2H), 4.97 (s, 2H), 2.73−2.69 (m, 1H), 2.54−2.48 (m, 1H). 13C NMR (500 MHz, CDCl3) δ 163.40, 148.17, 144.08, 137.34, 135.61, 134.86, 133.88, 129.40, 128.67, 128.01, 126.84, 122.47, 119.53, 118.22, 118.12, 72.24, 42.34. MS-ESI (m/z): [M+H]+ calculated for C19H17BrNO4S, 434.01 (79Br) and 436.00 (81Br); found 434.11 (79Br) and 436.10 (81Br).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>C1COCC1>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][NH:1][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)CCN
Solvent: C1CCOC1
Product: CC(C)CCNc1ccccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 59.8 %

Procedure:
A solution of amino 3-methylbutane (1.5 g) in THF (20 ml) was dropped into a solution of 2-fluoronitrobenzene (2.4 g) in THF (20 ml), at 23° under a nitrogen atmosphere. The mixture was stirred at 23° for 3 h, then heated at reflux for 1.5 h. The mixture was allowed to cool to 23°, then concentrated under vacuum to give a crude compound which was purified by flash chromatography on silica gel using CH-EA 9/1 as eluants to give the title compound as a yellow oil (2.12 g). T.l.c. CH-EA (8/2), Rf 0.79. IR:3383 (NH); 1620 (C=C) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4](F)[CH:3]=1.CN(C=O)C.[CH3:18][S-:19].[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([S:19][CH3:18])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1cc(Br)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.9 %

Procedure:
Dissolve 4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) into DMF (8 mL) and treat with sodium thiomethoxide (103 mg, 9.8 mmol). Stir at room temperature for 2 days. Add water (10 mL) and CH2Cl2 (20 mL). Separate the layers and wash the organic layer with aqueous lithium chloride (10%), then dry (magnesium sulfate) and evaporate in vacuo. Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane to give 286 mg (76%) of the title compound.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:10]=1>>[ClH:8].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cncc(N2CCNCC2)n1

Procedure:
In 15 ml of a 4M hydrochloric acid-ethyl acetate solution, 0.71 g of 2-chloro-6-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine was stirred at room temperature for 7 hours. The solvent was evaporated to obtain a crude product of 2-chloro-6-(piperazin-1-yl)pyrazine hydrochloride. The obtained crude product and 0.62 g of 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid were treated in a similar manner to Example 4 to obtain 594 mg of 2-chloro-6-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazine as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)O)=[O:4].[Cl:23][C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[Br:10][C:8]1[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH:14]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[C:25]=2[F:31])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cn1
Reactant: Nc1cccc(Cl)c1F
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cn1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(5-chloro-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BK2) and 3-chloro-2-fluoroaniline [367-21-5] were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a white foam. ESI-MS: tR=1.59 min, [M+H]+ 514/516/518 (LC-MS 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[OH:15].[C:16]1([CH3:25])[C:17]([N:22]=[C:23]=S)=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[CH3:9][O:8][C:7]1[C:2]2[N:1]=[C:23]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:25])[O:15][C:3]=2[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=1
Reactant: COC(=O)Cc1cc(O)c(N)c(OC)c1
Reactant: Cc1ccccc1N=C=S
Solvent: CCO
Product: COc1cc(CC(=O)O)cc2oc(Nc3ccccc3C)nc12
Temperature: 45 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
A mixture of methyl 4-amino-3-hydroxy-5-methoxy-phenylacetate [0.295 g, Reference Example 10(a)] and o-tolylisothiocyanate (2.14 g) in ethanol (25 mL) was left at room temperature for 3 days. The mixture was evaporated and a solution of the residue in ethanol (20 mL) was treated with dicyclohexylcarbodiimide (0.308 g). The mixture was heated at reflux temperature for 2.5 hours and then evaporated. The resulting brown oil was dissolved in methanol (30 mL) and the solution was treated with sodium hydroxide solution (10 mL, 1M) and then heated at 45° C. for one hour. The mixtures was diluted with water and then partially evaporated. The residue was washed twice with diethyl ether and the pH of the aqueous phase was adjusted to 1-2 by addition of dilute hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic phase was washed with water, then with brine, then dried and then evaporated to give the title compound (0.42 g) as a golden solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Temperature: 150 °C

Procedure:
A mixture of 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (400 mg), 4-(methanesulfonyl)phenyl boronic acid (321 mg), aqueous Na2CO3 solution (2 M; 1.60 mL), and dioxane (15 mL) is sparged with argon for 10 min and Pd(PPh3)4 (100 mg) is added. The resulting mixture is heated to 150° C. in a microwave oven until the conversion is complete. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 40:60→20:80) to give the title compound. LC (method 3): tR=1.32 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74–6.88 (m, 12H), 5.27–5.16 (m, 1H), 3.69–3.52 (m, br, 2H), 3.10–2.81 (br, 2H), 2.81–2.57 (m, br, 4H), 2.54 (s, 3H), 2.52–2.40 (m, br, 2H), 2.05–1.80 (m, br, 6H), 1.66–1.42 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C34H42Cl2N2O30.5CH2Cl2.1.0H2O: C, 63.46; H, 6.91; N, 4.30. Found: C, 63.46; H, 7.09; N, 4.00. ESMS m/e: 561.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[O:13]C(C)(C)CN=1)[CH3:2].CI.[OH-:21].[K+]>CS(C)=O.O>[CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]([OH:13])=[O:21])[CH3:2]
Reactant: [OH-]
Reactant: CCc1c(C2=NCC(C)(C)O2)ccc(C)c1OC
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CCc1c(C(=O)O)ccc(C)c1OC
Temperature: 0 °C

Procedure:
2-(2-Ethyl-3-methoxy-4-methylphenyl)-5,5-dimethyloxazoline, synthesized in like manner according to EXAMPLE 10, (2.7 g, 13.1 mmoles) and 2.2 mL (35.3 mmoles) of methyl iodide were dissolved in 4 mL of dimethyl sulfoxide. The resultant mixture was stirred for 18 hours at room temperature. A solution of 4.2 g of potassium hydroxide in 35 mL of water was added, and the mixture was heated at reflux for 8 hours. About 40 g ice was added, and the solution was extracted with ether. The aqueous layer was cooled on ice and acidified with 5% hydrochloric acid. The resulting precipitate was filtered and air-dried to yield 1.69 g of product. 1H NMR (200 MHz, CDCl3), δ=7.72 (1H, d, 8 Hz), 7.1 (1H, d, 8 Hz), 3.77 (3H, s), 3.06 (2H, q, 7 Hz), 2.36 (3H, s), 1.22 (3H, t, 7 Hz) ppm.