Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-:29].[NH4+]>CCOCC>[ClH:29].[F:2][C:3]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:17]1([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH:15]([N:13]([CH3:12])[CH3:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: Fc1cccc(CBr)c1F
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1cccc(F)c1F
Product: Cl
Temperature: 25 °C
Yield: 30 %

Procedure:
0.41 g (16.8 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.47 g (16.8 mmole) of 2,3-difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.23 g (14.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.13 g of crude base (102% of theory) were obtained, from which 1.67 g of 1-(2,3-difluorobenzyl)-2-(dimethylamino-phenylmethyl)cyclohexanol, hydrochloride (30.0% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 140° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:6].[CH2:10]1[CH2:15][O:14][CH:13]=[CH:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:15][O:14]1
Reactant: Oc1cccc(CBr)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Hydroxybenzyl bromide (1.00 g, 5.35 mmol), DHP (0.89 g, 10.09 mmol), pyridinium-p-toluenesulfonate (0.20 g, 0.80 mmol) were dissolved in methylene chloride (20 mL) and stirred at room temperature for 5 h. The mixture was concentrated and chromatographed without workup. The product 42 was obtained as colorless oil (1.25 g, 87% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH3:20])=[O:9])([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 2-nitrocinnamic acid (7) (10.38 g, 53.76 mmol) dissolved in methanol (200 ml) was dropped a small amount of concentrated sulfuric acid at room temperature, and the reaction mixture was stirred at 70° C. for 12 hours. After the reaction was completed, the resulting solution was basified with a saturated aqueous solution of sodium bicarbonate to weak basicity and extracted with dichloromethane three times. Then, the organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:5) to give the target compound (11.03 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][C:19]3[C:18]([CH3:27])([CH3:26])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>CO.C(OCC)C>[OH:25][CH2:24][CH2:23][CH2:22][C:21]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=2)=[CH:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][CH2:17][C:18]([CH3:26])([CH3:27])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CCCO)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(CCCO)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 27.0 g (0.66 mmol) of Methyl-4-{(E)-2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate in 10 mL of methyl alcohol was added 5 mL of 1 N LiOH. The reaction mixture was heated to reflux. After 4 hours, the reaction mixture was cooled to room temperature, diluted with diethyl ether and acidified with concentrated HCl. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by crystallization (hexane/ethyl acetate) to give 200 mg (76%) of 4-{(E)-2-[3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoic acid (m.p.: 212.8-213.2° C.) 12.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[N:41]=[C:42]([C:6]3[CH:5]=[C:4]([C:16]4[CH:17]=[N:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(OS(=O)(=O)C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 6′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl-2′-yl ester (Example A.5) (0.193 g, 0.5 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example C.2) (0.264 g, 0.455 mmol), tetrakis(triphenyl-phosphine)palladium (0.029 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (110 mg, 42%). MS (ISP) 527.0 [(M+H)+]; mp 187-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16]Br)[C:7]1=2)[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CC#N.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16][N:20]=[N+:21]=[N-:22])[C:7]1=2)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CN=[N+]=[N-])c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a crude (4-bromomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester in CH3CN/H2O (10/2 mL) was added sodium azide (3.1 g, 48 mmol). The solution was stirred overnight at r.t. The crude solution was purified by HPLC, yielded 450 mg of the title compound. 1H NMR (300 MHz, CD3CN) δ 7.21 (s, 1H), 6.99 (s, 1H), 5.61 (dd, 1H), 4.31-4.56 (dd, 2H), 4.10 (q, 2H), 3.02-3.14 (dd, 1H), 2.37-2.43 (m, 1H), 1.21 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])=[CH:3]1.[C:20](=S)=[S:21]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=[C:20]2[SH:21])=[CH:3]1
Reactant: Cn1cc(CNc2ccccc2N)c2ccccc21
Reactant: S=C=S
Solvent: c1ccncc1
Product: Cn1cc(Cn2c(S)nc3ccccc32)c2ccccc21
Yield: 38.7 %

Procedure:
212 mg (0.845 mmol) of ((1-methylindole-3-yl)methyl)(2-aminophenyl)amine were dissolved in 1 ml of pyridine followed by the addition of 1 ml (16.9 mmol) of carbon disulfide and refluxing for 1 hour in a nitrogen atmosphere. The solvent was distilled off followed by purification by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 96 mg of 1-((1-methylindole-3-yl)methyl)benzimidazole-2-thiol (yield: 39%).
Reaction SMILES: [F:1][C:2]([F:16])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[OH2:17].[OH2:18].O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=O.[Mg]>ClCCl.O>[F:16][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:18])=[O:17]
Reactant: O
Reactant: FC(F)=CCCSc1nc2ccccc2s1
Agent: O=C(O)c1ccccc1C(=O)OO
Agent: [Mg]
Solvent: ClCCl
Product: O=S(=O)(CCC=C(F)F)c1nc2ccccc2s1
Reaction time: 48 h

Procedure:
2-(4,4-difluorobut-3-enylthio)benzthiazole (prepared by the method described in United Kingdom Patent Application GB2270689A, 8.25 g) in dichloromethane ( 15 cm3) was added to a rapidly stirred mixture of monomagnesium peroxyphthalic acid hexahydrate (25.7 g, 70-80% technical grade) in water (25 cm3). The mixture was stirred for 2 days, diluted with dichloromethane and water, the organic phase separated, washed with aqueous sodium carbonate, water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure to give 2-(4,4-difluorobut-3-enylsulfonyl )benzthiazole as a colourless oil, 4.9 g.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[C:7](=[CH:10][S:11][CH:12]=2)[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:6]2[C:7](=[CH:10][S:11][CH:12]=2)[N:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c([N+](=O)[O-])c[nH]c2cscc12
Product: O=[N+]([O-])c1cnc2cscc2c1Cl
Temperature: 105 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 3.00 g of 3-nitrothieno[3,4-b]pyridin-4(1H)-one 10 and 9 ml of phosphorous oxychloride is stirred at 105° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with aqueous ammonia and water. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 2.02 g (60%) of Compound 11. Recrystallization from ether-petroleum ether affords colorless crystals melting at 139°-140° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 411.1 (M+1).
Reaction SMILES: C=O.[C:3](O)(=O)C.[C:7]([BH3-])#[N:8].[Na+].N[C@H:12]1[C@@H:17]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:16][CH2:15][N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:13]1>O1CCCC1.CO>[CH2:22]([O:21][C:19]([NH:18][C@H:17]1[CH2:16][CH2:15][N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:13][C@H:12]1[N:8]([CH3:7])[CH3:3])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A 37% aqueous formaldehyde solution (346 μL, 4.26 mmol), acetic acid (110 μL, 1.92 mmol) and sodium cyanoborohydride (67 mg, 1.07 mmol) were added to a mixed solution of tert-butyl cis(±)-3-amino-4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example (200a) (149 mg, 0.43 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) under ice-cooling, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 152 mg of the title compound (94%) as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([S:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:24])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([S:22]([CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3])(=[O:24])=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)O

Procedure:
2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)- 3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester (8.9 g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide (25 mL). Yield 6.0 g (72%).
Reaction SMILES: [OH:1][C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:1][C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2OC1(C)C

Procedure:
In 15 ml of anhydrous methylene chloride, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 1. Then, 0.49 ml of pyridine and 73 mg of 4-dimethylaminopyridine are added. Then, 0.43 ml of acetic anhydride is dropped thereinto at 0° C. and reacted at room temperature for 30 minutes. After stopping the reaction by adding water to the reaction mixture, it is extracted with ether. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/3 mixture of ethyl acetate/methylene chloride as a developing solvent to obtain 1.45 g of trans-3-acetoxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[N:28]=3)[C:21]3[CH:34]=[CH:35][CH:36]=[CH:37][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)C(=O)[O-])(C)C>CC(O)C.Br.C(O)(=O)C>[NH2:5][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[N:28]=3)[C:21]3[CH:34]=[CH:35][CH:36]=[CH:37][C:20]=3[N:19]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)N(CCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1)C(=O)[O-]
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)O
Product: NCCN1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Yield: 18.7 %

Procedure:
A mixture of compound (7) (0.0026 mol) in 2-propanol (30 ml) and HBr/acetic acid (2 ml) was stirred and refluxed for 90 minutes and then cooled. The solvent was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried. This fraction was purified again by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in diisopropyl ether. The precipitate was filtered off and dried, yielding 0.23 g of (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine (compound 9).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([C:12](=[CH:14][C:15](=[C:17]([CH:19]=1)[CH3:18])[CH3:16])[CH3:13])[CH3:11]>>[Cl:5][CH2:6][C:7]([C:19]1[C:17]([CH3:18])=[C:15]([CH3:16])[CH:14]=[C:12]([CH3:13])[C:10]=1[CH3:11])=[O:8]
Reactant: Cc1cc(C)c(C)cc1C
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(C)c(C(=O)CCl)c1C
Yield: 84.6 %

Procedure:
Example 1 was repeated but 1.33 g of aluminium trichloride, 1.13 g of chloroacetyl chloride and 1.34 g of durene were employed. 1.78 g of 3-chloroacetyl-durene were obtained, melting point 65.5°=66° C. The product was purified by distillation (bp 113°-117° C.)/0.4 mmHg) and crystallized from ethanol. Similarly, 3-bromoacetyl-durene, melting 53°-54° C. was obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:9]2)[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:9]2)[O:24]1
Reactant: OCCCCCCCCCCCCCCBr
Reactant: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC1CCC2(CC1(CCCCCCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (1.8 ml) was added dropwise to a 5 ml THF solution of 560 mg of 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane under an argon gas stream at −78° C. The resulting mixture was stirred for 10 minutes and then reacted at room temperature for one hour. HMPT (1 ml) was added and the resulting mixture was cooled to −78° C. again, followed by the dropwise addition of a 2 ml THF solution of 205 mg of 14-bromo-1-tetradecanol. After reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ether. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil (yield: 98%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[NH2:2].[OH:18]O.O>S(=O)(=O)(O)O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][OH:18])=[O:16])(=[O:3])[NH2:2]
Reactant: NC(=O)NCCCCCCCCCCC(=O)O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)NCCCCCCCCCCC(=O)OO
Temperature: 15 °C

Procedure:
61.6 g (0.25 mol) of N-carbamoyl-11-aminoundecanoic acid are dissolved in 74.4 g of sulfuric acid (96% strength by weight) and the solution is cooled to 15° C. 23.8 g (0.6 mol) of hydrogen peroxide (85% strength by weight) are added dropwise with cooling at such a rate that the internal temperature can be maintained between 15° and 20° C. The reaction mixture is subsequently stirred with occasional cooling at 20° C. internal temperature for 1 h and then cooled down to 10° C., 200 ml of water are added dropwise, and the precipitated peroxycarboxylic acid is filtered off with suction. The filter cake is washed with water until free of mineral acid and is dried at 40° C. under an aspirator vacuum.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][N:24]=1>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(-c2ccccc2)s1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (8-5), 1.00 g (4.19 mmol) was dissolved in 20 mL anhydrous THF at room temp, and NaH (60% dispersion, 0.670 g, 16.8 mmol) was added. When the bubbling stopped, 2-chloro-5-phenyl-thiazole (Hafez, E. A. A.; Abed, N. M.; Elsakka, I. A.; J.Heterocycl.Chem. 1983; 20, 285-288), 0.739 g (3.78 mmol) was added, and the reaction was heated to reflux. After 2 hours the THF was removed in vacuo and the resulting solution was taken to neutral pH with 1M HCl (aq) and filtered. The residue was purified by flash column chromatography using 20% EtOAc in hexane. 1H NMR (CDCl3): δ9.09 (bs, 1H), 8.32 (d, 1H, J=5.2 Hz), 7.62 (s, 1H), 7.56 (d, 2H, J=7.4 Hz), 7.38 (t, 2H, J=7.6 Hz), 7.26 (overlapping with CHCl3, 1H), 6.90 (s, 1H), 6.82 (d, 1H, J=5.2 Hz), 4.75 (s, 2H), 0.96 (s, 9H), 0.14 (s, 6H). mp 207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: Nc1cccc(Cl)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(Cl)cccc2n1
Yield: 67.7 %

Procedure:
A solution of 2-amino-6-chloropyridine (6.43 g, 50 mmoles) and ethyl bromopyruvate (9.75 g, 50 mmoles) in ethanol (150 ml) was heated at reflux for 4 hours. After the solvent was removed, chloroform was added to the residue, which was washed in turn with saturated sodium bicarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was concentrated, n-hexane was added to the mixture. Then, the crystals precipitated were filtered off and washed with n-hexane to obtain 7.60 g of the desired product (67.6%, pale yellow crystals).