Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:21]([OH:23])=O)[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C1C2C(COC(N[C@@H](C(Cl)=O)C)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:53]([N:55]([CH2:67][CH3:68])[C:56]([C:58]1[CH:59]=[CH:60][CH:61]=[C:62]2[C:66]=1[NH:65][CH:64]=[CH:63]2)=[O:57])[CH3:54].C[Mg]Br.C(OCC)C.Cl>C(Cl)Cl.CN(C)C=O>[CH:6]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([CH3:20])[C:21]([C:63]3[C:62]4[C:66](=[C:58]([C:56](=[O:57])[N:55]([CH2:67][CH3:68])[CH2:53][CH3:54])[CH:59]=[CH:60][CH:61]=4)[NH:65][CH:64]=3)=[O:23])[C:13]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)C(=O)c1cccc2cc[nH]c12
Reactant: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc2c(C(=O)[C@@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)c[nH]c12
Temperature: -20 °C
Yield: 43.4 %

Procedure:
To a suspension of N-(9-fluorenylmethoxycarbonyl)-D-alanine (21.61 g, 69.4 mmol), methylene chloride (230 ml) and N,N-dimethylformamide (0.37 ml) is added dropwise oxalyl chloride (6.46 ml, 74.0 mmol) at room temperature with stirring, and the mixture is further stirred for 2 hours. The reaction solution is concentrated to dryness under reduced pressure to give an oil containing N-(9-fluorenylmethoxy-carbonyl)-D-alanyl chloride. A solution of 1H-indole-7-carboxylic acid diethylamide (10.0 g, 46.3 mmol) in methylene chloride (120 ml) is cooled to −20° C., and thereto is added dropwise a 3M solution of methyl magnesium bromide/diethyl ether (54 ml, 162 mmol). After the addition, the mixture is further stirred at −20° C. for 2 hours. This reaction solution is cooled to −25-−15° C., and thereto is added dropwise a solution of the above obtained N-(9-fluorenylmethoxycarbonyl)-D-alanyl in methylene chloride (140 ml), and the mixture is further stirred at −20° C. for 2 hours. The mixture is warmed to about −5° C., and poured into 2N hydrochloric acid. The organic layer is separated, washed with water (25 ml) and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate/hexane=1/2→5/1) to give the desired (R)-[2-(7-diethylcarbamoyl-1H-indol-3-yl)-1-methyl-2-oxoethyl]carbamic acid 9H-fluoren-9-ylmethyl ester (10.24 g, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)NCC2
Yield: 94 %

Procedure:
6-Chloroindole was reduced in the usual way with sodium cyanoborohydride in glacial acetic acid to give the title compound (D36) (1.18 g, 94%).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH2:9][CH2:8][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc[cH-]c1
Reactant: C[Si](C)(C)OCCCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCC1=CC=CC1
Reaction time: 12 h
Yield: 43 %

Procedure:
To 50 ml of a 2.3 M solution of sodium cyclopentadienylide (115 mmol), a solution of 24.3 g (115 mmol) of 3-bromo-1-trimethylsiloxypropane in tetrahydrofurane is added. The quick formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours and then it is neutralised with an ammonium chloride solution; the organic phase is extracted and concentrated to dryness in order to give an orange oil. (9.8 g, 50 mmol. Yield: 43%). 1H-NMR (CDCl3): 6.47–6.00 (m, 3H), 3.62 (m, 2H), 2.95 (m, 1H), 2.87 (m, 1H), 2.43 (m, 2H), 1.80 (m, 2H), 0.17 (s, 9H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:29]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)ccc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {4-[4-(2,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.033 g, 0.063 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.027 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (br. s, 1 H) 8.33 (s, 1 H) 8.16 (d, J=7.82 Hz, 2 H) 7.99 (s, 1 H) 7.85-7.93 (m, 2 H) 7.77 (d, J=8.80 Hz, 1 H) 7.55 (d, J=8.80 Hz, 2 H) 7.49 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.86 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C25H16Cl2FO4S [(M−H)−] 501, obsd. 501.2.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10](N)=[O:11].Cl>C(O)CCCC>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([O:11][CH2:10][CH2:9][CH2:4][CH2:3][CH3:2])=[O:11]
Reactant: NC(=O)C(=O)c1ccccc1CCl
Agent: Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)C(=O)c1ccccc1CCl
Reaction time: 3 h
Yield: 107.7 %

Procedure:
1.5 g (7.6 mmol) of 2-(chloromethyl)phenylglyoxylamide were initially introduced into 200 ml of n-pentanol. Hydrogen chloride was then introduced into the mixture as a gas until it was saturated, the temperature rising to 80° C. The mixture was then stirred for a further 3 hours and concentrated, the residue was treated with water and the mixture was extracted with methyl tert-butyl ether. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. After purification by column chromatography on silica gel (methyl tert-butyl ether/n-hexane), 1.1 g (54% yield) of the title compound were obtained as a colorless oil.
Reaction SMILES: COC(=O)C(Cl)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[S:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C([SnH](CCCC)CCCC)CCC.C(C(C)(C)N=NC(C)(C)C#N)#N>CN(C)C1C=CN=CC=1.C(#N)C.C(OCC)(=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:23]=2[S:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccc2Sc2ccc(Cl)cc2)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2Sc2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Chloro-oxo-acetic acid methyl ester (1.37 g, 11.2 mmol) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-4-ol (0.98 g, 2.0 mmol) and dimethyl-pyridin-4-yl-amine (DMAP, 0.44 g, 3.6 mmol) in dry acetonitrile (6.4 mL) at 0° C. under argon. The reaction mixture was allowed to reach room temperature and then stirred overnight. Ethyl acetate (40 mL) was added and the precipitated salts were removed by filtration through celite. The organic phase was washed with saturated aqueous sodium bicarbonate (40 mL), saturated aqueous sodium chloride (40 mL), and dried over magnesium sulfate. The volatiles were evaporated off, and the crude material was dried in vacuo. This material was dissolved in dry toluene (13 mL) under argon. Tri-n-butyl tin hydride (0.81 g, 3.0 mmol) and 2-[(cyano-dimethyl-methyl)-azo]-2-methyl-propionitrile (AIBN, 82 mg, 0.5 mmol) were added. The solution was stirred under argon at 90° C. for 3.5 h. The solvent was evaporated, and the crude material was purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:9) to produce 4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.77 g, 82%). This oil was dissolved in methanol (8 mL) and hydrogen chloride in diethyl ether (2M, 8 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated off and ethyl acetate (25 mL) was added. The organic phase was extracted with aqueous sodium hydroxide (2M, 8 mL) and washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, and the solvent was evaporated off. This material (588 mg) was dissolved in ethyl acetate (2.2 mL) and fumaric acid (183 mg, 1.58 mmol) dissolved in hot ethanol (96%, 4.4 mL) was added. The target compound was collected as a white solid. LC/MS (m/z) 372.1 (MH+); RT=2.54; purity (UV, ELSD): 97%, 100%; yield: 0.187 g (19%).
Reaction SMILES: [CH3:1][C:2]1([C:14]#[N:15])[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH2:14][NH2:15])[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC1(C#N)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CN)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of 2.0 g (10 mmol) of 3-methyl-1-(phenylmethyl)-3-pyrrolidinecarbonitrile in 40 ml tetrahydrofuran was added 0.38 g (10 mmol) of lithium aluminum hydride in portions under nitrogen. The reaction mixture was stirred at room temperature for 18 hours. To the resulting suspension were added 0.3 ml of water, 0.4 ml of 40% sodium hydroxide, and 1.4 ml of water. The grainy precipitate was filtered and washed with tetrahydrofuran. The combined filtrates were concentrated to yield 1.9 g of the titled compound.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:25]3[C:21](=[CH:22][CH:23]=[N:24]3)[N:20]=[C:19]3[C:15]=2COC3)=[CH:10][CH:9]=1.[C:26]1(C)[CH:31]=CC(S(O)(=O)=O)=[CH:28][CH:27]=1>CO>[N:24]1[N:25]2[C:21]([N:20]=[C:19]3[C:15](=[C:14]2[C:11]2[CH:10]=[CH:9][C:8]([OH:7])=[CH:13][CH:12]=2)[CH2:28][CH2:27][CH2:26][CH2:31]3)=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1cc2nc3c(c(-c4ccc(OC5CCCCO5)cc4)n2n1)COC3
Solvent: CO
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-5H,7H-6-oxa-1,4,8a-triaza-s-indacene (500 mg, 2.5 mmol) was suspended in methanol and added with p-toluenesulfonic acid (50 mg) was catalyst. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was carried on to the next reaction without purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1(=[CH:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH:21]=[C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C=C1CCCCC1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)C=C2CCCCC2)nn2cccnc12

Procedure:
The product from Example 105B and 2-cyclohexylideneacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.50-1.63 (m, 6H), 2.15-2.18 (m, 2H), 2.80-2.82 (m, 2H), 5.80 (br s, 1H), 6.98 (dd, J=6.8, 4.1 Hz, 1H), 8.48 (dd, J=4.1, 2.0 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.58 (br s, 1H); MS (DCI) m/z 313 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[OH-].[K+]>C(O)(=O)C.C(O)C.O.[Fe]>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.95 g, 4.23 mmol) in acetic acid (8.46 mL), ethanol (8.46 mL) and water (4.23 mL) was added iron powder (1.18 g, 21.15 mmol) and the reaction was stirred at room temperature for 30 minutes. To this was added carefully 2 M KOH and extracted with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0-10% methanol/dichloromethane) to give the desired product as a white solid (0.66 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.6 Hz, 1H), 8.49 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.53 (s, 1H), 7.37 (ddd, J=8.4, 4.7, 0.6 Hz, 1H), 3.17 (bs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[N:11])[N:7]([CH3:9])[CH:8]=1)([O-])=O>CO.[Pd]>[C:10]([C:6]1[N:7]([CH3:9])[CH:8]=[C:4]([NH2:1])[CH:5]=1)#[N:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: Cn1cc(N)cc1C#N
Yield: 77.3 %

Procedure:
Compound 22-5 (500 mg) and 10% palladium/carbon (50 mg) were poured into the reactor and dissolved in methanol (10 ml), and then reacted under hydrogen gas atmosphere for 2 hours. After confirming the completion of the reaction, the resulting mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column-chromatography (ethyl acetate/hexane=3/1) to yield the compound 22-6 (310 mg, 77.4%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:24][CH:23]=1)(=[O:41])=[O:40]
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a mixture of 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml) was added dropwise, under ice-cooling, methanesulfonyl chloride (0.345 g). The mixture was stirred for 2 hours at room temperature, which was washed with water and dried (MgSO4). The solvent was distilled off to leave 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate (1.21 g, 92%). Recrystallization from dichloromethane-ether gave colorless prisms, m.p.132°-133° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.O>[Si:31]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 16 h

Procedure:
24 g (81 mmol) of the compound from Example 21A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 7.2 g (106 mmol) of imidazole and 27 g (98 mmol) of tert-butyl(chloro)diphenylsilane are added. After 16 h, the mixture is diluted with 1.2 l of water and extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. For crystallization, tert-butyl methyl ether is added, and the resulting crystals are filtered off and dried under reduced pressure. This gives 30 g (67% of theory) of the desired product.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[NH:14][C:15]([I:19])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].I[CH3:23]>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:23])[C:15]([I:19])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCCCc1cccc(-c2nc(I)c(I)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCc1cccc(-c2nc(I)c(I)n2C)c1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 8.45 g (17.6 mmol) of 2-(3-hexyl-phenyl)-4,5-diiodo-1H-imidazole in 150 ml of DMF was treated at 0° C. with 0.806 g (18.5 mmol) of sodium hydride (55% dispersion in mineral oil); 15 min later, a solution of 1.52 ml=3.47 g (24.2 mmol) of iodomethane in 25 ml of DMF was added drop by drop at 0° C. After 2 hours, the reaction mixture was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 1:0 to 4:1) to give 7.52 g (87%) of the title compound as light red oil. MS: 495.1 (MH+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:40]([C:37]5[CH:36]=[N:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:39][N:38]=5)=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1cnc(N2CCOCC2)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1cnc(N2CCOCC2)cn1

Procedure:
The title compound, white solid (107 mg, 82%), MS (ISP) m/z=522.5 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15]>[Fe](Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([O:14][CH3:15])=[CH:10][C:11]2[C:12]3[C:11](=[CH:10][C:9]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:13]=3)[C:12]3[C:11](=[CH:10][C:9]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:13]=3)[C:12]=2[CH:13]=1
Reactant: COc1ccccc1OC
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)(O)O
Product: COc1cc2c3cc(OC)c(OC)cc3c3cc(OC)c(OC)cc3c2cc1OC
Temperature: 0 °C
Yield: 43 %

Procedure:
In a 2-liter three-necked flask cooled with ice, 135 ml of ice water was placed, and 490 ml of concentrated sulfuric acid was gradually added to the ice water with stirring to prepare a sulfuric acid solution. Subsequently, 150 g of iron(III) chloride was added to the sulfuric acid solution at room temperature, and after reaction of 1 hour, 30 g of 1,2-dimethoxybenzene was further added to prepare a reaction mixture. After reaction of 3 hours, the reaction mixture was cooled with ice, and 1 liter of ice water was gradually added to the reaction mixture. After stirring of 1 hour, the reaction mixture was filtered through a glass filter to obtain crude crystals of the above compound (a) of 13 g (yield: 43%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH3:31])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1cc(I)ccn1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)ccn1
Temperature: 90 °C
Yield: 38 %

Procedure:
Prepared according to the method described in Example 21b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 21a), 4-iodo-2-methoxypyridine (0.235 g, Liebigs Annalen der Chemie (1992) Issue 9, 953-9), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC, eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.069 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:8]([N:6]1[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H]1CNCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CN(Cc2ccccc2)CCN1

Procedure:
(S)-(+)-2-Methylpiperazine (2.63 g), benzylbromide (3.12 ml) and potassium carbonate (5.4 g) were heated together in acetonitrile (120 ml) at 40° C. for 3 days. The mixture was evaporated to dryness in vacuo and the residue partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried (magnesium sulphate) and evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel using gradient elution (95/510 to 92/7/1 dichloromethane/methanol/ammonium hydroxide) to afford the title compound as a solid, 1.12 g.