Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10](=O)[NH:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10](=[S:27])[NH:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(=O)NCC2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(=S)NCC2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
In a round bottom flask under N2 atm. are the 1-[2-(4-Nitro-phenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid methyl ester (48.64 mmol), P4S10 (24.32 mmol) and 240 mL pyridine combined and heated at 65° C. for 8 hours. After cooling to RT it is poured over ˜600 mL ice and stirred for 2 hours. The yellow solid is filtered off, washed (2×) with water and dried on the high vacuum for 18 h to yield 1-[2-(4-Nitro-phenyl)-ethyl]-4-thioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylic acid methyl ester, 10.24 g, as a yellow solid (65%): 1H NMR (CD3OD) 2.43 (t, 2H), 3.16 (t, 2H), 3.28-3.33 (m, 2H), 3.75 (s, 3H), 4.21 (t, 2H), 7.16 (s, 1H), 7.30 (d, 2H), 8.13 (d, 2H); LRMS calcd 359.41, found [M+H] 360.2.
Reaction SMILES: [CH2:1]([O:5][C:6]([O:8][CH:9]([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:22]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1.CN(C)C=O.O>[CH2:22]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:9]([O:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH3:19])=[CH:17][CH:16]=3)=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCOC(=O)OC(C)COc1ccc(O)cc1
Reactant: CCCCCCCCc1ccc(-c2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(COc3ccc(OCC(C)OC(=O)OCCCC)cc3)cc2)cc1
Yield: 24.5 %

Procedure:
A solution of p-(2-(butoxycarbonyloxy)-propoxy)-phenol (1 g) prepared in Example 4 in tetrahydrofuran (20 ml) was dropwise added to a suspension of sodium hydride (0.2 g) in tetrahydrofuran, followed by dropwise adding to the mixture, a solution of 4'-octyl-4-chloromethylbiphenyl (1.2 g) in dimethylformamide (50 ml), agitating the mixture at 60° C. for 10 hours, pouring the reaction solution in water, extracting the resulting material with toluene (300 ml), washing the extract with an acid, then with an alkali and further with water, purifying it according to column chromatography using a column having activated alumina filled therein and recrystallizing from a mixed solvent of ethyl acetate with ethanol to obtain the objective 4'-octyl-4-(4-(2-(butoxycarbonyloxy)-propoxy)-phenoxymethyl)-biphenyl (0.5 g) having a m.p. of 94° C.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:10]([OH:11])=[C:9]([C:12]([NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:13])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:6]1=[O:33])([CH3:4])[CH3:3].CC(N1C(=O)CC(=O)N(CC2C=CC(C(C)(C)C)=CC=2)C1=O)(C)C.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>C(Cl)(Cl)Cl>[CH3:4][C:2]([N:5]1[C:10]([OH:11])=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:6]1=[O:33])([CH3:1])[CH3:3]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C(C)(C)C)c(=O)n(Cc2ccc(C(C)(C)C)cc2)c1=O
Agent: CC(C)(C)c1ccc(CN2C(=O)CC(=O)N(C(C)(C)C)C2=O)cc1
Agent: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C(C)(C)C)c2=O)cc1
Reaction time: 3 h

Procedure:
Ethyl N-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate. 1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g, 3.93 mmoles) and diisopropylethylamine (1.36 mL, 7.86 mmoles) were stirred together in dry chloroform (25 mL) and treated with ethyl isocyanatoacetate (335 uL, 3.93 mmoles). The mixture was stirred for 3 hours, washed twice with 1 molar hydrochloric acid, dried and evaporated to give the title compound (1.8 g, quant.) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 1.71 (s, 9 H) 1.73 (s, 9 H) 4.28-4.34 (m, 2 H) 5.03-5.07 (m, 2 H) 7.33-7.39 (m, 4 H) 10.21-10.30 (m, 1 H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCC1CCOCC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 220 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12])([O-:5])=[O:4].[CH3:17]I.O>CN(C=O)C>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([CH:13]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[O:16][CH3:17])[CH:11]=[O:12]
Reactant: CI
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (4.87 g, 121.7 mmole) in 18 mL dry DMF was cooled to 0° C. and then 5-nitrovanillin (20 g, 101.4 mmole) in 30 mL of DMF was added dropwise. After 30 minutes, methyl iodide (43.18 g, 304.2 mmole) was added dropwise at 0° C. When the addition was completed, the mixture was warmed to room temperature and stirred overnight. Water was added and the solution extracted with ethyl ether, the organic layer was washed with 10% NaOH solution, dried over MgSO4, filtered and evaporated in vacuo to an oil (8.7 g, 40.7%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[C:15]1([C:21]2([C:27](O)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)(Cl)=O>C(#N)C.CCOC(C)=O>[C:15]1([C:21]2([C:27]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C1(c2ccccc2)CCOCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of diethyl malonate (3.96 mL, 26.2 mmol) in ACN (52.4 mL) at 0° C. was added MgCl2 (2.74 g, 28.8 mmol) in one portion. TEA (7.30 mL, 52.4 mmol) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. 4-Phenyl-tetrahydro-2H-pyran-4-carboxylic acid (5.13 g, 24.9 mmol) was converted to the acid chloride by addition of thionyl chloride and reaction at 65° C. for 1 hour. The resulting acid chloride solution was then concentrated in vacuo, dissolved in ACN, and added to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound without further purification. MS m/e=349 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:17]1[CH:21]=[C:20]([C:22]([O:24]C)=O)[N:19]=[CH:18]1)[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:3].[CH3:26][NH2:27]>O1CCCC1.ClCCl>[CH3:26][NH:27][C:22]([C:20]1[N:19]=[CH:18][N:17]([C@H:4]([CH2:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[C@@H:2]([OH:1])[CH3:3])[CH:21]=1)=[O:24]
Reactant: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Temperature: 120 °C

Procedure:
A mixture of methyl 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylate (obtained in Example 23(7))(25 mg) and methylamine (40% in water; 1 ml) in tetrahydrofuran (3 ml) was heated in a steel sealed tube at 120° C. overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (30:1) to give a white powder of N-methyl-1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (18.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][C:6]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2c1CC(=O)N2
Product: COc1cccc2c1C(Cc1ccccc1)C(=O)N2
Yield: 73 %

Procedure:
3-Benzyl-4-methoxy-1,3-dihydro-indol-2-one is prepared from 4-methoxyoxindole (4.8 mmol) and benzyl bromide (5.3 mmol) substantially as described above for Epoxide 4. The compound is purified by flash chromatography (SiO2, 25% ethyl acetate:hexane) to obtain the desired compound (36%). MS (ESI+) 254.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[C:10]([F:39])[C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3c2ccc(Cl)c3F)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.3 g, 0.5 mmol), was reacted with diisopropylethylamine (0.33 g, 2.5 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 4-amino-3-methoxy benzonitrile prepared in Example 57 (0.11 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.13 g, 33%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1c[nH]c2ccccc12)OCc1ccccc1
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 3-indolebutyric acid (25 g) and potassium carbonate (20 g) in dimethylformamide (150 ml) was added benzylbromide (21 g) at room temperature. After stirring for 4 hours, the mixture was poured into ice and diluted hydrochloric acid (300 ml). The organic layer was extracted with ethyl acetate (150 ml), and the extract was washed with water (150 ml×3) and dried over magnesium sulfate. After the solvent was removed in vacuo, the residue was crystallized from n-hexane to give a solid of benzyl 4-(3-indolyl)butyrate (33.9 g).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1>>[O:23]1[C:22]2[CH:21]=[CH:20][C:17]([CH2:18][O:1][NH2:2])=[CH:16][C:15]=2[O:14][CH2:13]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCc1ccc2c(c1)OCO2

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 3,4-methylenedioxybenzyl chloride (Fluorochem). 13C-NMR (CDCl3) δ 147.5, 147.2, 131.0, 121.9, 108.7, 107.9, 100.8, 77.5.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1
Reactant: COc1cc(F)c(N2CCN(S(=O)(=O)CCc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=S(=O)(CCc1ccccc1)N1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 65.9 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(2,5-difluoro-4-methoxyphenyl)-1-phenethylsulfonylpiperazine (401 mg). The resulting crude product was purified on TLC (developer, hexane: ethyl acetate=2:1) to provide 4-(2,5-difluoro-4-hydroxyphenyl)-1-phenethylsulfonylpiperazine (255 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[C:13]1[CH:14]=[N:15][C:16](C(C)(C)C)=[CH:17][C:18]=1[NH2:19].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]1[C:11]2[C:2]3[N:3]([CH:4]=[N:5][C:6]=2[CH:7]=[CH:8][CH:9]=1)[C:17]1[C:18](=[CH:13][CH:14]=[N:15][CH:16]=1)[N:19]=3
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1cc(N)c(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)ncn1c3cnccc3nc21

Procedure:
A vigorously stirred mixture of 100 mmol of the 4-chloroquinazoline derivative, 29.8 g (130 mmol) of 3-bromo-4-amino-6-tert-butylpyridine (S40), 35.0 g (250 mmol) of potassium carbonate, 200 g of glass beads (diameter 3 mm), 2.6 g (10 mmol) of triphenylphosphine and 450 mg (2 mmol) of palladium(II) acetate in 500 ml of o-xylene is heated under reflux until the 4-chloroquinazoline derivative has been consumed (typically 16 h). Aft er cooling, the solid is filtered off via a silica-gel bed, rinsed with 1000 ml of THF, and the filtrate is evaporated to dryness. The residue is dissolved in 75 ml of ethyl acetate at the boiling temperature, and 250 ml of n-heptane are slowly added. After cooling, the solid which has crystallised out is filtered off with suction, washed twice with 50 ml of n-heptane each time and dried in vacuo and subsequently passed through a silica-gel column (heptane:ethyl acetate, 3:1 vv). The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 150-230° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:3][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Reactant: CN1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Yield: 73 %

Procedure:
A solution of N-(4,5-dichloropyridin-2-yl)pivalamide (0.400 g, 1.62 mmol), N-methyl-4-aminopiperidine (0.185 g, 1.62 mmol) in NMP (3 mL) was heated at 220° C. under microwave irradiation for 3 h. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (2 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: [CH2:1](Cl)CCCCC.[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28]CCCCC(C)C)=[CH:20][O:19][N:18]=1>CN(C)C=O>[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:27][NH2:28])[CH3:1])=[CH:20][O:19][N:18]=1
Reactant: CCCCCCCl
Reactant: CC(C)CCCCNCCCCCCc1conc1-c1ncc([N+](=O)[O-])n1C
Solvent: CN(C)C=O
Product: CC(CN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C

Procedure:
The product prepared above is treated in a similar fashion with hexyl chloride in dimethylformamide for two hours. The recrystallized product is identified as 1-methyl-2-(5-methylhexylaminohexylisoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Yield: 58 %

Procedure:
5 ml of ethanol were added to a mixture of 4.8 g of 4,7-dichloroquinazoline and 3.0 g of p-anisidine. The resulting mixture was heated, whereupon the solids dissolved and then the mixture immediately solidified. After cooling, the solidified compound was collected and washed with, in turn, ethanol, dilute aqueous sodium hydroxide and water. The resulting crystals were recrystallized from ethanol to give 4.0 g (yield 51%) of the desired Compound No. 9 in the form of pale yellow plates melting at 177°-179° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)NC=C2.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=1)[C:16]([CH3:21])=[CH:15]2
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Cc1cc2cc(Br)ccc2n1-c1ccccc1

Procedure:
The same reaction was performed as in Reference Example 1 except for using, instead of the 5-bromoindole, 5-bromo-2-methylindole to afford the above-identified compound (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][OH:28])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[CH:10][CH:9]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[O:28])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[CH:10][CH:9]=1
Reactant: OCc1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4.4 g of manganese dioxide (51 mmol) was added to 1.0 g of compound (28) (2.6 mmol) prepared in Example 16 dissolved in 6.5 mL of dichloromethane, and stirred at room temperature for 2 hours. The mixture was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=30/1) to obtain 0.94 g of 5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-pyridine-3-carbaldehyde (yield 90%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([OH:25])=O)[CH:20]([CH3:22])[CH3:21])=[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.[CH2:32]([O:34][C:35](=[O:45])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH2:32]([O:34][C:35](=[O:45])[CH2:36][N:37]([C:23](=[O:25])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:33]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.5 h

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-valine (1.0 g) was dissolved in a mixed solvent of dichloromethane (10 mL) and DMF (0.1 mL), and to the solution oxalyl chloride (374 mg) was added dropwise at 0° C. The mixture was stirred for 30 minutes and added dropwise into a solution of N-(benzyl)glycine ethyl ester (587 mg) and triethylamine (477 mg) in dichloromethane (10 mL) at 0° C. The resultant mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]=[O:46])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]([OH:46])[CH:19]([CH2:18][C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[C:20]([O:22][CH3:23])=[O:21])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CCc1cccs1
Reactant: CCCCc1nc2cccc(C=O)c2n1Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCc1nc2cccc(C(O)C(Cc3cccs3)C(=O)OC)c2n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A solution of n-butyl lithium (0.4 mL of 2.5M in hexane, 1 mmol) in dry tetrahydrofuran (5 mL) at -78° C. under argon was treated with diisopropylamine (108 mg, 1.06 mmol). This mixture was stirred 10 minutes at -78° C. and methyl 3-(2-thienyl)propanoate (156 mg, 0.92 mmol) was added in tetrahydrofuran. After being stirred an additional 30 minutes at -78° C., a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxaldehyde (200 mg, 0.61 mmol) in tetrahydrofuran (1.5 mL) was added. This mixture was stirred at -78° C. for 15 minutes and the reaction was quenched with saturated ammonium chloride. The product was extracted into ethyl acetate, washed with water, dried and concentrated product was flash chromatographed over silica gel with 5-10% of methanol in ethyl acetate to provide 0.17 g (56%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-benzimidazol-7-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate as an oil.